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Bo Zhang,1,* Jianchun Wu,1,* Peng Guo,1 Yi Wang,2 Zhihong Fang,1 Jianhui Tian,3 Yongchun Yu,4 Wenjing Teng,1 Yingbin Luo,1 Yan Li1 1Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, People’s Republic of China; 2Department of Pathology, Caner Hospital Affiliated Zhengzhou University, Henan, Zhengzhou 450008, People’s Republic of China; 3Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, People’s Republic of China; 4Institute for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Li; Yingbin LuoDepartment of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, 274 Middle Zhijiang Rode, Shanghai, People’s Republic of ChinaEmail yan.xiaotian@shutcm.edu.cn; dr.luo@qq.comBackground: Lung cancer is one of the most common causes of cancer-related deaths worldwide, metabolic disorders are also a problem that puzzles mankind. SREBP is overexpressed in non-small-cell lung cancer (NSCLC) and is also a key regulator of lipid synthesis. However, the mechanisms by which SREBP regulates the proliferation, migration and invasion in NSCLC remain unclear.Materials and Methods: CCK-8, colony formation assay, soft agar assay, scratch wound healing assay and transwell assays were performed to detect proliferation, and invasion in NSCLC cells, respectively. In addition, Western blotting assay, qPCR and immunofluorescence were applied to detect the expressions of SREBP1, SREBP2, ki-67, PCNA, Bax, bcl-2, E-cadherin, N-cadherin, Vimentin, PI3K, p-PI3k, AKT, p-AKT, mTOR, p-mTOR in NSCLC cells.Results: In this study, downregulation of SREBP significantly inhibited the proliferation, migration and invasion of A549 and H1299 cells. Moreover, the method of piecewise inhibition was adopted to prove that SREBP is a downstream molecule of the PI3K/Akt/mTOR signaling pathway.Conclusion: Our study indicated that downregulation of SREBP inhibited the growth in NSCLC cells via PI3K/AKT/mTOR signaling pathway. Thus, we suggested SREBP may serve as a potential target for the treatment of patients with NSCLC.Keywords: non-small-cell lung cancer, SREBP, proliferation, invasion, PI3K/AKT/mTOR

Yuanyuan Yu,1,* Yingbin Luo,1,* Zhihong Fang,1 Wenjing Teng,1 Yongchun Yu,2 Jianhui Tian,3 Peng Guo,1 Rongzhong Xu,1 Jianchun Wu,1 Yan Li1 1Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, People’s Republic of China; 2Institute for Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, People’s Republic of China; 3Institute of Traditional Chinese Medicine in Oncology, Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Li; Jianchun WuDepartment of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, No. 274, Zhijiang Road, Jing’an District, Shanghai 200071, People’s Republic of ChinaTel/Fax +86-21-63925588Email yan.xiaotian@shutcm.edu.cn; eq219@126.comObjective: Sanguinarine (SNG) is a benzophenanthridine alkaloid obtained from the roots of Sanguinaria canadensis and has an anticancer effect. The aim of this study was to explore the mechanism of SNG in inhibiting macrophages via regulating the exosomes derived from lung carcinoma cells to reduce metastasis and proliferation of lung carcinoma.Methods: Human lung cancer cells (A549 cells) were treated with 4μM of SNG. Exosomes of A549 cells were extracted from A549 cells supernatant, and THP-1 cells were cultured with exosomes. Then, the supernatant of THP-1 cells was collected and cultured with A549 cells. Cell proliferation was measured via plate clone formation and CCK-8 assays. Migration was assessed by using Transwell assay and scratch test. Cellular invasion was detected by Transwell assay. Apoptosis was determined using flow cytometry. Moreover, the protein expressions of GAPDH, P65 and P-P65 in THP-1 cells were measured by Western blot. Levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and chemotactic cytokines ligand 2 (CCL-2) extracted from THP-1 cells were determined by reverse transcription-polymerase chain reaction (RT-PCR).Results: Compared to the control group, exosomes could activate THP-1 cells, and the invasion, migration, and proliferation of A549 cells were consequently enhanced. Exosomes could increase the protein expression of p-p65 and the RNA expression levels of TNF-α, IL-6, and CCL-2 in THP-1 cells. Compared with the exosome group, SNG-treated exosomes inhibited THP-1 cells so that the invasion, proliferation, and migration of A549 cells were attenuated and apoptosis was promoted. In THP-1 cells, SNG-treated exosomes inhibited P-P65 expression and the RNA expression levels of TNF-α, IL-6, and CCL-2.Conclusion: Exosomes treated by SNG inhibited THP-1 cells so that the invasion, proliferation, and migration of A549 cells were inhibited, and the apoptosis was promoted. The mechanism is possibly associated with the inhibition of NF-κB pathway in THP-1 cells.Keywords: SNG, exosomes, THP-1 cells, NF-κB signaling pathway

Jingshen Tian,1,* Weinan Xue,2,* Huihui Yin,1 Nannan Zhang,1 Junde Zhou,3 Zhiping Long,1 Chengwei Wu,3 Zhengzi Liang,4 Kun Xie,1 Shuo Li,1 Liangliang Li,1 Zhen Wu,1 Volontovich Daria,1 Yashuang Zhao,1 Fan Wang,1 Maoqing Wang5 1Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 2Department of Colorectal Surgery, The Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 3Department of Colorectal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 4Department of Colorectal Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, People’s Republic of China; 5National Key Disciplines of Nutrition and Food Hygiene, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Fan WangDepartment of Epidemiology, School of Public Health, Harbin Medical University, 157 Baojian Road, Nangang District, Harbin, Heilongjiang Province, People’s Republic of ChinaTel + 0086-(0)451-87502960Fax + 0086-(0)451-87502885Email yifan.701@163.comMaoqing WangNational Key Disciplines of Nutrition and Food Hygiene, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of ChinaTel + 0086-(0)451-87502876Fax + 0086-(0)451-87502885Email wang_maoqing@126.comPurpose: Numerous metabolomics studies have been conducted to detect the metabolic mechanisms and biomarkers related to gastric cancer and colorectal cancer. Because of the common metabolic features between gastric cancer and colorectal cancer, a differential diagnosis is difficult. Here, we performed a systematic review and meta-analysis to identify differential metabolic biomarkers between these two types of cancers.Materials and Methods: PubMed, Embase, and ScienceDirect were searched to identify all metabolomics studies of gastric cancer and colorectal cancer published up to September 2018. Differential metabolites or altered pathways were extracted. The intersections and differences for these metabolites and pathways between gastric cancer and colorectal cancer were compared. Candidate biomarker sets for diagnosis were proposed from biofluid or feces by comparing them with tumor tissues.Results: Totally, 24 and 65 studies were included in gastric cancer and colorectal cancer, and 223 and 472 differential metabolites were extracted, respectively. Eight pathways were reproducibly enriched in blood, tissue and urine in gastric cancer, while, 11 pathways were reproducibly enriched in blood, urine, feces and tissue in colorectal cancer. Candidate metabolic biomarker sets in blood, urine, or feces for these two cancers were proposed. We found 27 pathways (categorized into eight classifications) common to both cancers, five pathways involving 35 metabolites enriched only in gastric cancer, and eight pathways involving 54 metabolites enriched only in colorectal cancer.Conclusion: The altered metabolic pathways showed signatures of abnormal metabolism in gastric cancer and colorectal cancer; the potential metabolic biomarkers proposed in this study have important implications for the prospective validation of gastric cancer and colorectal cancer.Keywords: metabolomics study, colorectal cancer, gastric cancer, metabolic biomarker

Jing Tian,1 Enqi Kong,2 Xiangyu Wang,3 Zhaoguang Xie,4 Cherry Yin-Yi Chang,5 Jim Jinn-Chyuan Sheu,6– 9 Quan Hao,1 Li Sun10,11 1Department of Gynecological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, People’s Republic of China; 2School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan 250200, People’s Republic of China; 3The Third School of Clinical Medicine, Southern Medical University, Guangzhou 510515, People’s Republic of China; 4Department of Maternity, Jinan Maternal and Child Health Hospital Affiliated to Shandong First Medical University, Jinan, 250001, People’s Republic of China; 5Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung 40447, Taiwan; 6Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan; 7Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; 8School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan; 9Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan; 10Department of Gynecological Oncology, Qingdao Central Hospital, The Second Affiliated Hospital of Medical College of Qingdao University, Qingdao, 266042, People’s Republic of China; 11Department of Gynecological Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, People’s Republic of ChinaCorrespondence: Li SunDepartment of Gynecological Oncology, Qingdao Central Hospital, The Second Affiliated Hospital of Medical College of Qingdao University, Qingdao 266042, People’s Republic of ChinaTel +86-532-84962590Email sunli766@163.comBackground: Remodeling and spacing factor-1 (RSF-1) is an identified tumor biomarker that is overexpressed in a variety of human cancers, but its effect on radiotherapy remains unclear. In this study, we aimed to explore the effect of RSF-1 siRNA on sensitizing cervical cancer cells to radiation and its underlying mechanism.Methods: The mRNA and protein expression of RSF-1 in tissue and cells were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell counting kit-8 (CCK-8) and colony formation assay were used to examine cell proliferation. Flow cytometry was used to analyzed the cell cycle and cell apoptosis. DNA damage was examined by the comet assay. ATM, ATR, CHK1, CHK2, H2AX, γH2AX and phosphorylated ATM, ATR, CHK1 and CHK2 were detected by Western blotting. γH2AX foci were demonstrated by immunofluorescence staining.Results: RSF-1 was upregulated in cervical cancer tissue and decreased after effective treatment. RSF-1 siRNA in combination with radiation suppressed cell viability, redistributed cell cycles and also induced cell apoptosis in HeLa and SiHa cell lines. Further, knockdown of RSF-1 induced DNA damage by attenuating DNA repair capability, thereby sensitizing cervical cancer cells to radiation.Conclusions: These data demonstrate that RSF-1 siRNA enhanced the sensitivity of radiotherapy, and targeting RSF-1 may be a promising approach for the development of novel radiosensitizing agents for the treatment of cervical cancer.Keywords: RSF-1, cervical cancer, radiotherapy, DNA damage

Fucun Gao, Juan Tian Breast Department, Linyi Central Hospital, Linyi, Shandong 276400, People’s Republic of ChinaCorrespondence: Juan TianBreast Department, Linyi Central Hospital, No. 17 Health Road, Yishui County, Linyi, Shandong 276400, People’s Republic of ChinaTel +86 539-2251731 Email tianjuanji@126.comBackground: Forkhead box K1 (FOXK1) is members of the FOX transcription factor family. Previous work has found out that FOXK1 promotes cell proliferation, migration and invasion in several cancers, such as gastric cancer, glioma cancer and lung cancer; however, the exact role of FOXK1 in breast cancer is still poorly known.Methods: Here, the association between FOXK1 expression and the clinicopathological characteristics of patients with breast cancer was identified. To further decipher the functional roles of FOXK1, it was overexpressed or knocked down in MCF-7, MDA-MB-231 and MCF-10A cells. Cell Counting Kit-8, colony formation and cell cycle assays were performed to examine the proliferation of breast cancer cells. Moreover, wound-healing and Transwell invasion analyses were carried out to explore the effect of FOXK1 on breast cancer cell migration and invasion.Results: Our findings discovered that FOXK1 promotes cell proliferation, migration and invasion in breast cancer. In addition, consistent with the previous report, FOXK1 also facilitates EMT in breast cancer. TargetScan was used to predict up-stream of FOXK1, indicating that miR-365-3p could regulate FOXK1 expression in breast cancer.Conclusion: The findings of the present study demonstrated that miR-365-3p-FOXK1 axis plays a key role in breast cancer.Keywords: FOXK1, EMT, miR-365-3p, migration, breast cancer

Xue-wu Wu,1,* Yang Zhang,2,* Yu-feng Li,1 Ye Li,1 Xiang-xiang Zhang,1 Wei Wang,1 Jun-hai Ma,1 Pei-long Wang,1 Zhi-chun Dong,1 Wei Shi,1 Jun-qiang Tian1 1Department of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Urological Diseases in Gansu Province, Gansu Nephro-Urological Clinical Center, Lanzhou 730000, People’s Republic of China; 2Department of Ultrasound in Medicine, Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai Institute of Ultrasound in Medicine, Shanghai 200233, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jun-qiang TianDepartment of Urology, The Second Hospital of Lanzhou University, Cuiyingmen 82, Chengguan District, Lanzhou 730030, People’s Republic of ChinaEmail tjq007263@sina.comAbstract: This paper presents an extremely rare case of testicular metastasis arising from renal pelvis carcinoma. The testicle is a rare site of clinically detectable tumor metastasis, originating rarely from upper tract urothelial carcinoma (UTUC). There are only two cases concerning UTUC metastasis to the testis available in the literature. In this report, we presented a patient who developed serial testicle, lung, liver and retroperitoneal lymph node metastasis from primary urothelial carcinoma of the renal pelvis within one year after surgery and chemotherapy. In conclusion, for patients with a history of UTUC who present with testicular symptoms, clinicians should be highly alert for the possibility of malignant involvement at this site.Keywords: urothelial carcinoma, renal pelvis, testicular metastasis

Jing Tian,1,2,* He-Xi Sun,3,* Ying-Chun Li,4 Li Jiang,5 Shan-Ling Zhang,6 Quan Hao1,2 1Department of Gynecological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 2Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 3Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China; 4Department of Gynecology II, Cangzhou Central Hospital, Cangzhou, People’s Republic of China; 5Department of Gynecology and Obstetrics, First Hospital of Qinhuangdao, Qinhuangdao, People’s Republic of China; 6Comprehensive Surgery Department, Tianjin Taishan Cancer Hospital and International Personalized Cancer Center, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Quan HaoDepartment of Gynecological Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, No. 1 Huanhuxi Road, Hexi District, Tianjin 300060, People’s Republic of ChinaTel +86 130 1139 7857Email haoquandoctor1967@126.comPurpose: Increasing evidence suggests that lysyl oxidase-like 2 (LOXL2) contributes to tumor progression. However, the role of LOXL2 in cervical cancer still remains unclear.Patients and methods: We used the TCGA database to analyze the expression of LOXL2 in cervical cancer and its role on survival. The effects of LOXL2 on cervical cancer metastasis and EMT were verified by transwell and wound healing assay. Western blot assay was used to detect the effect of LOXL2 on EMT-related gene expression. In addition, we used animal experiments to observe the role of LOXL2 on tumor genesis and metastasis in cervical cancer.Results: Here we found that LOXL2 participates in epithelial–mesenchymal transition-related cervical cancer progression. LOXL2 ablation in cervical cancer cells inhibited cell metastatic ability, whereas LOXL2 overexpression promoted cell metastasis. In addition, more clinical data from TCGA revealed that LOXL2 is closely related to the prognosis and is highly expressed in highly malignant and metastatic cervical tumors.Conclusion: Taken together, our findings established a pathophysiologic role and new function for LOXL2 in cervical cancer metastasis.Keywords: cervical cancer, LOXL2, epithelial–mesenchymal transition, metastasis

Fubin Feng,1 Tingting Zhang,2 Fang Yin,3 Cun Liu,2 Jing Zhuang,1 Lingyu Qi,2 Xue Wang,4 Jia Li,5 Lu Wang,1 Jinhui Tian,6 Changgang Sun1,7 1Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, Shandong Province, China; 2College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China; 3Department of Pediatrics, Weifang People’s Hospital, Weifang, Shandong Province, China; 4Department of Medicine, Qingdao University, Qingdao, Shandong Province, China; 5Department of Oncology, Weifang Medical University, Weifang, Shandong Province, China; 6Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province, China; 7Department of Oncology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China Purpose: Numerous HER2-targeted therapy clinical trials have demonstrated efficacy and safety in the first-line treatment of metastatic breast cancer (MBC). However, the direct or indirect comparison of these drugs is unclear. This network meta-analysis can solve this issue to some extent. Materials and methods: PubMed, Embase, and the Cochrane Library were searched for Phase II/III randomized controlled trials (RCTs) on metastatic HER2-positive breast cancer for first-line treatment up to December 16, 2017. Paired meta-analyses were performed to compare the regimens directly with the TP (trastuzumab plus taxane) regimen. Bayesian network meta-analysis was used to synthesize available evidence of direct or indirect comparison. Results: The database search identified 1,935 articles, among which 13 articles (10 RCTs) were eligible for the analysis involving 5,177 patients treated with 11 different regimens. The progression-free survival (PFS) in the Bayesian network meta-analysis suggested that the PTP (pertuzumab and trastuzumab plus taxane) regimen had the highest probability to be the preferred treatment (surface under the cumulative ranking [SUCRA]: 0.967) followed by the TPC (carboplatin and trastuzumab plus taxane) regimen (SUCRA: 0.923). The PTP regimen (SUCRA: 0.926) was similarly preferred for overall survival (OS). For objective response rate (ORR), the PTC regimen might be the optimal treatment (SUCRA: 0.935), followed by the PTP regimen. Conclusion: Overall, PTP might be the optimal first-line treatment for HER-2-positive MBC to improve the PFS and OS. Meanwhile, TPC might be most effective treatment in terms of the ORR. Regarding safety, the two regimens showed acceptable grade 3 or greater hematologic toxicity and heart failure. Keywords: breast cancer, metastasis, HER2-positive, HER2-targeted agents, network meta-analysis, randomized controlled trial

Jiajun Tian,1 Xianfang Liu,2 Xiuxiu Liu,2 Peihang Jing,1 Na Sa,1 Haibo Wang,1,2 Wei Xu1,2 1Department of Otorhinolaryngology–Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China; 2Shandong Provincial Key Laboratory of Otology, Jinan 250022, Shandong, China Objective: Hypopharyngeal squamous cell carcinoma (HSCC) remains one of the most lethal malignancies in head and neck. Notch1 has been validated to play prominent roles in the occurrence and development of various types of cancer. The aim of this study was to explore the function and underlying mechanism of Notch1 in HSCC. Patients and methods: Seventy-one cancer tissue samples and adjacent noncancerous formalin-fixed paraffin embedded tissue specimens were analyzed by immunohistochemistry. As Notch1 is overexpressed in HSCC, we further questioned whether there was a relationship between Notch1 and the clinicopathological characteristics. After confirming the successful knockdown of Notch1 by siRNA, the migration and invasion after gene knockdown were investigated by Transwell chambers. We then tried to identify YBX1 and EGFR expression using real-time PCR (RT-PCR) and Western blot analyses. To further determine whether the downexpression of EGFR was caused by YBX1 and the overexpression of YBX1 was caused by gene amplification, the expression of EGFR was detected by RT-PCR and Western blot assays. Results: We found that the expression of Notch1 and EGFR in HSCC tissues was upregulated compared with those in the adjacent noncancerous tissues. Further clinicopathological characteristics analysis revealed that the expression of Notch1 was positively correlated with distant metastasis (P=0.003) and tumor differentiation (P=0.031). The high expression of Notch1 is an independent prognostic factor for a poor overall survival in patients with HSCC (P=0.015, χ2=10.403). Knocking down of Notch1 significantly inhibits the migration and invasion of FaDu cells in vitro. Mechanistic investigation reveals that Notch1 knockdown is found suppressing the expression of EGFR at transcriptional level. Interestingly, we further found that Notch1 knockdown also decreased the expression of YBX1, which is a transcription factor of EGFR. Moreover, the upregulation of YBX1 reverses the suppression of Notch1 on EGFR. Furthermore, forced overexpression of YBX1 induced the invasion of FaDu cells. Conclusion: Taken together, we found a positively cross-linked role of Notch1 signaling in the outcome of HSCC, providing a novel valuable prognostic marker and potential therapeutic target for the treatment of HSCC patients. Notch1 is a core signaling molecule for regulating migration and invasion via interplaying with EGFR in HSCC cells. Keywords: hypopharyngeal squamous cell carcinoma, metastasis, Notch1, EGFR

Lin Su, Junyan Tian, Jinsong Sun, Nuan Han, Lin Feng, Baohua Yu, Yuepeng Wang Department of Pediatric Surgery, Affiliated Hospital of Jining Medical University, Jining City 272029, Shandong Province, People’s Republic of China Background: The overexpression of sphingosine kinase 1 (SPHK1) is responsible for the progress of many cancers. However, the role of SPHK1 in the development and progression of neuroblastoma (NB) remain largely unknown. Here in this study, we explored whether silencing SPHK1 by lentivirus-mediated siRNA could be employed as a potential therapeutic target for NB.Materials and methods: Lentivirus was adopted to load SPHK1 siRNA. The results were obtained using RT-qPCR, Western blot, cell proliferation assay, transwell cell migration/invasion assays as well as in vivo xenograft tumor models in nude mice.Results: Our results demonstrated that SPHK1 mRNA was upregulated in SH-SY5Y and SK-N-SH cells as well as in human NB tissues. SPHK1 knockdown by siRNA resulted in impaired proliferation, increased apoptosis, as well as impaired migration and invasion of SH-SY5Y and SK-N-SH cells. In addition, the in vivo study suggested that SPHK1 knockdown significantly reduced the tumorigenesis of SH-SY5Y xenograft model. Furthermore, intratumorally administered lentivirus-SPHK1 siRNA could significantly inhibit tumor growth in an SH-SY5Y xenograft mice model. Intensive investigations on mechanism revealed that these effects were achieved through the deactivation of STAT3 pathways.Conclusion: These data suggest that SPHK1 inhibition via downregulation of STAT3 pathways by lentivirus-mediated siRNA knockdown can significantly suppress NB progression, which could be a promising target for future gene therapy of NB. Keywords: lentivirus, siRNA, SPHK1, STAT3, neuroblastoma

Tingting Zhang,1 Fubin Feng,2 Wenge Zhao,3 Jinhui Tian,4 Yan Yao,3 Chao Zhou,2 Shengjie Dong,5 Congcong Wang,6 Chuanxin Zang,1 Qingliang Lv,7 Changgang Sun2,8 1College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, WeiFang, China; 2Department of Oncology, Weifang Traditional Chinese Hospital, WeiFang, China; 3Department of Oncology, Clinical Medical Colleges, Weifang Medical University, WeiFang, China; 4Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; 5Department of the Joint and Bone Surgery, Yantaishan Hospital, Yantai, China; 6Department of Oncology, Zibo Maternal and Child Health Hospital, Zibo, China; 7Department of Radiology, Weifang people’s Hospital, WeiFang, China; 8Department of Oncology, Affiliated Hospital of Weifang Medical University, WeiFang, China Background: Endocrine therapy is the cornerstone treatment for patients with hormone receptor-positive advanced breast cancer. We aimed to assess the effectiveness of various first-line endocrine monotherapies or combinations to determine the optimal sequence in a network meta-analysis. Materials and methods: We searched PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) from inception up to November 21, 2017. We included only RCTs that assessed the effectiveness of the following treatments as a monotherapy or in combination as the first-line treatment: tamoxifen, anastrozole, letrozole, exemestane, fulvestrant, palbociclib, and ribociclib. The results were presented with pooled odds ratio or hazard ratio (HR), and 95% credible interval (CrI). The primary outcomes were objective response rate (ORR) and progression-free survival/time to progression. Results: A total of 16 eligible articles (14 RCTs) involving 6,602 patients treated with 10 different first-line endocrine therapies were assessed in our network meta-analysis. Palbociclib plus letrozole was superior to anastrozole, letrozole, exemestane, fulvestrant 500 mg, and anastrozole plus fulvestrant (loading dose) (HR=0.44, 95% CrI: 0.33–0.58; HR=0.56, 95% CrI: 0.45–0.68; HR=0.45, 95% CrI: 0.32–0.61; HR=0.58, 95% CrI: 0.42–0.81; HR=0.50, 95% CrI: 0.37–0.68; respectively). However, there is no significant advantage compared with ribociclib plus letrozole (HR=1.00, 95% CrI: 0.72–1.39). In terms of ORR, ribociclib plus letrozole is more effective than palbociclib plus letrozole (odds ratio=1.30, 95% CrI: 0.83–2.02). Conclusion: Palbociclib plus letrozole and ribociclib plus letrozole might be the optimal first-line endocrine therapeutic choices for hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer due to a longer progression-free survival/time to progression and a more efficacious ORR. Keywords: first-line endocrine therapy, progression-free survival, objective response rate, advanced breast cancer, network meta-analysis, randomized controlled trial

Wenge Zhao,1,* Chuanxin Zang,2,* Tingting Zhang,2 Jia Li,1 Ruijuan Liu,3 Fubin Feng,3 Qingliang Lv,4 Liang Zheng,5 Jinhui Tian,6 Changgang Sun3 1Department of Oncology, College of Clinical Medicine, Weifang Medical University, Weifang, People’s Republic of China; 2College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China; 3Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, People’s Republic of China; 4Department of Interventional Radiology, Weifang People’s Hospital, Weifang, People’s Republic of China; 5Department of Cardiovascular Medicine, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 6Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, People’s Republic of China *These authors contributed equally to this work Background: The clinicopathological and prognostic values of the cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1) in ovarian cancer (OC) remain unknown. The aim of our meta-analysis was to evaluate ALDH1’s association with clinicopathological characteristics and its prognostic significance in patients with OC. Materials and methods: PubMed, Embase, and China Biology Medicine were systematically searched for eligible studies (up to October 2017). Pooled odds ratios (ORs) or hazard ratios (HRs) with 95% CIs were used to evaluate the association of ALDH1 expression with clinicopathological features and survival outcomes. Results: A total of 17 papers (18 studies) that included 2,531 patients with OC were analyzed. The results showed a significant association between increasing ALDH1 expression and International Federation of Gynecology and Obstetrics stage (OR 2.02, 95% CI 1.16–3.52), lymph node metastasis (OR 1.91, 95% CI 1.01–3.61), and distant metastasis (OR 5.43, 95% CI 1.44–20.42) in OC. However, no significant correlation was found between increasing ALDH1 expression and age (OR 0.90, 95% CI 0.25–3.28), tumor size (OR 1.13, 95% CI 0.75–1.71), tumor location (OR 0.69, 95% CI 0.22–2.13), ascite status (OR 0.74, 95% CI 0.49–1.11), resistance status (OR 0.70, 95% CI 0.14–3.51), or clinicopathological type (OR 1.14, 95% CI 0.69–1.86). Moreover, a high ALDH1 expression was significantly associated with overall survival (HR 1.56, 95% CI 1.21–2.02) but not with disease-free survival (HR 1.38, 95% CI 0.99–1.93). Conclusion: The meta-analysis indicates that increasing ALDH1 predicts poor prognosis and clinicopathological characteristics in OC. Future studies are needed to explore tailored treatments that directly target ALDH1 for the improvement of survival in OC. Keywords: ovarian cancer, ALDH1, prognosis, clinicopathological characteristics, meta-analysis

Nan Wu, Xiaowei Zhang, Jinlong Tian, Shuang Yu, Ying Qiao The Core Laboratory for Public Health Science and Practice, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China Abstract: Gem-associated protein 4 (GEMIN4) gene is a key regulator for the miRNA biogenesis processes. Recent studies have demonstrated that some single-nucleotide polymorphisms (SNPs) in GEMIN4 gene are associated with the risk of cancer, but the results are still controversial. Therefore, we conducted a meta-analysis to analyze the association between three major SNPs (rs2740348, rs7813, and rs3744741) in the GEMIN4 gene and the risk of cancer. Relevant articles were searched in Web of Science, PubMed, Cochrane Library, Chinese Wan Fang, and Chinese National Knowledge Infrastructure databases. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to quantitatively estimate the association. Publication bias and sensitivity analyses were undertaken to evaluate the stability of the results. Overall, the pooled results showed that rs2740348 involving 3,604 cases and 3,770 controls was significantly associated with increased cancer risk (GG vs GC/CC: OR =1.16, 95% CI =1.05–1.29, P=0.004) and rs7813 involving 4,729 cases and 4,562 controls was also related to increased cancer risk (TT vs TC/CC: OR =1.12, 95% CI =1.03–1.22, P=0.009). However, there was no significant association between rs3744741 and cancer risk under overall genetic models. In conclusion, our study has demonstrated that rs2740348 and rs7813 are associated with increased risk of cancer, and they may be new biomarkers for predicting cancer risk. Keywords: gem-associated protein 4, single-nucleotide polymorphism, cancer, meta-analysis

Bin Zhang,1,* Rui Li,2,3,* Chun-Xiao Chang,2,3 Yong Han,2,3 Sheng-Bin Shi,2,3 Jing Tian2,3 1Department of Medical Oncology, Shandong Ji Ning First People’s Hospital, 2Department of Medical Oncology, Shandong Cancer Hospital, Shandong University, Shandong 3Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, People’s Republic of China*These authors contributed equally tothis workAbstract: This study was conducted to evaluate the toxicity and efficacy of pemetrexed plus dendritic cells (DCs) when administered as third-line treatment for metastatic esophageal squamous cell carcinoma (ESCC). All patients in the study group had previously failed first-line treatment with 5-fluorouracil and cisplatin-based regimens, as well as second-line treatment with taxane-based regimens. A total of 31 patients were treated with pemetrexed (500mg/m2) plus DCs on day 1, every 3weeks. DCs were given for one cycle of 21days. Thirty patients were evaluated for their response. No patient had a complete response, three patients (10.0%) had a partial response, ten patients (33.3%) had stable disease, and 17 patients (56.7%) had progressive disease. The overall response rate was 10.0%. The median progression-free survival (PFS) time was 2.9months (95% CI, 2.7–3.2), and the median overall survival (OS) time was 7.1months (95% CI, 6.4–7.9). The median PFS and OS times among patients with high and low levels of miR-143 expression in their blood serum were significantly different: median PFS times =3.2months (95% CI, 2.9–3.4) and 2.7months (95% CI, 2.4–3.0), respectively (P=0.017), and median OS times =7.8months (95% CI, 6.8–8.9) and 6.3months (95% CI, 5.3–7.3), respectively (P=0.036). No patient experienced Grade 4 toxicity. Combined third-line treatment with pemetrexed and DCs was marginally effective and well tolerated in patients with advanced ESCC. Serum miR-143 levels are a potential biomarker for predicting the efficacy of pemetrexed plus DCs in the treatment of ESCC.Keywords: metastatic esophageal cancer, pemetrexed, dendritic cells, serum miR-143