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Xiang-Qiong Wen,1,* Xian-Ling Qian,2,3,* Huan-Kui Sun,1 Lin-Lin Zheng,1 Wei-Quan Zhu,1 Tai-Yuan Li,1 Jia-Ping Hu1 1Department of General Surgery, The First Affiliated Hospital of Nanchang University; Medical College of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China; 2Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of Medical Imaging, Shanghai Medical College,Fudan University, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jia-Ping Hu Email hujiaping1967@sina.comAbstract: Colorectal cancer (CRC) is the third-commonest malignant cancer, and its metastasis is the major reason for cancer-related death. The process of metastasis is highly coordinated and involves a complex cascade of multiple steps. In recent years, miRNAs, as highly conserved, endogenous, noncoding, single-stranded RNA, has been confirmed to be involved in the development of various cancers. Considering that miRNA is also involved in a series of biological behaviors, regulating CRC occurrence and development, we review and summarize the role of miRNAs and related signaling pathways in several CRC-metastasis stages, including invasion and migration, mobility, metabolism, epithelial–mesenchymal transition, tumor-microenvironment communication, angiogenesis, anoikis, premetastatic–niche formation, and cancer stemness. In addition, we review the application of miRNAs as diagnostic CRC markers and in clinical treatment resistance. This review can contribute to understanding of the mechanism of miRNAs in CRC progression and provide a theoretical basis for clinical CRC treatment.Keywords: colorectal cancer, miRNA, metastasis, invasion, migration, stemness

Bing Yuan,1,* Feng Liao,1,* Zhi-Zhou Shi,2 Yuan Ren,1 Xiao-Li Deng,1 Ting-Ting Yang,1 Deng-Yuan Li,1 Ru-Fang Li,1 Dan-Dan Pu,1 Yu-Jue Wang,1 Yan Tan,1 Zhen Yang,1 Yun-Hui Zhang1 1Department of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China; 2Medical School, Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of China*These authors contributed equally to this work.Correspondence: Zhen YangDepartment of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of ChinaEmail 49387127@qq.comYun-Hui ZhangDepartment of Pulmonary and Critical Care Medicine, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People’s Republic of ChinaEmail yunhuizhang3188@126.comObjective: Lung cancer is the first leading cause of cancer-related deaths both worldwide and in China and threatens human health and quality of life. New drugs and therapeutic methods are urgently needed. Our study evaluated the roles of dihydroartemisinin (DHA) in lung cancer and further explored its underlying mechanisms.Methods: CCK-8, colony formation and trypan blue exclusion assays were used to detect the cell viability, colony formation ability and cell death. qRT-PCR and Western blotting assays were applied to analyze the expressions of key molecules.Results: DHA inhibited the proliferation and colony formation abilities and enhanced the cell death and induced ferroptosis of lung NCI-H23 and XWLC-05 cancer cells. DHA reduced PRIM2 expression and silencing PRIM2 mimicked the inhibitory roles on proliferation and colony formation and promotive roles on cell death and ferroptosis of DHA in lung NCI-H23 and XWLC-05 cancer cells. We further found that DHA treatment and loss of PRIM2 reduced the GSH level and increased the cellular lipid ROS and mitochondrial MDA levels, and further downregulated the expressions of SLC7A11 and β-catenin in lung cancer cells, respectively. Exogenetic overexpression of PRIM2 recovered the inhibitory effects of DHA on proliferation and colony formation in lung NCI-H23 cancer cells, meanwhile loss of PRIM2 sensitizes NCI-H23 cells to DHA therapy. In vivo experiment further showed that DHA treatment significantly suppressed the tumor growth and downregulated PRIM2 and SLC7A11.Conclusion: Our study suggested that DHA inhibited the proliferation, colony formation and enhanced cell death and induced ferroptosis of lung cancer cells by inactivating PRIM2/SLC7A11 axis. Loss of PRIM2 induced ferroptosis might developed to be a novel therapeutic method in lung cancer therapy.Keywords: dihydroartemisinin, lung cancer, proliferation, ferroptosis, PRIM2, SLC7A11

Shi-An Liao,1 Jian Guan,2 Hao Mo,2 Ju-Liang He,2 Xin-Li Zhan1 1Department of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, People’s Republic of China; 2Department of Bone and Soft Tissue Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Province, People’s Republic of ChinaCorrespondence: Xin-Li ZhanDepartment of Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of ChinaTel +86-13907864389Email zhan3cstar@163.comBackground: More and more evidence has shown that non-coding RNA (ncRNA), including long ncRNA (lncRNA) and micro RNA (miRNA), plays a crucial regulatory role in osteosarcoma (OS). Previously, we revealed a Rho-related coiled coil incorporating protein kinase 1(XIAP). A transfer-related gene is negatively regulated by microRNA-20a-5p (miR-20a-5p) and plays the role of oncogene in OS. It is not clear if any lncRNA is involved in the axial upstream of miR-20a-5p/XIAP.Methods: Expression of LSINCT5 and miR-20a-5p/XIAP in OS tissues was determined through qRT-PCR (qP). The proliferation and migration/invasion activity of OS cells were tested through CCK-8/and transwell assay, respectively. The changes on expression of XIAP were examined through qRT-PCR and Western blot (WB). Targeted binding between LSINCT5, miR-20a-5p, and XIAP has been verified using dual luciferase reporter gene analysis, RNA Immunoprecipitation (RIP), and RNA pull-down experiments. The effect of LSINCT5 on tumor growth was determined by tumor allograft test.Results: In this study, elevated LSINCT5 was found in OS tissue samples and OS cell strains, and the increased LSINCT5 was strongly related to the adverse prognosis of clinical patients. Functional assays showed that inhibition of LSINCT5 could up-regulate miR-20a-5p-mediated OS cells proliferation and metastasis. WB analysis and qP analysis showed that LSINCT5 regulated XIAP by mediating miR-20a-5p. Further cell behavior experiments showed that LSINCT5 acted as a miR-20a-5p sponge to inhibit proliferation and metastasis caused by XIAP. Finally, the results of animal models in vivo showed that LSINCT5 could regulate the tumor growth of OS.Conclusion: LncRNA LSINCT5 acts as an oncogene and promotes XIAP mediated growth and metastasis as competitive endogenous RNA (ceRNA) in OS.Keywords: lncRNA, LSINCT5, miR-20a-5p, osteosarcoma, growth, invasion

Xin-Long Li,1,2,* Shan Zeng,1,2,* Hai-Ping He,1,2 Xu Zeng,1,2 Li-Lei Peng,1,2 Li-Gang Chen1,2 1Department of Neurosurgery, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, People’s Republic of China; 2Neurosurgery Clinical Medical Research Center of Sichuan Province, Luzhou, Sichuan 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-Gang Chen; Li-Lei PengDepartment of Neurosurgery, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou, Sichuan, People’s Republic of ChinaEmail chenligang199066@163.com; lileipeng246@163.comBackground: Conventional immunotherapy for glioma is not only expensive but also demonstrates less-than-desired clinical efficacy. In this study, we evaluated the immunotherapeutic efficacy of a tumor cell lysate-based hybrid glioma vaccine developed using a molecular-based approach.Methods: First, the ability of the autologous (9L-cell lysate) and allogeneic (C6-cell lysate) vaccines against glioma, individually and in combination, to activate Fischer344 rat dendritic cells (DCs) was determined. Next, the activated DCs were co-cultured with T lymphocytes and screened for the optimal DC-to-T-cell ratio. The in vitro efficacy of the DC/T-cell vaccine formulations subjected to different immunogen treatments and co-cultured with glioma cells was evaluated based on glioma cell viability and monocyte chemoattractant protein (MCP)-2 and interferon (IFN)-γ secretion. Subsequently, the efficacy of the 9L + C6 hybrid vaccine was evaluated in 32 glioma rat models, randomly allocated to the following five treatment groups: blank control, tumor, vaccine treatment, thymosin treatment, and vaccine + thymosin treatment (combined treatment). Changes in survival duration, intracranial tumor volume, peripheral blood immune-cell (CD4+ T, CD8+ T, and natural killer [NK] cell) count, and serum cytokine (interleukin [IL]-2, IL-10) levels were assessed in these groups.Results: The hybrid vaccine demonstrated the highest glioma cell apoptosis and the lowest cell viability and promoted MCP-2 and IFN-γ secretion in vitro. The vaccine treatment and combined treatment groups demonstrated longer survival duration, lower intracranial tumor volume, and higher immune cell glioma tissue infiltration and IL-2 secretion than the untreated tumor group, indicating the vaccine’s good in vivo efficacy. Thymosin treatment had minimal effect in enhancing anti-glioma immunity.Conclusion: We demonstrated the feasibility of combining autologous and allogeneic tumor cell lysates to stimulate specific host cell immune response against glioma cells. The good clinical efficacy of our developed glioma hybrid vaccine in rat models suggests its potential clinical application.Keywords: tumor cell lysate, vaccine, glioma, molecular simulation, rat, immunotherapy

You-Yi Huang, Hai-Xing Jiang, Qiu-Yue Shi, Xin Qiu, Xi Wei, Xiang-Lian Zhang, Shan-Yu Qin Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People’s Republic of ChinaCorrespondence: Shan-Yu QinDepartment of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, People’s Republic of ChinaTel +86 13977110511Email qsy0511@163.comPurpose: Our previous experiments confirmed that T helper type 9 (Th9) cells were involved in the occurrence and development of malignant ascites caused by liver cancer. The current study investigated the mechanism underlying microRNA (miR-145)-mediated inhibition of Th9 cells in an malignant ascites model with liver cancer.Materials and Methods: CD4+ T cells were induced to differentiate Th9 cells after transfection with miR-145 mimics or negative control. A malignant ascites mouse model was transfected with miR-145agomir or negative control. Th9 cells were detected by flow cytometry. Enzyme-linked immunosorbent assay was applied to detect the interleukin 9 (IL-9) cytokine and hypoxia-inducible factor 1 alpha (HIF-1α). RT-PCR was used to detect the expression of miR-145 and phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin/p70 ribosomal protein S6 kinase/HIF-1α (PI3K/Akt/mTOR/p70S6K/HIF-1α) mRNA. Western blotting and immunofluorescence were performed to detect the expression of PI3K/Akt/mTOR/p70S6K/HIF-1α-related proteins.Results: In vitro experiments showed that miR-145 inhibited Th9 cell polarization, HIF-1α expression, and PI3K/Akt/mTOR/p70S6K pathway activation. In the malignant ascites mouse model, miR-145 also demonstrated inhibitory effects on Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway.Conclusion: miR-145 may inhibit Th9 cell differentiation through the PI3K/Akt/mTOR/p70S6K/HIF-1α pathway. These findings suggest a novel therapeutic target for malignant ascites from liver cancer.Keywords: miR-145, Th9 cells, PI3K/Akt, HIF-1α, hepatoma malignant ascites

Zhi-Hui Wang,1– 3,* Xiao-Feng Pei,2,3,* Zhi-Quan Zhu,2,3,* Zhong Lin,2,3 Yin-Yan Mao,2,3 Xiao-Lu Xu,2,3 You-Li Luo,4 Li Zhang,1 Pei-Jian Peng2,3 1State Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People’s Republic of China; 2Department of Thoracic Oncology, The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 3Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China; 4Department of Interventional Oncology, The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li ZhangState Key Laboratory of Oncology in South China, Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, Guangdong, People’s Republic of ChinaTel +86-20-87343533Fax +86-20-87343292Email zhangli6@mail.sysu.edu.cnPei-Jian PengGuangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong, People’s Republic of China, Department of Thoracic Oncology, The Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University, 52 Meihua Road East, Zhuhai 519000, Guangdong, People’s Republic of ChinaTel +86-756-2528015Fax +86-756-2528022Email pengpjian@163.comPurpose: Little is known about the clinical significance of CD47 expression and its association with Epstein–Barr virus (EBV) infection in patients with nasopharyngeal carcinoma (NPC). The aim of this study was to clarify the prognostic value and role of CD47 in EBV-associated NPC.Materials and Methods: Sixty-six cases of non-metastatic NPC were retrospectively reviewed. Tissues were collected for immunohistochemical staining of CD47 and the EBV-encoded oncoprotein latent membrane protein 1 (LMP1). Western blotting and quantitative real-time PCR were performed to determine the CD47 and LMP1 levels in common human NPC cell lines. Additionally, CD47 and LMP1 expression in a constructed EBV-positive human NPC cell (CNE-2-EBV+) and a stable cell line transfected with LMP1 plasmid (CNE-2-LMP1) was assessed. Next, we used Western blotting to assess the decrease in CD47 expression on CNE-2-LMP1 cells after transfecting them with small interfering RNA (siRNA)-targeting LMP1.Results: In NPC patients, CD47 overexpression was significantly associated with disease recurrence (P=0.010), leading to poorer disease-free survival (DFS; P=0.002) and overall survival (P=0.021). Multivariate Cox proportional hazards models demonstrated that CD47 (HR=5.452, P=0.016) was an independent prognostic factor of DFS. Moreover, CD47 expression was associated with plasma EBV-DNA copy number and LMP1 tissue expression. Among the human NPC cell lines, CD47 and LMP1 expression was notably higher in the EBV-positive C666-1 cell line than in the EBV-negative cell lines. Furthermore, EBV infection upregulated CD47 expression via LMP1-mediated pathways in human NPC cells.Conclusion: This study indicated that CD47 is related to EBV infection in NPC patients, and it is a feasible biomarker.Keywords: CD47, Epstein–Barr virus, latent membrane protein 1, nasopharyngeal carcinoma

Yu-Han Hu,1,* Shuai Ma,1,* Xiang-Nan Zhang,2 Zhe-Ying Zhang,1 Hui-Fang Zhu,1,2 Ying-Hua Ji,3 Jian Li,4 Xin-Lai Qian,1,2 Yong-Xia Wang1,2 1Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453000, People’s Republic of China; 2Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453000, People’s Republic of China; 3Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453000, People’s Republic of China; 4Department of Surgery, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yong-Xia Wang; Xin-Lai QianDepartment of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453000, People’s Republic of ChinaTel +86-15090325842; +86-13839073820Email 58866999@qq.com; qxlfssws@163.comBackground: Colorectal cancer (CRC) is one of the most common malignancies worldwide. Studies have demonstrated that epigenetic modifications play essential roles in the development of CRC. ADHFE1 is a differentially expressed gene that has been reported to be hypermethylated in CRC. However, the role and mechanism of ADHFE1 in the proliferation of CRC remain unclear.Materials and methods: ADHFE1 expression was analyzed in CRC tissues by IHC and qRT-PCR, and the relationship between ADHFE1 expression and the clinicopathological parameters was analyzed. Cell proliferation were assessed by the in vitro and in vivo experimental models. GSEA assay was performed to explore the mechanism of ADHFE1 in the proliferation of CRC. Flow cytometry and Western blot were used to detect the activation of the cell cycle signaling. Bisulfite genomic sequence (BSP) assay was used to test the methylation degree of ADHFE1 gene promoter in CRC tissues.Results: Here, we verified that ADHFE1 was down-regulated and hypermethylated in CRC tissues. The down-regulation of ADHFE1 was correlated with poor differentiation and advanced TNM stage of CRC patients. And ADHFE1 expression restored when the CRC cell line SW620 was treated with the demethylating agent 5-Aza-CdR. Overexpression of ADHFE1 inhibited the proliferation of CRC, while ADHFE1 knockdown promoted the proliferation of CRC cells in vitro and in vivo. Moreover, ADHFE1 overexpression could induce a significant G1-S cell cycle arrest in CRC cells and vice versa.Conclusion: Hypermethylation of ADHFE1 might promote cell proliferation by modulating cell cycle progression in CRC, potentially providing a new therapeutic target for CRC patients.Keywords: ADHFE1, colorectal cancer, hypermethylation, proliferation, cell cycle

Xiu-Li Yuan, Fei-Qiu Wen, Xiao-Wen Chen, Xian-Ping Jiang, Si-Xi LiuDepartment of Hematology/Oncology, Shenzhen Children’s Hospital, Shenzhen 518036, People’s Republic of ChinaIntroduction: Previous studies have shown that miR-373 functions as either a tumor suppressor or an oncogene depending on which type of cancer it’s operating in. However, the functional role of miR-373 in neuroblastoma (NB) remains largely unclear. Methods: Expression of miR-373 and SRC kinase signaling inhibitor 1 (SRCIN1) in 20 metastatic and 20 primary NB tissues was detected by quantitativereal-time PCR(qRT-PCR) and Western blotting. MTT assay, flow cytometry analysis and transwell migration and invasion assays were performed to evaluate the influence of miR-373 inhibition on the growth, migration and invasion of NB cells, respectively. In vivo experiment was applied to determine the effect of miR-373 inhibition on tumor growth. Dual-luciferasereporter assay was used to confirm the interaction between miR-373 and SRCIN1. Results: We observed a significant increase in the expression of miR-373 in metastatic NB samples compared with primary NB samples, and this was inversely correlated with SRCIN1 expression. Functional studies revealed that depletion of miR-373 inhibited in vitro NB cell growth, migration and invasion, and also suppressed tumor growth in an in vivo mouse model. Moreover, we identified that SRCIN1 was a direct and functional target gene of miR-373. Silencing of SRCIN1 partially rescued the antimiR-373-mediated inhibition of cell growth, migration and invasion. Conclusion: The data from our study verified a potential oncogenic role of miR-373 in NB cells that occurs through direct targetingSRCIN1. The newly identified miR-373/SRCIN1 axis represents a new potential candidate for therapeutic intervention of malignant NB.Keywords: miR-373, NB, growth, migration, invasion, SRCIN1

Zi-Jin Cui,1,2 Xiao-Li Xie,1 Wei Qi,1 Yi-Chao Yang,1 Yun Bai,2 Jing Han,1 Qian Ding,1 Hui-Qing Jiang1 1Department of Gastroenterology, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Gastroenterology, Hebei General Hospital, Shijiazhuang, People’s Republic of China Purpose: Gastric cancer (GC) patients display aberrant miRNA expression and defective dendritic cell function. However, the role of cancer cell-derived oncomiR in GC detection and dendritic cell (DC) maturation remains largely elusive. Methods: Candidate miRNAs were selected by deep sequencing (8 GC plasma samples vs 8 control plasma samples; 8 GC tissues vs 8 adjacent normal gastric tissues) and confirmed by PCR with 164 plasma samples and 72 formalin-fixed paraffin-embedded GC tissue samples. Their diagnostic performance was evaluated by receiver operating characteristic curve. Cy3 fluorescence signals in DCs, exposed to conditioned medium obtained from BGC-823 cells pre-transfected with Cy3-miR-17-5p, were determined by flow cytometry and visualized by confocal microscopy. Functional and phenotypical alterations of DCs were assayed when DCs were transfected with miR-17-5p invitro. Results: Deep sequencing and RT-PCR confirmed that five shared miRNAs were upregulated in plasma and tissue samples of GC patients. Cell-free miR-17-5p was superior to others in GC detection with an area under the curve of 0.82, and correlated with lymphatic metastasis and poor overall survival. GC cell-shuttled miR-17-5p can be delivered to immature DCs, and they significantly inhibited LPS-stimulated phenotypic maturation by diminishing the expression of maturation markers (MHC II, CD80 and CD86 molecules). In line with those alterations in the phenotypic markers, functional experiments demonstrated that miR-17-5p triggered an inhibitory effect on DCs endocytic activity and decreased tumor necrosis factor-α and IL-12 secretion, while enhancing IL-10 production. Mixed lymphocyte reaction showed that miR-17-5p inhibited the T cell stimulating effect of DCs and favored regulatory T cells expansion. Conclusion: GC cell-derived miR-17-5p is a potential biomarker for GC detection. Taken up by DCs, miR-17-5p weakened antitumor immune responses via inhibiting the maturation of dendritic cells. Keywords: gastric cancer, cell-free miRNA, biomarker, intracellular communication, dendritic cell

Xian-Ling Qian,1,2 Yi-Hang Pan,1,2 Qi-Yuan Huang,1,3 Yu-Bo Shi,1 Qing-Yun Huang,1 Zhen-Zhen Hu,1,4 Li-Xia Xiong1,4 1Department of Pathophysiology, Basic Medical College, Nanchang University, Nanchang 330006, China; 2First Clinical Medical College, Nanchang University, Nanchang 330006, China; 3Second Clinical Medical College, Nanchang University, Nanchang 330006, China; 4Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang 330006, China Abstract: Human breast cancer is one of the most frequent cancer diseases and causes of death among female population worldwide. It appears at a high incidence and has a high malignancy, mortality, recurrence rate and poor prognosis. Caveolin-1 (Cav1) is the main component of caveolae and participates in various biological events. More and more experimental studies have shown that Cav1 plays a critical role in the progression of breast cancer including cell proliferation, apoptosis, autophagy, invasion, migration and breast cancer metastasis. Besides, Cav1 has been found to be involved in chemotherapeutics and radiotherapy resistance, which are still the principal problems encountered in clinical breast cancer treatment. In addition, stromal Cav1 may be a potential indicator for breast cancer patients’ prognosis. In the current review, we cover the state-of-the-art study, development and progress on Cav1 and breast cancer, altogether describing the role of Cav1 in breast cancer progression and application in clinical treatment, in the hope of providing a basis for further research and promoting CAV1 gene as a potential target to diagnose and treat aggressive breast cancers. Keywords: breast cancer, caveolin-1, migration, metastasis, prognosis, invasion

Yihao Wang,1,2,* Dan Hong,1,* Yuqin Qian,3 Xuezi Tu,1 Keke Wang,1 Xianhong Yang,1 Sijia Shao,1 Xinlong Kong,1 Zhefeng Lou,1 Longjin Jin1 1School of Laboratory Medicine and Life Science, Wenzhou Medical University, Zhejiang, People’s Republic of China; 2School of Ophthalmology and Optometry, Wenzhou Medical University, Zhejiang, People’s Republic of China; 3School of the first Clinical Medical Sciences, Wenzhou Medical University, Zhejiang, People’s Republic of China *These authors contributed equally tothis work Background: Lupeol, a triterpene isolated from various herbal plants, possesses an anti-inflammatory function and has been proposed as a candidate for anticancer agents. The purpose of this research was to investigate the effect of lupeol on the viability, apoptosis, cell-cycle distribution, and migration of colorectal cancer cell lines and its molecular mechanism.Methods: Lupeol was assessed for its anticancer effect using two human colorectal cancer cell lines: SW480 and HCT116. These cells were treated with lupeol, and their viability, apoptosis, migration, and cycle distribution were detected by CCK8, flow cytometry, and the transwell method. Quantitative PCR, Western blot, and immunofluorescence were applied to detect the expressions of CTNNB1, TCF4, cMYC, CCND1, CLDN1, and CCNA2.Results: Lupeol suppressed cell viability and migration and induced cellular apoptosis of both cell lines, with increased p53 and decreased Bcl2 protein levels (P

Xin Xia,1,* Ying-Ying Zhu,1,* Wen-Wen Diao,1 Xiao-Li Zhu,1 Xiao-Hua Shi,2 Wu-Yi Li,1 Zhi-Qiang Gao,1 Guo-Jun Li,1 Xing-Ming Chen1 1Department of Otolaryngology-Head and Neck Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; 2Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China *These authors contributed equally to this work Background: The survival outcomes between supracricoid partial laryngectomy (SCPL) and total laryngectomy (TL) were compared in the groups of matched-pair patients with T3 laryngeal squamous cell carcinoma (LSCC).Methods: Patients with T3 LSCC were matched based on prognostic factors. The Kaplan–Meier curve and the Cox proportional hazards model were used for analysis on survival.Results: A total of 212 patients with T3 LSCC were included after matching (106 underwent SCPL and 106 underwent TL). Multivariable analysis showed no differences in overall survival (hazard risk [HR]=1.15; 95% CI: 0.79–1.67; P=0.47), disease-specific survival (HR=1.11; 95% CI: 0.69–1.80; P=0.66), and recurrence-free survival (HR=1.07; 95% CI: 0.68–1.68; P=0.77) between the SCPL group and TL group.Conclusion: SCPL provides reliable therapeutic outcomes and can be used to avoid a TL surgery in some patients with advanced primary laryngeal cancer. Keywords: survival analysis, matched-pair analysis, laryngeal neoplasms, laryngectomy, squamous cell carcinoma

Qiang Tong,1 Xiao-long Wang,2 Sheng-bao Li,1 Gong-li Yang,1 Shu Jin,1 Zi-ye Gao,3 Xiao-bo Liu1 1Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China; 2Department of Gastroenterology, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China; 3Department of Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China Background: The diagnosis rate of early stage esophageal squamous cell carcinoma (ESCC) is low due to the lack of specific tumor markers. Seeking for these markers is beneficial to improve the early diagnosis rate and the prognosis of patients. This study profiles the differentially expressed proteins of early stage ESCC patients via the AAH-BLG-507 protein chip, which further consolidates the clinical evidence of ESCC diagnosis. Materials and methods: In this study, 20 serum samples were collected from Taihe Hospital between August 2016 and June 2017. Ten of them carried ESCC, while the rest were healthy controls. To profile the proteins’ expression level, the AAH-BLG-507 protein chip was used, and both highly expressed and lowly expressed proteins were fished out. Meanwhile, their biological roles were examined by using Gene Ontology (GO) database and String database, and they were further verified by ELISA. Results: Results showed that the expression levels of AXL, ARTN, Ang2, BDNF, BMP7, cripto-1, CCL28, E-selectin, IL-6, IL-8 and SHH in the serum of early ESCC were significantly upregulated (P

Ya-Fei Zhang,1 Hao Shang,1 Xian-Ling Zeng,2 Hong Ji,1 Yi-Ming Li,1 Hong-Wei Lu1 1Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China; 2Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China Background: The present meta-analysis was aimed to evaluate the effects of postoperative adjuvant chemotherapy/transarterial chemoembolization (TACE) on the survival/disease-free survival (DFS) rate in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). Methods: The relevant trials were collected using a database search of MEDLINE, Embase, Cochrane Library, Web of Science, ScienceDirect, the China Journal Full-text Database, and the National Institute of Health Clinical Trials Database. The 1-, 3-, and 5-year survival/DFS rates were considered to be the primary end points. A sensitivity analysis was conducted by reanalyzing the data using different statistical approaches. Results: Eight studies met the inclusion criteria. When compared with surgery alone, the pooled OR showed that the postoperative adjuvant therapy significantly increased the 1-, 3-, and 5-year survival rates for HCC patients with PVTT (the pooled OR and 95% CI of the 1-, 3-, and 5-year survival rates, respectively, were as follows: 2.72, 1.98–3.74; 1.62, 1.13–2.33; 1.99, 1.20–3.29). In addition, when compared with surgery alone, subgroup analysis showed that the postoperative chemotherapy improved the 1-, 3-, and 5-year survival rates of HCC patients with PVTT. Conclusion: Compared with surgery alone, postoperative adjuvant chemotherapy can improve the 1-, 3- and 5-year survival rates of HCC patients with PVTT. However, postoperative TACE can only increase the 1-year survival rate. However, due to the limitations of this meta-analysis, additional relevant trials are required to confirm these findings. Keywords: hepatocellular carcinoma, portal vein tumor thrombosis, meta-analysis, transarterial chemoembolization, survival rate, postoperative, chemotherapy

Fei Gao,1,* Xiaolin Yu,2,* Rongqin Meng,2 Jisheng Wang,1 Lin Jia1 1Department of Oncology, Sichuan Mental Health Center, The Third Hospital of Mianyang, Mianyang, People’s Republic of China; 2Department of Oncology, AVIC 363 Hospital, Chengdu, People’s Republic of China *These authors contributed equally to this work Background: STARD13 has been revealed to suppress tumor progression. However, the roles in regulating the stemness of hepatocellular carcinoma (HCC) cells are unclear. Methods: Quantitative real-time PCR (qRT-PCR) was used to detect STARD13 expression in HCC tissues and normal adjacent tissues. Kaplan Meier (KM)-plotter analysis was performed to analyze the correlation between STARD13 expression and overall survival of HCC patients. Cell spheroid formation and ALDH1 activity analysis were carried out to detect the effects of STARD13 on the stemness of HCC cells. Furthermore, immunofluorescent, luciferase reporter, RhoA GTPase and F-actin visualization assays were performed to explore the mechanisms contributing to STARD13-mediated effects. Results: STARD13 expression was significantly downregulated in HCC tissues compared with normal adjacent tissues, and was positively correlated with the overall survival of HCC patients. Functionally, overexpression of STARD13 inhibited cells stemness and enhanced 5-FU sensitivity in HCC cells. Mechanistically, STRAD13 overexpression suppressed RhoGTPase signaling and thus inhibited transcriptional factor YAP translocation from nuclear to cytoplasm, leading to the downregulation of transcriptional activity of YAP. Notably, the inhibitory effects of STARD13 on HCC cells stemness and 5-FU sensitivity were rescued by RhoA or YAP-5SA overexpression. Conclusion: Our results indicate that STARD13 could enhances 5-FU sensitivity by suppressing cancer stemness in hepatocellular carcinoma cells via attenuating YAP transcriptional activity. Keywords: 5-FU, hepatocellular carcinoma, STARD13, stemness, YAP

Xiaoli Ren,1 Huatao Li,2 Xianyi Song,1 Yuhong Wu,1 Yun Liu1 1Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Department of Veterinary Surgery, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China; 2Department of Veterinary Obstetrics, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, China Background: Canine mammary gland tumors (CMGTs) are the most common, spontaneous types of neoplasias in female dogs. Aberrant DAPK1 and MGMT methylation associated with tumor formation and development in various cancers. 5-Azacytidine is a known specific demethylation drug that covalently binds to DNA methyltransferase. However, the methylation of the DAPK1 and MGMT is unknown with respect to CMGTs. Therefore, we sought to demonstrate the effects of 5-azacytidine on the proliferation of CMGTs cell, and elucidate the potential molecular mechanisms of action in these cancerous cells.Materials and methods: The effects of 5-azacytidine on CHMm and CHMp cell proliferation were evaluated by MTT assay. The DAPK1 and MGMT gene methylation patterns in CHMm and CHMp cells and CMGTs blood/tissue samples were analyzed by MSP assay. Effect of 5-azacytidine on the methylation of DAPK1 and MGMT gene, and DAPK1 and MGMT mRNA expression in CHMm and CHMp cells were analyzed by MSP assay and qRT-PCR assay, respectively.Results: 5-Azacytidine may suppress the proliferation of CHMm and CHMp cells. Furthermore, the DAPK1 and MGMT genes were hypermethylated in CHMm/CHMp cells and clinical malignant tumor samples, but not in normal female dogs’ blood and tissue. However, the DAPK1 and MGMT genes were re-inducible in CHMm and CHMp cells treated with 5 μM 5-azacytidine. Meanwhile, 5-azacytidine increased the expression of DAPK1 and MGMT mRNA.Conclusion: These results suggest that DAPK1 and MGMT methylation can serve as sensitive diagnostic biomarkers and therapeutic targets for CMGTs. 5-Azacytidine also could be a potential therapeutic candidate for CMGTs. Keywords: canine mammary gland tumor, CHMm, CHMp, 5-azacytidine, DAPK1, MGMT, DNA methylation

Xingxing Chen,1,2,* Fan Xia,1,2,* Jurui Luo,1,2,* Jinli Ma,1,2 Zhaozhi Yang,1,2 Li Zhang,1,2 Yan Feng,1,2 Zhimin Shao,2,3 Xiaoli Yu,1,2 Xiaomao Guo1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; 3Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China *These authors contributed equally to this work Background: This study investigated the effect of postmastectomy radiotherapy (PMRT) in patients with stage II–III triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC) and modified radical mastectomy (MRM).Patients and methods: A total of 104 women with stage II–III TNBC who received NAC and MRM at our institution between January 2000 and July 2007 were identified. Patients were divided into 2 groups (PMRT and non-PMRT) for statistical analysis.Results: The median follow-up time was 64months (range 12–123months). The 5year cumulative locoregional recurrence (LRR) and disease recurrence (DR) rates were 26.5% and 49.6%, respectively. Despite their more adverse prognostic features, patients with PMRT had lower 5year cumulative LRR and DR rates than those without PMRT (LRR: 18.3% vs 52.2%, respectively, p=0.0005; DR: 45% vs 69.1%, p=0.0334, respectively). On multivariate analysis of the entire study cohort, forgoing PMRT was significantly associated with developing LRR and DR. Subset analysis revealed that PMRT significantly reduced the 5year LRR rate in patients with pre-chemotherapy clinical stages IIA (8.3% vs 46.2%, p=0.019) and IIIA (16% vs 66.7%, p=0.003). PMRT also significantly reduced the 5year DR rate in patients with pre-chemotherapy clinical stage IIA (24.5% vs 69.3%, p=0.0151) and ≥IIIB (70.8% vs 100%, p=0.0481).Conclusion: In our cohort of patients with TNBC treated with NAC and MRM, PMRT significantly improved locoregional control and disease-free survival in the entire cohort as well as in patients with stage IIA disease. Our results may help in tailoring adjuvant treatment decisions for these particular patient populations. Keywords: triple-negative breast carcinoma, neoadjuvant chemotherapy, surgery, adjuvant radiation therapy, locoregional recurrence, disease recurrence

Wan-Wei Wang,1 Xi-Lei Zhou,1 Ying-Jian Song,2 Chang-Hua Yu,1 Wei-Guo Zhu,1 Yu-Suo Tong1 1Department of Radiation Oncology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu, China; 2Department of Respiratory Medicine, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu, China Purpose: Long noncoding RNAs (lncRNAs) are present in body fluids, but their potential as tumor biomarkers has never been investigated in malignant pleural effusion (MPE) caused by lung cancer. The aim of this study was to assess the clinical significance of lncRNAs in pleural effusion, which could potentially serve as diagnostic and predictive markers for lung cancer-associated MPE (LC-MPE). Patients and methods: RNAs from pleural effusion were extracted in 217 cases of LC-MPE and 132 cases of benign pleural effusion (BPE). Thirty-one lung cancer-associated lncRNAs were measured using quantitative real-time polymerase chain reaction (qRT-PCR). The level of carcinoembryonic antigen (CEA) was also determined. The receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were established to evaluate the sensitivity and specificity of the identified lncRNAs and other biomarkers. The correlations between baseline pleural effusion lncRNAs expression and response to chemotherapy were also analyzed. Results: Three lncRNAs (MALAT1, H19, and CUDR) were found to have potential as diagnostic markers in LC-MPE. The AUCs for MALAT1, H19, CUDR, and CEA were 0.891, 0.783, 0.824, and 0.826, respectively. Using a logistic model, the combination of MALAT1 and CEA (AUC, 0.924) provided higher sensitivity and accuracy in predicting LC-MPE than CEA (AUC, 0.826) alone. Moreover, baseline MALAT1 expression in pleural fluid was inversely correlated with chemotherapy response in patients with LC-MPE. Conclusion: Pleural effusion lncRNAs were effective in differentiating LC-MPE from BPE. The combination of MALAT1 and CEA was more effective for LC-MPE diagnosis. Keywords: malignant pleural effusion, lncRNA, MALAT1, lung cancer, diagnosis

Junsheng Fan,1,2,* Zengfei Xia,1,* Xiaoli Zhang,1,* Yuqing Chen,1 Ruolan Qian,1 Sihan Liu,1 Danming You,1 Jian Zhang,1 Peng Luo1 1Department of Oncology, Zhujiang Hospital of Southern Medical University, Guangzhou, China; 2Department of Respiratory Medicine, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China *These authors contributed equally to this work Background: Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the US Food and Drug Administration to treat crizotinib-refractory non-small cell lung cancer. We performed this meta-analysis to synthesize the results of different clinical trials to evaluate the efficacy and safety of alectinib. Methods: A search of 3 databases, including PubMed, Web of Science, and the Cochrane Library, was performed from the inception of each database through September 5, 2017. We have pooled the overall response rate (ORR), disease control rate, progression-free survival, and intracranial ORR to evaluate the efficacy of alectinib. Discontinuation rate, rate of dose reduction or interruption due to adverse events as well as the incidence of several adverse events were aggregated to evaluate its safety. Results: A total of 8 studies with 626 patients have been included in our study. The pooled efficacy parameters are as follows: ORR 70% (95% CI: 57% to 82%), disease control rate 88% (95% CI: 82% to 94%), progression-free survival 9.36 months (95% CI: 7.38% to 11.34%), and intracranial ORR 52% (95% CI: 45% to 59%). ALK inhibitor-naïve patients tend to have better responses than crizotinib-pretreated patients. The aggregate discontinuation rate is 7% (95% CI: 4% to 10%), and the pooled rate of dose reduction or interruption is 33% (95% CI: 24% to 42%). The incidences of most adverse events were relatively low, while the incidences of 2frequently reported adverse events, myalgia (18%) and anemia (25%), were even higher than with the first-generation ALK inhibitor crizotinib. Conclusion: Generally, alectinib is a drug with preferable efficacy and tolerable adverse effects, and it is suitable for the treatment of intracranial metastases. Keywords: alectinib, anaplastic lymphoma kinase, ALK, ALK inhibitor, non-small cell lung cancer, NSCLC, meta-analysis

Bo Wang,1–3,* XueBin Zhang,2–4,* Wei Wang,1–3 ZhiZhong Zhu,5 Fan Tang,2–4 Dong Wang,6–8 Xi Liu,9 Hao Zhuang,10 XiaoLing Yan2–4 1Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin, China; 2Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin, China; 3Tianjin Neurosurgical Institute, Tianjin, China; 4Department of Pathology, Tianjin Huanhu Hospital, Tianjin, China; 5Department of Rehabilitation, Tianjin Huanhu Hospital, Tianjin, China; 6Department of Neurosurgery, Tianjin Medical University, General Hospital, Tianjin, China; 7Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China; 8Tianjin Neurological Institute, Tianjin, China; 9Department of Gastroenterology, Tianjin NanKai Hospital, Tianjin, China; 10Department of Hepatic Biliary Pancreatic Surgery, Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou, China *These authors contributed equally to this work Purpose: Forkhead box K2 (FOXK2) is a member of the forkhead box family of transcription factors. Recently, researchers discovered that overexpression of FOXK2 inhibits the proliferation and metastasis of breast cancer, non-small cell lung cancer, and colorectal cancer, and is related to the clinical prognosis. However, in hepatocellular carcinoma, FOXK2 results in the opposite phenotypes. Currently, the contribution of FOXK2 to glioma pathogenesis is not clear. Patients and methods: We evaluated the expression of FOXK2 in 151 glioma patients using immunohistochemistry assays. The associations among the expression of FOXK2, clinicopathological parameters, and the prognosis of glioma patients were statistically analyzed. We downregulated and upregulated the level of FOXK2 in glioma cells by transfections with small interfering RNA and plasmids. Then, we investigated the effects on tumor cell behavior in vitro by Cell Counting Kit-8 assays, colony-formation assay, transwell assay, and the epithelial-to-mesenchymal transition (EMT) biomarker levels.Results: The clinical data showed that expression of FOXK2 gradually decreased with increasing World Health Organization (WHO) grades and a low level of FOXK2 indicates a poor prognosis. FOXK2 expression is negatively correlated with Ki67 expression and the WHO degree but is not correlated with other clinicopathological parameters, including sex, age, Karnofsky Performance Status, tumor diameter, O-6-methylguanine-DNA methyltransferase, and glutathione S-transferase pi. FOXK2 knockdown enhances glioma cell proliferation, migration, invasion, and EMT process, and, in contrast, FOXK2 overexpression inhibits glioma cell proliferation, migration, invasion, and the EMT process.Conclusion: Expression of FOXK2 gradually decreases with increasing WHO grades. FOXK2 inhibits tumor proliferation, migration, and invasion. FOXK2 is a critical mediator of the EMT process. Keywords: Forkhead box K2, FOXK2, glioma, oncology

Hai-Sheng Wang,1,* Xiaobo Nie,2,* Rui-Bing Wu,1 Hong-Wei Yuan,1 Yue-Hong Ma,1 Xiu-Lan Liu,1 Jian-Yu Zhang,1 Xiu-Ling Deng,1 Qin Na,1 Hai-Yan Jin,1 Yan-Chao Bian,1 Yu-Min Gao,3 Yan-Dong Wang,4 Wei-Dong Chen,1,2 1Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, 2Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, 3Epidemiology Section, Public Health School, Inner Mongolia Medical University, Hohhot, 4State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: Aberrant activation of Wnt/β-catenin signaling pathways is closely involved in the occurrence and progression of several types of human malignancies. However, as a fundamental component in this cascade, Wnt3 has not been well understood for the expression level and pathogenic mechanism in gastric carcinogenesis. Here, this research was undertaken to elucidate the important role of Wnt3 in gastric cancer. Wnt3 expression in gastric carcinomas and their respective normal tissues was examined by immunoblotting and immunohistochemistry. In all cases, Wnt3 expression was significantly elevated in gastric carcinomas compared with normal tissues. Knocking down Wnt3 in MGC-803 gastric cancer cells by small interfering RNAs transfection led to an obvious decrease in both transcript and protein levels. Silence of Wnt3 expression in gastric cancer cells inhibited the expression of β-catenin and cyclin D1 genes in Wnt/β-catenin pathway, significantly blocked cellular proliferation, delayed cell cycle, suppressed cell invasion and metastasis, accompanied by a higher apoptosis rate. Together, we conclude that upregulation of Wnt3 plays a crucial role in gastric tumorigenesis by inducing proliferation, migration, and invasion and inhibiting apoptosis of cancer cells, and Wnt3 might be a potential target for the treatment of gastric cancer. Keywords: gastric carcinogenesis, gastric carcinoma, β-catenin, siRNA, invasion

Yanyan Hu,1,2 Erpeng Qi,1 Fangyi Liu,1 Yuhan Lu,1 Shuilian Tan,1 Ya Sun,1 Zhiyu Han,1 Ping Liang,1 Xiaoling Yu1 1Department of Interventional Ultrasound, General Hospital of People’s Liberation Army, Beijing, China; 2Medical Department, First Affiliated Hospital of PLA General Hospital, Beijing, China Objectives: To evaluate the effectiveness of iodine-125 (125I) seed implantation for pancreatic cancer (PC), and preliminarily evaluate the clinical value of a self-developed three-dimensional (3D) visualized seed planning and navigation system in 125I seed implantation for treatment of PC. Patients and methods: Our team retrospectively reviewed 25 PC patients who underwent 125I seed implantation between December 2010 and November 2016. The patients were divided into two groups: 3D visualization preoperative planning group (12 patients, 13 lesions) and two-dimensional (2D) regular group (13 patients, 14 lesions). We compared and analyzed the parameters of the two groups, such as number of needle insertions, one-time treatment success rate, proportion of added seeds, local control rate, rate of complications, rate of pain relief, and the survival rate and risk factors of the two groups. There was no significant difference in clinical data of the two groups. Results: 125I seed implantation was performed successfully in all PC patients, with no occurrence of serious complications during and after the procedure. The one-time treatment success rate of 3D group (80%) was higher than that of 2D group (45.5%) (P

Xiao-lei Gao,1,2 Mei Zhang,1,3 Ya-ling Tang,1,3 Xin-hua Liang1,2 1State Key Laboratory of Oral Diseases, 2Department of Oral and Maxillofacial Surgery, 3Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China Abstract: More recently, disease metastasis and relapse in many cancer patients several years (even some decades) after surgical remission are regarded as tumor dormancy. However, the knowledge of this phenomenon is cripplingly limited. Substantial quantities of reviews have summarized three main potential models that can be put forth to explain such process, including angiogenic dormancy, immunologic dormancy, and cellular dormancy. In this review, newly uncovered mechanisms governing cancer cell dormancy are discussed, with an emphasis on the cross talk between dormant cancer cells and their microenvironments. In addition, potential mechanisms of reactivation of these dormant cells in certain anatomic sites including lymph nodes and bone marrow are discussed. Molecular mechanism of cellular dormancy in head and neck cancer is also involved. Keywords: cancer cell dormancy, disseminated tumor cells, head and neck cancer, hypoxia, lymph node metastasis

Meng Li,1,* Zeng-Shan Liu,1,* Xi-Lin Liu,1,* Qi Hui,2,* Shi-Ying Lu,1 Lin-Lin Qu,1 Yan-Song Li,1 Yu Zhou,1 Hong-Lin Ren,1 Pan Hu1 1Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, China-Japan Union Hospital, The First Hospital, Jilin University, Changchun, 2School of Pharmacy, Wenzhou Medical University, Wenzhou, People’s Republic of China *These authors contributed equally tothis work Abstract: Recombinant immunotoxins (RITs) are proteins that contain a toxin fused to an antibody or small molecules and are constructed by the genetic engineering technique. RITs can bind to and be internalized by cells and kill cancerous or non-cancerous cells by inhibiting protein synthesis. A wide variety of RITs have been tested against different cancers in cell culture, xenograft models, and human patients during the past several decades. RITs have shown activity in therapy of several kinds of cancers, but different levels of side effects, mainly related to vascular leak syndrome, were also observed in the treated patients. High immunogenicity of RITs limited their long-term or repeat applications in clinical cases. Recent advances in the design of immunotoxins, such as humanization of antibody fragment, PEGylation, and modification of human B- and T-cell epitopes, are overcoming the above mentioned problems, which predict the use of these immunotoxins as a potential therapeutic method to treat cancer patients. Keywords: targeted therapy, hematologic malignancies, solid tumors, vascular leak syndrome, immunogenicity&nbsp

Yingdan Huang,1,2 Xiuli Hong,2 Jiasheng Hu,2 Quanyi Lu2 1Department of Blood Transfusion, The First Affiliated Hospital of Xiamen University, 2Department of Hematology, Zhongshan Hospital of Xiamen University, Xiamen, People’s Republic of China Background: miRNA is a microRNA that negatively regulates protein expression at post-transcriptional or translational level. It is widely involved in the pathogenesis of tumors. miR-98 belongs to the let-7 family, and its overexpression can increase the sensitivity to drugs in solid cancer cells. However, the function of miR-98 in leukemia is still unclear. In this study, the effect of miR-98 on drug resistance and proliferation of leukemia cells were investigated. Methods: Real-time quantitative polymerase chain reaction analyzed the expression difference between miR-98 and E2F1 in leukemia cell lines, K562 and K562/A02. The downstream target gene of miR-98 was predicted by TargetScan; K562/A02 was transiently transfected with miR-98 mimic to upregulate the expression of miR-98; real-time quantitative polymerase chain reaction and Western blot were used to analyze the expression alterations of E2F1; cell counting kit-8 was used to evaluate the influence on K562/A02 proliferation and sensitivity to chemotherapeutic drugs; meanwhile, Western blot was used to analyze the expression of p21, Bax, matrix metalloproteinase 9 and ABCG2 proteins. Results: E2F1 is one of the target genes of miR-98 proved by bioinformatics. Compared with the K562, the level of miRNA-98 expression was decreased in K562/A02, but the level of E2F1 expression was upregulated. Leukemia cell line K562/A02 was transfected with miR-98 mimic to upregulate the expression of miR-98, the expression of E2F1 was significantly decreased. After upregulating the miR-98 expression in K562/A02, the proliferation was weakened, and the sensitivity to chemotherapy was increased. Western blot showed that upregulated miR-98 expression increased the levels of p21 and BAX proteins in K562/A02 cells, and decreased the levels of matrix metalloprotease 9 and ABCG2 proteins, which were significantly different compared with those before miR-98 mimic transfection. Conclusion: In the leukemia drug-resistant cell line K562/A02, the targeted upregulated expression of miR-98 could decrease the proliferation of leukemia cells and improve the sensitivity to chemotherapeutics by inhibiting E2F1 expression. miR-98 might be a potential target for overcoming leukemia multidrug resistance. Keywords: miRNA-98, leukemia cells, E2F1, drug resistance, K562/A02

Yunfeng Zhang,1,* Jinbo Lin,2,* Wenjie Huang,3,* Yong Cao,4 Yi Liu,4 Tieqiang Wang,4 Weiyi Zhong,4 Dongli Wang,4 Rongrong Mao,4 Xiaoliang Chen4 1Surgical Operating Room, Longgang District People’s Hospital of Shenzhen, 2Medical Oncology, Longgang District Central Hospital of Shenzhen, 3Medical Oncology, Guangming District Central Hospital of Shenzhen, 4Chronic Disease Control and Prevention Center, Shenzhen Guangming District Center for Disease Control and Prevention, Shenzhen, China *These authors contributed equally to this work Purpose: Abnormal expression of miR-223 in cancerous tissue has confirmed it as an important player in tumorigenesis of cancers, such as hepatocellular carcinoma, colorectal carcinoma, osteosarcoma, gastric cancer, and chronic lymphocytic leukemia. The present meta-analysis aimed to explore the association between circulating miR-223 and prognosis of cancers. Methods: The studies were accessed by an electronic search of multiple databases. RevMan5.3 and STATA14.0 were used to estimate the heterogeneity among studies, pooled effects, and publication bias. Results: Ten studies with data of 1,002 patients with cancer were included in this meta-analysis. The risk of metastasis from stages 3 to 4 of TNM did not decrease when high versus low circulating expression of miR-223 were compared (pooled odds ratio =0.50, 95% CI: 0.24–1.03). In case of prognosis, the overall survival time was not significantly longer with high circulating miR-223 expression (pooled hazard ratio [HR] =0.64, 95% CI: 0.38–1.11) in all cancer types. However, the overall survival time of chronic lymphocytic leukemia (pooled HR =0.19, 95% CI: 0.07–0.54) increased in subgroup analysis. Moreover, the treatment-free survival of chronic lymphocytic leukemia was significantly increased with high circulating miR-223 expression (pooled HR =0.38, 95% CI: 0.23–0.64). Conclusion: Circulating miR-223 was not an effective biomarker in prognosis surveillance in all cancers but in chronic lymphocytic leukemia. Keywords: miR-223, carcinoma, metastasis, prognosis, meta-analysis

Yan Liu,1 Zhong Zheng,1 Qixin Zhang,2 Xinling Zhou,3 Yikuan Feng,1 Anquan Yan2 1Department of Gastroenterology, 2Department of Health Care, 3Digestive Endoscopy Center, Weifang People’s Hospital, Weifang, China Purpose: To systematically investigate the efficacy and safety of the combination of FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin) regimen and cocultured dendritic cells and cytokine-induced killer cells (DC-CIK) immunotherapy for the treatment of colorectal cancer (CRC).Methods: Publications reporting the clinical trials’ responses or safety of FOLFOX regimen combined with DC-CIK immunotherapy in treating CRC patients were searched in PubMed, Embase, Cochrane Library, China National Knowledge Internet, and Wanfang databases. Trials meeting the selection criteria were analyzed. The overall survival (OS), overall response rate (ORR), disease control rate (DCR), tumor markers, immune function, and adverse events were evaluated.Results: Ten trials including 881 CRC patients were analyzed in this meta-analysis. The combined therapy showed advantages over FOLFOX treatment-alone in 2-year OS (odds ratio [OR] =2.77, confidence interval [CI] =1.58–4.86, P=0.0004), ORR (OR =1.85, CI =1.34–2.56, P=0.0002), and DCR (OR =2.54, CI =1.76–3.67, P0.05). Moreover, the level of carcinoembryonic antigen was also decreased significantly upon immunotherapy (P

Liao SA, Guan J, Mo H, He JL, Zhan XL. Onco TargetsTher. 2020;13:8209—8221. The Editor and Publisher of OncoTargets and Therapywish to retract the published paper. The journal was notified of potential image manipulationin Figure 6D Panel U20S si-XIAP. The authors wereunable to provide the necessary raw data for the studyand the Editor has determined the findings of the paperare unreliable and requested for the article to be retracted. Our decision-making was informed by our policy on publishingethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Wang YH, Hong D, Qian YQ, et al. Onco Targets Ther.2018;11:7987—7999. The Editor-in-Chief and Publisher of OncoTargets andTherapy wish to retract the published article. We were notified of the alleged duplication of western blotbands between Figure 6B Cyclin A2 and 6D Cyclin A2 inthe published paper. The authors provided an explanation for the duplicationbut were unable to provide satisfactory raw data for the western blots shown in the article. The editor determinedthe findings of the study could no longer be supported andrequested for the article to be retracted. The authors wish to apologise for this error. Our decision-making was informed by our policy on publishingethics and integrity and the COPE guidelines onretraction. The retracted article will remain online to maintain thescholarly record, but it will be digitally watermarked oneach page as “Retracted”. This retraction relates to this paper &nbsp

Qidong Ye, Xuelian Liao, Pan Fu, Jiaying Dou, Kai Chen, Hui Jiang Department of Hematology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China Abstract: Acute myeloid leukemia (AML) is a highly malignant hematopoietic tumor. This study aimed to explore the effect of portulacerebroside A (PCA) on the adhesion, migration, and invasion in human leukemia HL60 cells and U937 cells and clarify the possible mechanisms involved, which could provide potential strategies for the treatment of AML. By methyl thiazolyl tetrazolium analysis, it was found that PCA (1–10µM) suppressed the cell viability in a time- and dose-dependent manner. A total of 1, 2, and 5µM of PCA dramatically inhibited the adhesion, migration, and invasion of HL60 cells and U937 cells in a dose-dependent manner. Phosphorylation level of JNK and P38 protein level was measured by Western blot. After the real-time quantification polymerase chain reaction and Western blot detection of the total RNA and protein, messenger RNA, and protein expression levels of Ras homologous C (RhoC), metastasis-associated gene 1 (MTA1) and matrix metalloproteinase-2/9 (MMP-2/9) were decreased significantly in a dose-dependent manner. The phosphorylation level of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (P38) was decreased dramatically in HL60 cells and U937 cells after PCA treatment. In conclusion, PCA significantly inhibits the adhesion, migration, and invasion of HL60 cells and U937 cells by suppressing the p38/JNK pathway and regulating the expressions of related genes. Keywords: portulacerebroside A, PCA, p38/JNK, leucocythemia, adhesion, migration, invasion

Fu-Jun Li, Xin-Juan Wang, Xiao-Li Zhou Department of Stomatology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, People’s Republic of China Background: WISP-1 is a member of the CCN family of growth factors and has been reported to play an important role in tumorigenesis by triggering downstream events via integrin signaling. However, little is known about the role of WISP-1 in proliferation of salivary gland carcinoma (SGC) cells.Methods: In this study, we investigated the WISP-1 expression in SGC tissues via immunohistochemical staining, Western blotting assay, and real-time quantitative polymerase chain reaction method, and then evaluated the regulatory role of WISP-1 in the growth of SGC A-253 cells. In addition, the role of MMP-2 in the WISP-1-mediated growth regulation was also investigated.Results: It was demonstrated that the WISP-1 expression was upregulated at both mRNA and protein levels in 15 of 21 SGC tumor tissues, compared to the non-tumor tissues (five of 21), associated with the lymph node dissection and bone invasion. The in vitro CCK-8 assay and colony-forming assay demonstrated that the exogenous WISP-1 treatment or the WISP-1 overexpression promoted the growth of A-253 cells. In addition, we confirmed that the WISP-1 overexpression upregulated the MMP-2 expression in A-253 cells with the gain-of-function and loss-of-function strategies, and that the MMP-2 knockdown attenuated the WISP-1-mediated growth promotion of A-253 cells.Conclusion: We found that WISP-1 was overexpressed in the human SGCs, and the WISP-1 overexpression promoted the salivary gland cell proliferation via upregulating MMP-2 expression. Our study recognized the oncogenic role of WISP-1 in human SGCs, which could serve as a potential target for anticancer therapy. Keywords: WISP-1, SGCs, proliferation, MMP-2

Xuejuan Dong, Xin Li, Jie Yu, Ming-an Yu, Xiaoling Yu, Ping Liang Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, People’s Republic of China Purpose: To retrospectively review the complications of ultrasound (US)-guided percutaneous microwave ablation (MWA) of renal cell carcinoma.Patients and methods: In this study, 101 patients with 105 tumors seen from April 2006 to Feb 2014 were enrolled retrospectively. The patients were treated with US-guided percutaneous MWA and were followed up with contrast-enhanced US and computed tomography or magnetic resonance imaging at 1, 3, and 6months and every 6months thereafter.Results: Technical success was achieved in 99 of 105 tumors (94.3%). The median follow-up time was 25 (range 1.13–93.23)months. Among the 105 tumors, 26 complications in 24.8% of patients and 23 minor complications (Clavien–Dindo Grades I and II) in 21.9% of patients were noted, accounting for 88.5% of all complications. All the minor complications were cured. Three major complications (Clavien–Dindo Grade ≥III) occurred in 2.9% of the patients, accounting for 11.5% of all complications: hydrothorax in two patients and bowel injury in one. The two patients who had hydrothorax post-MWA had a history of cirrhosis and were treated with catheter drainage. The bowel injury was treated surgically. In all patients, the changes in serum creatinine and urea nitrogen levels from before to after the procedure were small.Conclusion: US-guided percutaneous MWA is a beneficial treatment for renal cell carcinoma in selected patients; however, if the renal tumor is close to the bowel, or the patient has serious comorbidities or has undergone abdominal surgery, the procedure must be performed more carefully. Keywords: microwave ablation, renal cell, complications, carcinoma

Haisheng Guo,1,* Yunhui Xing,2,* Ailan Mu,1 Xia Li,3 Tingshan Li,4 Xia Bian,1 Chunmei Yang,1 Xiaolei Zhang,1 Yuefen Liu,1 Xunguo Wang1 1Department of Oncology, Dongying People’s Hospital, 2Department of Tuberculosis, Shengli Hospital ofShengli Oil Field, 3Department of Health, 4Personnel Department, Dongying People’s Hospital, Dongying, Shandong, People’s Republic of China *These authors contributed equally tothis work Abstract: Proliferation, growth, and differentiation of cells are strictly controlled by the signal system of epidermal growth factor receptor (EGFR). If any link of the EGFR signals system is interfered with or damaged, the proliferation, growth, and differentiation of cells would become uncontrolled. EGFR is overexpressed in a variety of malignant tumors, such as non-small-cell lung cancer, colorectal cancer and breast cancer. Results of the study have proved that EGFR overexpression is closely associated with mutations and variants of the EGFR genes, whose mutations and variants are associated with occurrence, metastasis, and prognosis of different types of tumors, including lung cancer. This study is aimed at investigating whether the polymorphisms of CA simple sequence repeat in intron 1 (CA-SSR1), -216G/T, and R497K in the EGFR are able to induce EGFR activation and whether overexpression is associated with pleural metastasisof lung adenocarcinoma. A total of 432 lung adenocarcinoma patientswith pleural metastasis (metastasis group) and 424patients with lung adenocarcinoma but without pleuralmetastasis (nonmetastasis group) were enrolled in this study. For all patients, the CA-SSR1 genotypeswere determined by capillary electrophoresis, polymerase chain reaction amplification, and direct DNA sequencing, and the R497K and -216G/T genotypes were determined by polymerase chain reaction amplification and direct DNA sequencing. EGFR expression was evaluated by immunohistochemical staining in primary tumor tissues with different -216G/T, R497K, and CA-SSR1 genotypes. Our results showed significant differences between pleural metastasis and nonmetastasis groups in the genotype and allele distribution of -216G/T, R497K, and CA-SSR1 polymorphisms of the EGFR gene. The -216T allele, Arg allele, and shorter CA-SSR1 (

Xiaoli Zhang,1,2 Jinming Yu,1,2 Minghuan Li,2 Hui Zhu,2 Xindong Sun,2 Li Kong2 1Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 2Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People’s Republic of China Background: The association of high mobility group box 1 (HMGB1) expression with clinicopathological significance and prognosis in Asian patients with colorectal carcinoma (CRC) remains controversial. The purpose of this study was to conduct a meta-analysis and literature review to identify the role of HMGB1 in the development and prognosis of CRC in Asians. Methods: All eligible studies regarding the association between HMGB1 expression in tissue with clinicopathological significance and prognosis in Asian patients with CRC published up to January 2015 were identified by searching PubMed, Web of Science, Chinese National Knowledge Infrastructure, and WanFang database. Analysis of pooled data was performed, while odds ratio (OR) or hazard radio with 95% confidence interval (CI) was calculated and summarized to evaluate the strength of this association in fixed- or random-effects model. Results: The expression level of HMGB1 in CRC tissues was much higher than normal colorectal tissues (OR =27.35, 95% CI 9.32–80.26, P

Xiao-Yi Chen,1,* Guo-Qing Ru,2,* Ying-Yu Ma,1 Jun Xie,3 Wan-Yuan Chen,2 Hui-Ju Wang,1 Shi-Bing Wang,1 Li Li,1 Ke-Tao Jin,4 Xiang-Lei He,2 Xiao-Zhou Mou1 1Clinical Research Institute, 2Department of Pathology, Zhejiang Provincial People’s Hospital, Hangzhou, 3Department of Anus-Intestines, Affiliated Hospital of Shaoxing University, 4Department of Gastrointestinal Surgery, Shaoxing People’s Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, People’s Republic of China *These authors contributed equally tothis work Background: Epidemiologic evidence suggests that chronic inflammation and/or chronic infection is associated with cancer development, and the inflammatory process may play a crucial role in the carcinogenesis and prognosis of colorectal cancer (CRC). Substance P (SP) belongs to the family of tachykinins and acts as an immunomodulator, binding to the neurokinin-1 receptor (NK1R) to initiate tumor cell proliferation, angiogenesis, and migration, steps that are critical for tumor cell invasion and metastasis. It is suggested that SP/NK1R signaling may play an important role in cancer progression and metastasis. However, the exact involvement and significance of SP and NK1R in CRC pathologies remain to be adequately deciphered.Patients and methods: We performed immunohistochemistry staining on tissue microarrays containing 267 pairs of CRC and adjacent normal tissues to evaluate the clinical significance of SP or NK1R in the progression and prognosis of CRC. We also explored the potential correlation between SP and NK1R in CRC development.Results: Expression levels of SP and NK1R were upregulated in CRC compared with their expressions in adjacent normal tissues (P

Long Su, SuJun Gao, XiaoLiang Liu, YeHui Tan, Lu Wang, Wei Li Cancer Center, The First Hospital, Jilin University, Changchun, People’s Republic of China Background: This study was aimed to explore the clinical characteristics and prognoses of acute myeloid leukemia (AML) patients with CEBPA mutations. Patients and methods: Three hundred and forty-five patients with de novo AML were retrospectively analyzed with regard to CEBPA mutations, clinical characteristics, therapeutic responses, and long-term outcomes. Results: CEBPA mutations were detected in 59 patients (17.10%), with 47 cases harboring double mutations and 12 cases harboring single mutations. In those with a normal karyotype (NK), 44 cases (25.29%) were detected with CEBPA mutations. The following characteristics were observed in CEBPA-mutated patients: most (66.10%) of them were M1 or M2; they presented with higher peripheral white blood cell counts (23.71 [12.6, 60.02] ×109/L versus 7.34 [2.38, 26.63] ×109/L; u=4.944, P

Xian-Liang Zeng,* Huan-Huan Wang,* Mao-Bin Meng, Zhi-Qiang Wu, Yong-Chun Song, Hong-Qing Zhuang, Dong Qian, Feng-Tong Li, Lu-Jun Zhao, Zhi-Yong Yuan, Ping Wang Department of Radiation Oncology, Tianjin’s Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China *These authors contributed equally to this work Background and aim: The aim of this study is to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) using CyberKnife in the treatment of patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Patients and methods: Between October 1, 2006 and May 1, 2015, patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery were enrolled and treated with SBRT at our hospital. The primary end point was local control rate after SBRT. Secondary end points were overall survival, time to symptom alleviation, and toxicity, assessed using the Common Terminology Criteria for Adverse Events version 4.0. Results: Twenty-four patients with 24 lesions (17 abdominal lymph nodes and seven stumps) were treated with SBRT, of which five patients presented with abdominal lymph nodes and synchronous metastases in the liver and lung. The 6-, 12-, and 24-month actuarial local control rates were 95.2%, 83.8%, and 62.1%, respectively. For the entire cohort, the median overall survival from diagnosis and SBRT was 28.9 and 12.2months, respectively. Symptom alleviation was observed in eleven of 14 patients (78.6%) within a median of 8days (range, 1–14days) after SBRT. Nine patients (37.5%) experienced Common Terminology Criteria for Adverse Events version 4.0 grade 1–2 acute toxicities; one patient experienced grade 3 acute toxicity due to thrombocytopenia. Conclusion: SBRT is a safe and effective treatment for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Further studies are needed before SBRT can be recommended routinely. Keywords: stereotactic body radiation therapy, pancreatic adenocarcinoma, recurrent disease, overall survival

Xiaoli Wang,1,2 Hongjiang Yan,1 Yijun Luo,1,2 Tingyong Fan1 1Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, 2School of Medicine and Life Sciences, Shandong Academy of Medical Sciences, University of Jinan, Jinan, People’s Republic of China Abstract: Low-grade nasopharyngeal papillary adenocarcinoma is an extremely rare tumor, with only a limited number of cases reported in the literature. Some published studies have paid more attention to the clinicopathological features of nasopharyngeal adenocarcinoma, while little effort has been made to study the optimal therapeutic strategies. We report about a woman diagnosed with low-grade nasopharyngeal papillary adenocarcinoma. She received the treatment approach that combined transnasal endoscopic surgery to remove the lesion with postoperative radiotherapy for nasal cavity. There was no evidence of recurrence after 4months of surgery, and further follow-up is being continued. Through this example, we wanted to explore the optimal therapeutic strategies for primary nasopharyngeal adenocarcinomas. Keywords: nasopharyngeal adenocarcinoma, immunohistochemistry, treatment policy, survival and prognosis&nbsp

Fengqin Xu,1,* Zhi-qiang Zhang,2,* Yong-chao Fang,2 Xiao-lei Li,2 Yu Sun,2 Chuan-zhi Xiong,2 Lian-qi Yan,2 Qiang Wang2 1Department of Orthopaedics, Hongquan Hospital, 2Department of Orthopaedics, Subei People’s Hospital, Yangzhou, Jiangsu Province, People’s Republic of China *These authors contributed equally tothis work Background: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) is identified to be overexpressed in several cancers. However, the role of MALAT-1 in chondrosarcoma is poorly understood.Methods: The expression of MALAT-1 and Notch-1 signaling pathway was detected in chondrosarcoma tissues and chondrosarcoma cells by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was performed to examine the cell viability of chondrosarcoma cells transfected with si-MALAT-1 or pcDNA-MALAT-1. Then the expression of Notch-1 signaling pathway was detected when MALAT-1 was upregulated or downregulated in chondrosarcoma cells. A subcutaneous chondrosarcoma cells xenograft model was used to confirm the effect of MALAT-1 on tumor growth in vivo.Results: We found the increased expression of MALAT-1 and Notch-1 signaling pathway in chondrosarcoma tissue and cells. MALAT-1 promoted the proliferation of chondrosarcoma cells. In addition, MALAT-1 activated the Notch-1 signaling pathway at posttranscriptional level in chondrosarcoma cells. Meanwhile, overexpression of Notch-1 reversed the effect of si-MALAT-1 on the proliferation of chondrosarcoma cells. Finally, we found that MALAT-1 promoted the tumor growth in a subcutaneous chondrosarcoma cells xenograft model, which confirmed the promoted effect of MALAT-1 on the tumor growth in vivo.Conclusion: Taken together, our study demonstrated that MALAT-1 promoted the proliferation of chondrosarcoma cell via activating Notch-1 signaling pathway. Keywords: MALAT-1, cell proliferation, chondrosarcoma, Notch-1, molecular pathophysiology

Yao Sun,1 Monika Joks,2 Li-Ming Xu,1 Xiu-Li Chen,1 Dong Qian,1 Jin-Qiang You,1 Zhi-Yong Yuan1 1Department of Radiation Oncology, CyberKnife Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 2Department of Hematology and Bone Marrow Transplantation, Poznan University of Medical Science, Poznan, Poland Background: The breast is a rare site of extranodal involvement of diffuse large B-cell lymphoma (DLBCL). We aimed to assess the clinical characteristics, prognostic factors, and treatment outcomes of breast DLBCL.Patients and methods: We retrospectively analyzed 113 patients (from our institution and the literature) between 1973 and 2014. The primary end point was overall survival (OS). Kaplan–Meier OS curves were compared with the log-rank test. Cox regression analysis was applied to determine the prognostic factors for OS, progression-free survival (PFS), local control (LC), and cause-specific survival (CSS).Results: A total of 113 patients were included in the study: 42 cases from our hospital and 71cases from 12 publications. The median age at diagnosis was 58 years. With a median follow-up time of 39.2 months, the estimated 5-year OS, PFS, LC, and CSS were 71.4%, 58.8%, 75.6%, and 74.9%, respectively. In multivariate analysis, more than four cycles of chemotherapy, having localized cancer, lumpectomy with or without axillary lymph node (ALN) dissection,and low to low-to-intermediate International Prognostic Index were favorable factors for OS. For PFS, significant prognostic factors were rituximab use, B symptoms, and tumor size. As for the local group, lumpectomy with or without ALN dissection and more than four cycles of chemotherapy were favorable factors for OS. Tumor size >4 cm and nonuse of rituximab were adverse factors for PFS. Twenty-one patients (18.6%) developed local relapse and 33 (29.2%) developed systemic relapse. Eight patients had central nervous system relapse (7.3%).Conclusion: Our results reveal that local and extended staging criteria can reflect the different prognosis and treatment outcomes of breast DLBCL. Rituximab use, lumpectomy, and more than four cycles of chemotherapy are recommended as a treatment regimen. However, further study is warranted to validate our data. Keywords: diffuse large B-cell lymphoma, breast, rituximab, surgery, chemotherapy

Han Wu,1,* Xue-Liang Shi,1,* Hai-Jian Zhang,2 Qing-Jie Song,1 Xiao-Bing Yang,1 Wei-Dong Hu,1 Guang-Lin Mei,1 Xi Chen,1 Qin-Sheng Mao,1 Zhong Chen1 1Department of General Surgery, The Affiliated Hospital of Nantong University, 2Research Center of Clinical Medicine, The Affiliated Hospital of Nantong University, Nantong, People’s Republic of China *These authors contributed equally tothis work Purpose: Excessive ST3Gal-I levels predict a poor outcome for patients with several types of tumors. This study aims to investigate the role of ST3Gal-Iin determining the invasive and metastatic potential of human hepatocellular carcinoma (HCC) and clinical prognosis for patients with HCC.Methods: We compared the expression of ST3Gal-I in various HCC cell lines and in 20 pairs of tumor and peritumor tissue samples using Western blot analysis. Changes in the degree of invasiveness and migration were determined before and after small interfering RNA-induced knockdown of ST3Gal-I using a Transwell matrigel invasion assay and scratch wound assay. The correlation between ST3Gal-I expression and prognosis was determined in a large HCC patient cohort (n=273).Results: ST3Gal-I expression was higher in metastatic HCCLM3 cells and tumor tissue compared with normal adjacent tissue. Following the ST3Gal-I knockdown, the invasiveness and migration of HCCLM3 cells were markedly reduced. ST3Gal-I expression in HCC correlated closely with tumor thrombus (P5.0 cm, P=0.032), tumor node metastasis stages II–III (P=0.002), and Barcelona Clinic Liver Cancer stages B–C (P

Conghui Jin, Xunlei Zhang, Kuiling Zhao, Jun Xu, Min Zhao, Xiaohong Xu Department of Medical Oncology, Nantong Tumor Hospital, Nantong, People’s Republic of China Background: Nivolumab has become a therapeutic regimen for the treatment of patients with advanced melanoma. The goal of this study was to assess the efficacy and safety of nivolumab in patients with advanced melanoma.Methods: A systematic search from January 2008 to August 2015 with “nivolumab” and “advanced melanoma” as search terms was performed for possible clinical trials. According to the hazard ratio and the 95% confidence interval (CI) for progression-free survival (PFS), rates of objective response, complete response, partial response, rates of toxic effects, and the efficacy and safety of nivolumab were assessed. Using the software Review Manager (version5.3) a meta-analysis was performed.Results: There were four trials with 1,910 patients included. Based on the four trials, the pooled hazard ratio of PFS was 0.53 (95% CI, 0.43–0.66; P

Yun-Long Liu,1 Hao-Min Zhang,1 Hong-Ming Pan,2 Yu-Hang Bao,2 Jing Xue,2 Tian-Chang Wang,1 Xiao-Cheng Dong,1 Xiao-Ling Li,3 Hong-Guang Bao1 1Department of Chest Surgery, The Second Affiliated Hospital of Qiqihar Medical University, 2Basic Medical Science College, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China; 3Department of Anatomy, Basic Medical Science College, Qiqihar Medical University, Qiqihar, Heilongjiang, People’s Republic of China Objective: We conducted a systematic review and meta-analysis aiming to assess the relationship between apolipoprotein E (APOE) gene ε2/ε3/ε4 polymorphism and breast cancerrisk. Methods: Yun-Long Liu and Hao-Min Zhang independently completed literature retrieval and data collection, and statistical analyses were performed by Stata. Individual odds ratio (OR) and 95% confidence interval (CI) were pooled in a random-effects model using the DerSimonian–Laird method. Heterogeneity was evaluated by I2 statistic at a significance level of 50%. Publication bias was assessed by Egger’s test. Results: Eleven articles including 2,074 breast cancer patients and 2,372 controls were summarized. Using the most common allele ε3 as a reference, the ε2 (OR =0.87, 95% CI=0.72–1.05, P=0.154, I2=0.0%) and ε4 (OR =1.07, 95% CI =0.80–1.42, P=0.654, I2=71.8%) alleles were not found to be significantly associated with breast cancer risk in the overall analyses. Subgroup analyses revealed that the comparison of allele ε4 with ε3 was significant in Asians (OR =1.58, 95% CI =1.17–6.32, P=0.003, I2=12.1%) and in studies that used the restriction fragment length polymorphism (RFLP) genotyping method (OR =1.27; 95% CI =1.01–1.61, P=0.045, I2=34.3%), and was marginally significant in hospital-based studies (OR =1.33; 95% CI=0.98–1.79, P=0.065, I2=30.2%), without heterogeneity. Moreover, the presence of the ε2 allele was significantly associated with breast cancer in small studies (total sample size

Xiao-Ling Xu,1,* Li Dan,1,* Wei Chen,1 Shuang-Mei Zhu,2 Wei-Min Mao1 1Key Laboratory of Diagnosis and Treatment Technology for Thoracic Cancer, Zhejiang Cancer Research Institute, Zhejiang ProvinceCancer Hospital, Zhejiang Cancer Center, Hangzhou, 2Department of Radiotherapy, Lishui People’s Hospital, Lishui, People’s Republic of China *These authors contributed equally tothis work Background: Approximately 30% of all cases of nonsmall-cell lung cancer (NSCLC) are of a locally advanced (IIIA or IIIB) stage. However, surgical therapy for patients with stageIIIA (N2) NSCLC is associated with a disappointing 5-year survival rate. The optimal treatment for stage IIIA (N2) NSCLC is still in dispute. Methods: A literature search was performed in the PubMed, Embase, and MEDLINE databases (last search updated in March 2015), and a meta-analysis of the available data was conducted. Two authors independently extracted data from each eligible study. Results: A total of nine studies, including five randomized controlled trials and four retrospective studies, were enrolled in this meta-analysis. Significant homogeneity (χ2=49.62, P=0.000, I2=81.9%) was detected between four of the studies, including a total of 11,948 selected cases. Among the nine studies that investigated overall survival, the pooled hazard ratio (HR) was 0.70 (95% confidence interval (CI): 0.56–0.87; P=0.000). Subgroup analyses were performed according to the study design and the extent of resection. We observed a statistically significant better outcome after lobectomy (pooled HR: 0.52; 95% CI: 0.47–0.58; P=0.000) than after pneumonectomy (pooled HR: 0.82; 95% CI: 0.69–0.98; P=0.028). Unfortunately, there was no significant difference between the randomized controlled studies, as the pooled HR was 0.94 (95% CI: 0.81–1.09; P=0.440). Conclusion: Neoadjuvant chemoradiotherapy or chemotherapy followed by surgery (particularly lobectomy) is superior to following these therapies with definitive chemoradiation or radiotherapy, particularly in patients undergoing lobectomy. Keywords: nonsmall cell lung carcinoma, N2 stage, therapy, surgery, chemoradiotherapy, lobectomy&nbsp

Tao Lei,1,* Xiao-Ling Xu,1,* Wei Chen,2 Ya-Ping Xu,3 Wei-Min Mao2 1Department of Medical Oncology, Zhejiang Cancer Hospital, 2Key Laboratory of Diagnosis and Treatment Technology for Thoracic Cancer, Zhejiang Cancer Research Institute, 3Department of Radiotherapy, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, People’s Republic of China *These authors contributed equally tothis work Abstract: The use of additional radiotherapy for resected stage IIIA N2 non-small-cell lung cancer in the setting of standard adjuvant chemotherapy remains controversial. A comprehensive search (last search updated in March 2015) for relevant studies comparing patients with stage IIIA N2 non-small-cell lung cancer undergoing resection after treatment with adjuvant postoperative chemotherapy alone or adjuvant postoperative chemoradiotherapy (POCRT) was conducted. Hazard ratios (HRs) were extracted from these studies to give pooled estimates of the effects of POCRT on overall survival (OS) and disease-free survival (DFS). Six studies were included. The meta-analysis demonstrated that POCRT had a greater OS benefit than postoperative chemotherapy (HR =0.87, 95% confidence interval [CI]: 0.79–0.96, P=0.006). Unfortunately, there was no significant difference in DFS between the two groups: the combined HR for DFS was 0.91 (95% CI: 0.57–1.46, P=0.706). In a subgroup analysis of two randomized controlled trials (n=172 patients), adding radiation was of no benefit to either OS (HR =0.72, 95% CI: 0.49–1.06, P=0.094) or DFS (HR =1.45, 95% CI: 1.00–2.09, P=0.047). In summary, compared with postoperative chemotherapy, POCRT was beneficial to OS but not DFS in patients with stage IIIA N2 non-small-cell lung cancer. Keywords: NSCLC, N2-stage, therapy, surgery

Qun-Chao Hu,1–3,* Xin Mei,1,2,* Yan Feng,1,2 Jin-Li Ma,1,2 Zhao-Zhi Yang,1,2 Zhi-Min Shao,2,4 Xiao-Li Yu,1,2 Xiao-Mao Guo1,2 1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 3Department of Radiation Oncology, Suzhou Municipal Hospital, Suzhou, 4Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China *These authors contributed equally tothis work Background: Primary angiosarcoma of breast (PAOB) is a rare and highly aggressive malignancy. There is no general agreement on optimal treatments or prognostic factors for this orphan disease. The objective of this study was to investigate the clinicopathologic features and management experiences of PAOB.Methods: We performed a retrospective review of medical and pathologic records of 17 consecutive patients diagnosed with PAOB between January 2000 and February 2014 at FuDan University Shanghai Cancer Center. We evaluated the clinical characteristics, multimodality treatments, and associated clinical outcomes.Results: A total of 16 patients were included in this retrospective study (median age at PAOB presentation 33.5years, range: 19–56years). Palpable tumor with or without breast skin ecchymosis presented as the most common initial symptom. All patients underwent surgery with curative intent. Median disease-free survival and overall survival (OS) were 9months and 13.6months, respectively. One-year and 3-year disease-free survival rates were 43.8% and 6.3%, with OS rates of 93.8% and 78.1%, respectively. High histologic grade indicated poorer OS by univariate analysis (P=0.01). However, neither adjuvant chemotherapy nor radiotherapy contributed to clinical outcomes in our series.Conclusion: PAOB is considered as an infrequent breast neoplasm with aggressive characteristics. Histologic grade and early metastasis (within 12months after diagnosis) are associated with poor prognosis. Regardless of grade, additional benefit was not observed with adjuvant therapy. Keywords: primary angiosarcoma, breast neoplasm, histologic grade, adjuvant therapy

Yaqin Ling,1 Xiaoling Ling,2 Lu Fan,1 Yong Wang,3,* Qing Li1,* 1Department of Pathophysiology, College of Basic Medical, Lanzhou University, 2Medical Oncology, Lanzhou University First Hospital, 3Department of Gastroenterology, Lanzhou General Hospital of Lanzhou Military Command of PLA, Lanzhou, Gansu Province, People’s Republic of China *These authors contributed equally to this work Purpose: There are a growing number of reports suggesting that the aberrant expression and mutation of the thyroid hormone receptor β1 (TRβ1) gene is associated with the development of human neoplasms. However, its exact role in the pathogenesis of breast cancer remains elusive. In the present study, we analyzed the mRNA expression and mutations of the TRβ1 gene in the Chinese breast cancer population.Methods: The expression of TRβ1 mRNA was examined by real-time quantitative reverse transcription polymerase chain reaction, and mutations in the TRβ1 gene in the hotspot region that spans exons 7–10 were analyzed by polymerase chain reaction single-strand conformation polymorphism and automated DNA sequencing.Results: TRβ1 mRNA expression was significantly reduced in all 105 breast cancer specimens examined. A total of 20 samples showed truncating mutations within the exons 7–10 of the TRβ1 gene, where eight cases harbored a frame shift mutation (five cases of c.850insA in exon7 and three cases c.1028delA in exon 8), whereas missense mutations were observed in 12 breast cancer cases. The 20 cases with mutation in the TRβ1 gene showed a reduction in TRβ1 mRNA expression compared with that observed in matched normal tissues. The mutation was also correlated with menopausal stage and estrogen receptor status.Conclusion: The findings of the present study suggest that the aberrant expression and mutations of the TRβ1 gene are associated with the development of breast cancer and that the ­mutations in the TRβ1 gene partly serve as the underlying mechanism for TRβ1 inactivation in the Chinese breast cancer population. Keywords: breast cancer, mutation, thyroid hormone receptor β1, biomarker

Zhenhua Yang,1,* Xunlei Zhang,2,* Surong Fang,1 Yan Tan,1 Haijun Yan,1 Wei Gu,1 Jianhong Wang2 1Department of Pneumology, Nanjing First Hospital, Nanjing Medical University, Nanjing, 2Department of Medical Oncology, Nantong University Affiliated Tumor Hospital, Nantong, People’s Republic of China *These authors contributed equally tothis work Background: The association between telomerase reverse transcriptase (TERT) rs2736098 G>A and risk of lung cancer (LC) remains inconclusive. To explore the association more precisely, we performed a comprehensive search and conducted a meta-analysis on all eligible case–control studies involving 3,354 cases and 3,518 controls.Methods: The 95% confidence interval (95% CI) and the pooled odds ratio (OR) were calculated using a random or fixed effect model. Publication bias, heterogeneity, and sensitivity analysis were also explored.Results: All studies were case–control studies on LC in patients of Asian descent, consisting of one Korean study and five Chinese studies. Overall, the variant A allele of TERT rs2736098 G>A was found to significantly increase the risk of LC in all genetic models (GA vs GG: OR=1.13, 95% CI =1.02–1.25, P=0.017; AA vs GG: OR =1.78, 95% CI =1.53–2.07, PA polymorphism significantly increased the risk of LC in Asian populations. Keywords: genetic polymorphism, TERT, rs2736098 G>A, lung cancer, meta-analysis

Dan Cong,1 Mengzi He,2 Silin Chen,2 Xiaoli Liu,1 Xiaodong Liu,2 Hui Sun11Jilin Provincial Key Laboratory of Surgical Translational Medicine, Department of Thyroid and Parathyroid Surgery, People’s Republic of China–Japan Union Hospital, 2Key Laboratory of Radiobiology (Ministry of Health), School of Public Health, Jilin University, Changchun, Jilin, People’s Republic of ChinaAbstract: In the present study, we analyzed microRNA (miRNA) and gene expression profiles using 499 papillary thyroid carcinoma (PTC) samples and 58 normal thyroid tissues obtained from The Cancer Genome Atlas database. A pivotal regulatory network of 18 miRNA and 16 targets was identified. Upregulated miRNAs (miR-222, miR-221, miR-146b, miR-181a/b/d, miR-34a, and miR-424) and downregulated miRNAs (miR-9-1, miR-138, miR-363, miR-20b, miR-195, and miR-152) were identified. Among them, the upregulation of miR-424 and downregulation of miR-363, miR-195, and miR-152 were not previously identified. The genes CCNE2 (also known as cyclin E2), E2F1, RARA, CCND1 (cyclin D1), RUNX1, ITGA2, MET, CDKN1A (p21), and COL4A1 were overexpressed, and AXIN2, TRAF6, BCL2, RARB, HSP90B1, FGF7, and PDGFRA were downregulated. Among them, CCNE2, COL4A1, TRAF6, and HSP90B1 were newly identified. Based on receiver operating characteristic curves, several miRNAs (miR-222, miR-221, and miR-34a) and genes (CCND1 and MET) were ideal diagnostic indicators, with sensitivities and specificities greater than 90%. The combination of inversely expressed miRNAs and targets improved diagnostic accuracy. In a clinical feature analysis, several miRNAs (miR-34a, miR-424, miR-20b, and miR-152) and genes (CCNE2, COL4A1, TRAF6, and HSP90B1) were associated with aggressive clinical features, which have not previously been reported. Our study not only identified a pivotal miRNA regulatory network associated with PTC but also provided evidence that miRNAs and target genes can be used as biomarkers in PTC diagnosis and clinical risk evaluation.Keywords: thyroid carcinoma, miR-34a, miR-424, miR-20b, miR-152

Hai-Ling Hou, Mao-Bin Meng, Xiu-Li Chen, Lu-Jun Zhao, Li Zhu, Bai-Lin Zhang, Ping Wang Department of Radiation Oncology, CyberKnife Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China Objective: This retrospective study evaluated the role of adjuvant radiotherapy (AR) after surgery in patients with uterine sarcoma and analyzed the prognostic factors of local-regional failure-free survival (LRFFS) and overall survival (OS).Patients and methods: A study of a total of 182 patients with uterine sarcoma was conducted between June 1994 and October 2014. Adjuvant radiotherapy was defined as postoperative external beam radiation to the pelvis (30–50Gray/10–25 fractions at five fractions/week). The primary end point was LRFFS, and the secondary end point was OS. Kaplan–Meier curves were compared using the log-rank test. Cox regression analyses were used to determine prognosticators for LRFFS and OS.Results: The median follow-up time of all patients was 75 months, with a 5-year LRFFS of 62.1%. The 2-year and 5-year LRFFS rates were longer for those who received AR than for those who did not receive AR (83.4% vs 70.3%; 78% vs 55.3%; P=0.013). The 5-year OS of all patients was 56.2%, and no significant differences were observed in the 2-year and 5-year OS rates between these two groups (82.7% vs 71.4%; 64.1% vs 51.7%; P=0.067). Importantly, in patients with leiomyosarcoma, the 2-year and 5-year LRFFS and OS rates were longer for those who received AR than for those who did not receive AR (P=0.04 and P=0.02 for the 2-year and 5-year LRFFS, respectively).Conclusion: Patients with uterine sarcoma who were treated with AR after surgery demonstrated an improved LRFFS compared with those who were treated with surgery alone, especially those patients with leiomyosarcoma. Therefore, the role of personalized adjuvant radiation for patients with uterine sarcoma still requires further discussion. Keywords: uterine neoplasm, radiation, local-regional failure-free survival, overall survival