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Background The National Surgical Adjuvant Breast and Bowel Project (NSABP) B32 trial reported that the detection rate of sentinel lymph nodes by core needle biopsy (CNB) is higher than that by segmental resection. However, there are few reports regarding the detection rate of sentinel lymph nodes by vacuum-assisted breast biopsy (VABB). Therefore, we analyzed the impact of preoperative biopsy methods on the surgical modes of 3,966 patients with breast cancer in our center. Methods In total, 3,966 female breast cancer patients [clinical tumor node metastasis (TNM) stage I-III] were enrolled in this study. Preoperative pathological diagnosis methods included fine needle aspiration (FNA) biopsy, CNB, excision biopsy, and VABB. According to the time of diagnosis. The data were analysis by chi square test, variance analysis and the Kaplan-Meier time series in SPSS 22.0. Results There was a decrease in the number of patients that underwent excision biopsy (7.3% to 2.7%) and intraoperative freezing (89.4% to 28.9%) over time, while CNB exhibited an increasing trend (1.6% to 55.3%). The positive rates of VABB, CNB, excision biopsy, and FNA were 99.5%, 97.1%, 97.9%, and 82.2%, respectively, and the false negative rates were 0%, 1.8%, 0.34%, and 8.9%, respectively. The overall breast-conserving rate was 36.7%, while the breast-conserving rate for VABB was 57.1%. The axillary sentinel lymph node biopsy rate of cN0 patients was 48.3%, and the intraoperative frozen group (36.7%) and excision biopsy group (39.5%) were lower than the CNB (57.1%) and VABB (77.9%) groups. Until December 2019, there were 350 cases with tumor recurrence or metastasis. The methods of biopsy were not correlated to the cumulative survival time. Conclusions Changes to the diagnosis and treatment of breast cancer has a profound impact on the method of tumor biopsy. VABB biopsy offers advantages such as accurate diagnosis, a greater volume of tissue taken at one time, minimally invasive and repeatable, and does not affect the surgical approach and prognosis of patients. It will gradually become the primary method of preoperative pathological evaluation of breast cancer.

Tamoxifen resistance remains the major obstacle to the estrogen receptor positive breast cancer endocrine therapy. Placenta-specific 8 (PLAC8) has been implicated in epithelial-mesenchymal transition and tumorigenesis. However, the molecular mechanisms underlying PLAC8 function in the context of tamoxifen resistance are unclear. Curcumin has attracted considerable attention in the last decades. It is isolated from Curcuma longa and has beneficial effects in cancer therapy. We studied this property by using MCF-7 and tamoxifen-resistant breast cancer cells (MCF-7/TAM) cell lines. PLAC8 can regulate MCF-7/TAM cell drug sensitivity through the MAPK/ERK pathway and shows the potential effects of curcumin or as a possible druggable target against tamoxifen failure. Supplementary Information The online version contains supplementary material available at 10.1007/s00109-021-02047-5.

Purpose: FKBP4 is a member of the immunophilin protein family, which plays a role in immunoregulation and basic cellular processes involving protein folding and trafficking associated with HSP90. However, the relationship between abnormal expression of FKBP4 and clinical outcome in luminal A subtype breast cancer (LABC) patients remains to be elucidated. Methods: Oncomine, bc-GenExMiner and HPA database were used for data mining and analyzing FKBP4 and its co-expressed genes. GEPIA database was used for screening co-expressed genes of FKBP4. Results: For the first time, we found that higher FKBP4 expression correlated with LABC patients and worse survival. Moreover, the upregulated co-expressed genes of FKBP4 were assessed to be significantly correlated with worse survival in LABC, and might be involved in the biological role of FKBP4. Conclusion: The expression status of FKBP4 is a significant prognostic indicator and a potential drug target for LABC.

Chemoresistance is a daunting challenge to the prognosis of patients with breast cancer. Signal transducer and activator of transcription (STAT) 5a plays vital roles in the development of various cancers, but its function in breast cancer is controversial, and its role in chemoresistance in breast cancer remains unexplored. Here we identified STAT5a as a chemoresistance inducer that regulates the expression of ABCB1 in breast cancer and can be targeted by pimozide, an FDA-approved psychotropic drug. First, we found that STAT5a and ABCB1 were expressed at higher levels in doxorubicin-resistant cell lines and chemoresistant patients, and their expression was positively correlated. Then, we confirmed the essential roles of STAT5a and ABCB1 in doxorubicin resistance in breast cancer cells and the regulation of ABCB1 transcription by STAT5a. Subsequently, the efficacy of pimozide in inhibiting STAT5a and sensitizing doxorubicin-resistant breast cancer cells was tested. Finally, we verified the role of STAT5a in doxorubicin resistance in breast cancer and the efficacy of pimozide in reversing this resistance in vivo. Our study demonstrated the vital role of STAT5a in doxorubicin resistance in breast cancer. Targeting STAT5a might be a promising strategy for treating doxorubicin-resistant breast cancer. Moreover, repurposing pimozide for doxorubicin resensitization is attractive due to the safety profile of pimozide.

Autophagy is a conserved intracellular degradation system that plays a dual role in cell death; thus, therapies targeting autophagy in cancer are somewhat controversial. Ferroptosis is a new form of regulated cell death featured with the iron-dependent accumulation of lethal lipid ROS. This pathway is morphologically, biochemically and genetically distinct from other forms of cell death. Accumulating studies have revealed crosstalk between autophagy and ferroptosis at the molecular level. In this review, we summarize the mechanisms of ferroptosis and autophagy, and more importantly, their roles in the drug resistance of cancer. Numerous connections between ferroptosis and autophagy have been revealed, and a strong causal relationship exists wherein one process controls the other and can be utilized as potential therapeutic targets for cancer. The elucidation of when and how to modulate their crosstalk using therapeutic strategies depends on an understanding of the fine-tuned switch between ferroptosis and autophagy, and approaches designed to manipulate the intensity of autophagy might be the key.

Background Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxidation and is involved in various pathophysiological conditions, including cancer. Targeting ferroptosis is considered to be a novel anti-cancer strategy. The identification of FDA-approved drugs as ferroptosis inducers is proposed to be a new promising approach for cancer treatment. Despite a growing body of evidence indicating the potential efficacy of the anti-diabetic metformin as an anti-cancer agent, the exact mechanism underlying this efficacy has not yet been fully elucidated. Methods The UFMylation of SLC7A11 is detected by immunoprecipitation and the expression of UFM1 and SLC7A11 in tumor tissues was detected by immunohistochemical staining. The level of ferroptosis is determined by the level of free iron, total/lipid Ros and GSH in the cells and the morphological changes of mitochondria are observed by transmission electron microscope. The mechanism in vivo was verified by in situ implantation tumor model in nude mice. Results Metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, we demonstrate that metformin increases the intracellular Fe2+ and lipid ROS levels. Specifically, metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system xc− inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells. Conclusions This study is the first to demonstrate that the ability of metformin to induce ferroptosis may be a novel mechanism underlying its anti-cancer effect. In addition, we identified SLC7A11 as a new UFMylation substrate and found that targeting the UFM1/SLC7A11 pathway could be a promising cancer treatment strategy.

Ferroptosis is a recently discovered distinct type of regulated cell death caused by the accumulation of lipid-based ROS. Metabolism and expression of specific genes affect the occurrence of ferroptosis, making it a promising therapeutic target to manage cancer. Here, we describe the current status of ferroptosis studies in breast cancer and trace the key regulators of ferroptosis back to previous studies. We also compare ferroptosis to common regulated cell death patterns and discuss the sensitivity to ferroptosis in different subtypes of breast cancer. We propose that viewing ferroptosis-related studies from a historical angle will accelerate the development of ferroptosis-based biomarkers and therapeutic strategies in breast cancer.

Mastoscopic axillary lymph node dissection (MALND) is a currently used and safe surgical treatment option for breast cancer. However, the extensive application of MALND is still debatable because of the use of conventional axillary lymph node dissection (CALND). Therefore, in the current study, we aimed to compare the efficacy and safety of MALND and CALND for obtaining evidence-based conclusions about the short-term and long-term outcomes of MALND for patients with breast cancer. PubMed, Web of Science, Cochrane Library, and CNKI were comprehensively searched for articles published between January 1998 and January 2019. Then Newcastle-Ottawa scale was used for quality assessment. The Review Manager software version 5.0 was utilized for generating forest maps and funnel plots. Twelve studies including 2157 patients were selected for the meta-analysis. There were no significant differences in the number of lymph node dissections, tumor recurrence rate, axillary drainage, postoperative hospitalization time, and tumor size between the MALND and CALND groups ( P > .05). In the MALND group, the surgery time was longer, while the incidence of intraoperative bleeding was lesser and the duration of drainage was shorter than those in the CALND group ( P < .01). The complications in the MALND group were also fewer than those in the CALND group ( P < .05). The results of the current study showed that MALND is reliable and feasible for breast cancer owing to the lesser incidence of intraoperative bleeding, shorter drainage duration, and lower incidence of complications compared to CALND.

Background Adriamycin (ADM) is currently one of the most effective chemotherapeutic agents in breast cancer treatment. However, growing resistance to ADM can lead to treatment failure and poor outcome. The underlying molecular mechanisms in ADM resistance in breast cancer remains unclear. PLAC8 is reported as a novel highly-conserved protein and functions as an oncogene or tumor suppressor in various tumors. Methods Here, we analyzed the expression profile of PLAC8 in breast cancer tissues and breast cancer cell lines, and explored the correlation of PLAC8 expression levels with patients’ outcomes and ADM response. One ADM resistant MCF-7 breast cancer cell (MCF-7/ADM) and its parental cell was used as in vitro models to identify the underlying mechanism of PLAC8 and ADM resistance. Breast cancer cells were transfected with PLAC8 knockdown and overexpression vectors, and MTT and colony formation assays were performed to test the cell response to ADM. Then, we tested the effect of PLAC8 on autophagy pathway by flow cytometry and immunofluorescence analysis, and the change of main autophagy-correlated factors expressions: LC3 and p62. Next, combining treatment of autophagy inhibitor/inducer and PLAC8 downregulation/upregulation revealed the participation of PLAC8 in autophagy pathway to synergistically regulate ADM resistance in breast cancer. Results Here, higher PLAC8 expression was correlated with poorer outcome and aggressive phenotype in breast cancer, and breast cancer patients with higher PLAC8 expression showed potential ADM resistance. PLAC8 expression level was also significantly elevated in ADM resistant MCF-7 breast cancer cells (MCF-7/ADM), compared to parental MCF-7 cells. In vitro experiments further confirmed that PLAC8 inhibition by siRNA or enforced overexpression by infecting pcDNA3.1(C)-PLAC8 plasmid correspondingly decreased or increased the ADM resistance. Subsequently, we demonstrated that ectopic PLAC8 expression in MCF-7/ADM cell blocked the accumulation of the autophagy-associated protein LC3II, and resulted in cellular accumulation of p62. Rapamycin-triggered autophagy significantly increased cell response to ADM, while the autophagy inhibitor 3-MA enhanced ADM resistance. Actually, 3-MA and PLAC8 could synergistically enhance ADM resistance via blocking the autophagy process. Additionally, the downregulation of p62 by siRNA attenuated the activation of autophagy and PLAC8 expression in breast cancer cells. Conclusion Our findings suggest that PLAC8, through participation of p62, inhibits autophagy and consequently results in ADM resistance in breast cancer. PLAC8/p62/autophagy pathway may act as novel therapeutic targets in breast cancer treatment and has potential clinical application in overcoming ADM resistance.

Long non‑coding RNA (lncRNA) H19 and Lin28 protein have been shown to participate in various pathophysiological processes, including cellular proliferation, autophagy and epithelial‑mesenchymal transition (EMT). A number of studies have investigated lncRNAs, microRNAs and mRNAs, and their roles in the initiation and progression of cancer, in doing so identifying competitive endogenous RNA (ceRNA) networks, including the H19/let‑7/Lin28 network. However, whether the H19/let‑7/Lin28 ceRNA network is involved in autophagy and EMT in breast cancer (BC) remains unclear. The present study demonstrated that the H19/let‑7/Lin28 loop was required for the downregulation of autophagy in BC cells via western blot analysis, reverse transcription‑quantitative PCR and autophagy flux monitoring. Using wound healing, migration and invasion assays, and morphological assays, the H19/let‑7/Lin28 loop was revealed to promote EMT in BC cells. Moreover, the H19/let‑7/Lin28 network was found to contribute to autophagy by inhibiting EMT in BC cells. To the best of our knowledge, the present study is the first to suggest the important roles of the H19/let‑7/Lin28 ceRNA network in BC autophagy and EMT, thus providing insight for the use of these molecules as prognostic biomarkers and therapeutic targets in BC metastasis.

Tamoxifen resistance represents a daunting challenge to the successful treatment for breast cancer. Krüppel-like factor 4 has critical roles in the development and progression of breast cancer, but its expression, function and regulation in the efficacy of TAM therapy in breast cancer have yet to be investigated. Here, we examined the clinical significance and biologic effects of KLF4 in breast cancer. Firstly, higher expression of KLF4 correlated with increased TAM sensitivity in breast cancer cells, and analysis of GEO datasets indicated that KLF4 expression was positively correlated with ERα and enhanced expression of KLF4 sensitized breast cancer patients to endocrine therapy. Knockdown of KLF4 in MCF-7 and BCAP37 cells led to increased TAM resistance, while ectopic KLF4 expression promoted the responsiveness to TAM in T47D and TAM-resistant MCF-7/TAM cells. Secondly, ectopic KLF4 overexpression suppressed MCF-7/TAM cell growth, invasion and migration. Moreover, KLF4 expression was down-regulated in breast cancer tumor tissues and high expression of KLF4 was associated with favorable outcomes. Mechanistically, KLF4 may enhance the responsiveness of breast cancer cells to TAM through suppressing mitogen-activated protein kinase (MAPK) signaling pathway. We found that ERK and p38 were more activated in MCF-7/TAM compared with MCF-7, and treatment with MAPK-specific inhibitors significantly suppressed cell viability. Knockdown of KLF4 activated ERK and p38 and drove MCF-7 cells to become resistant to TAM. Conversely, overexpression of KLF4 in MCF-7/TAM cells suppressed ERK and p38 signaling and resulted in increased sensitivity to TAM. Therefore, our findings suggested that KLF4 contributed to TAM sensitivity in breast cancer via phosphorylation modification of ERK and p38 signaling. Collectively, this study highlighted the significance of KLF4/MAPK signal interaction in regulating TAM resistance of breast cancer, and suggested that targeting KLF4/MAPK signaling may be a potential therapeutic strategy for breast cancer treatment, especially for the TAM-resistant patients.

Cervical cancer is the third most common cancer in women worldwide. Human papillomavirus (HPV) has been identified as an etiological factor for cervical cancer. Data on the prevalence and subtype distribution of HPV infection in Jiangxi Province are incomplete. In this study, we investigated HPV subtype distribution and prevalence in Jiangxi Province between August 1, 2010, and December 31, 2015. A total of 71,435 individuals ranging in age from 16 to 77 years were recruited. Cervicovaginal swabs were collected from each participant, and HPV screening was performed. Our results showed that the HPV prevalence was 22.49% in Jiangxi Province. Overall, 14.99% of individuals were positive for a single HPV type, and 7.49% were positive for multiple types. The most frequently detected low-risk genotypes were HPV-6, and high-risk genotypes were HPV-16, -18, -33, -52, and -58. The prevalence and type distribution of HPV infection exhibits regional and age differences; Yingtan had the highest incidence for high-risk HPV infection (32.00%), and peaks in the frequencies of HPV infections were seen for patients under 20 and over 60 years of age. In conclusion, we present data showing that the HPV prevalence varies significantly with age and regions in Jiangxi Province. These results can serve as valuable reference to guide Jiangxi cervical cancer screening and HPV vaccination programs. Keywords: Human papillomavirus, Jiangxi Province, Subtypes, Age

Matrix metalloproteinase-1 (MMP1) is a member of the matrix metalloproteinases family, and its aberrant expression is implicated in tumor invasion and metastasis. However, the relationship between MMP1 abnormal expression and clinical outcome in breast cancer patients remains to be elucidated. To address this issue, we conducted immunohistochemistry in breast cancer and adjacent normal tissues, and mined the transcriptional and survival data of MMP1 in breast cancer patients through Oncomine, Kaplan-Meier Plotter, bc-GenExMiner, COSMIC and cBioPortal databases. First, we found that both protein and mRNA levels of MMP1 expression were significantly higher in breast cancer tissues. Second, high MMP1 mRNA expression correlated with worse overall survival among grade II (HR = 1.75; p = 0.011), nodal-negative (HR = 2.00; p = 0.00028), ER-positive (HR = 1.61; p = 0.00027) and HER2-negative (HR = 3.17; p = 0.029) patients with breast cancer by using Kaplan-Meier plotter database. Third, the overexpression of MMP1 was associated with unfavorable survival results including overall survival (HR = 1.6; p = 1.6e-05), relapse free survival (HR = 1.78; p < 1e-16) and distant metastasis free survival (HR = 1.65; p = 5.3e-05) in patients with breast cancer. Taken together, the expression status of MMP1 is a significant prognostic indicator and a potential drug target for breast cancer.

// Ji Wang 1, 2, * , Chenyang Ye 3, * , Cong Chen 1, 2 , Hanchu Xiong 1, 2 , Binbin Xie 1, 2 , Jichun Zhou 1, 2 , Yongxia Chen 1, 2 , Shu Zheng 3, 4 , Linbo Wang 1, 2 1 Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310016, China 2 Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, 310016, China 3 Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China 4 Reseach Center for Air Pollution and Health, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China * These authors contributed equally to this work Correspondence to: Linbo Wang, email: linbo.wang@aliyun.com Shu Zheng, email: zhengshu@zju.edu.cn Keywords: GLUT1, solid tumors, prognosis, overall survival, disease-free survival Received: November 17, 2016 Accepted: January 26, 2017 Published: February 07, 2017 ABSTRACT Glucose transporter 1 (GLUT1), the uniporter protein encoded by the SLC2A1 gene, is a key rate-limiting factor in the transport of glucose in cancer cells, and frequently expressed in a significant proportion of human cancers. Numerous studies have reported paradoxical evidence of the relationship between GLUT1 expression and prognosis in solid human tumors. To address this discrepancy, we conducted a thorough search of Pubmed and Web of Science for studies evaluating the expression of GLUT1 and overall survival (OS) and disease-free survival (DFS) in patients with solid cancer from 1993 to April 2016. Data from published researches were extracted and computed into odds ratio (OR). A total of 26 studies including 2948 patients met our search criteria and were evaluated. Overexpression of GLUT1 was found to significantly correlate with poor 3-year OS (OR: 2.86; 95% CI, 1.90–4.32, P < 0.00001) and 5-year OS (OR: 2.52; 95% CI, 1.75–3.61, P < 0.00001) of solid tumors. Similar results were observed when analysis of DFS was performed. Subgroup analysis revealed that elevated GLUT1 expression was associated with worse prognosis of oral squamous cell carcinoma and breast cancer. Taken together, overexpression of GLUT1 is correlated with poor survival in most solid tumors, suggesting that the expression status of GLUT1 is a vital prognostic indicator and promising therapeutic target in solid tumors.

// Qinchuan Wang 1 , Xiang Shu 4 , Yong Dong 2 , Jichun Zhou 1 , Rongyue Teng 1 , Jianguo Shen 1 , Yongxia Chen 1 , Mingjun Dong 1 , Wenjun Zhang 3 , Yasheng Huang 5 , Shuduo Xie 1 , Qun Wei 1 , Wenhe Zhao 1 , Wenjun Chen 1 , Xiaoming Yuan 1 , Xu Qi 1 and Linbo Wang 1 1 Department of Surgical Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China 2 Department of Oncology, Affiliated Sir Runrun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China 3 Zhejiang Academy of Medical Science, Zhejiang University School of Medicine, Hangzhou, China 4 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA 5 Department of Unrology, Hangzhou Chinese Medicine Hospital, Hangzhou, China Correspondence to: Linbo Wang, email: wanglinbo@medmail.com.cn Keywords: gamma-glutamyl transpeptidase, gastric cancer, prognosis, serum, chemotherapy Received: November 01, 2016 Accepted: January 24, 2017 Published: February 22, 2017 ABSTRACT Background: Gastric Cancer is one of the most lethal malignancies worldwide. Gamma-glutamyl transpeptidase (GGT) is an enzyme mainly involved in cellular glutathione homeostasis. We aim to explore the clinical value of GGT in gastric cancer. Results: Among 322 patients enrolled, 65/82 patients were determined as GGT positive in serum/tumor, respectively. High tumor GGT expression is significantly associated with lymph node metastasis, histological subtype, and Her2 expression. Kaplan-Meier curve shows that high tumor GGT patients have shorter overall survival ( P log-rank =0.001) and progress-free survival ( P log-rank =0.001). Patients with both high tumor and serum GGT have the poorest prognosis. The multivariable Cox analysis shows that the hazard ratio of overall survival for high tumor GGT is 1.69 (95% CI 1.19-2.37). High serum GGT is a poor prognostic factor in adjuvant chemotherapy hazard ratio=2.18, 95%CI (1.15-4.47). These findings were further validated in six online datasets. Gene Sets Enrichment Analysis showed that GGT promotes cancer progression through EMT, KRAS, SRC and PKCA pathways. Methods: Tumor GGT and serum GGT levels were evaluated with immuno-histochemistry staining and enzymatic assay, respectively. Kaplan-Meier curve and Cox regression model were used to test the association between GGT and gastric cancer prognosis. Independent datasets from Gene Expression Omnibus and Gene Sets Enrichment Analysis were applied to validate the findings and explore the potential mechanisms. Conclusion: Both tumor GGT and serum GGT are poor prognostic factors in gastric cancer. Patients with high tumor and serum GGT levels require more intense treatment and follow-up.

// Hanchu Xiong 1,2,* , Wenhe Zhao 1,2,* , Ji Wang 1,2,* , Benjamin J. Seifer 3 , Chenyang Ye 4 , Yongxia Chen 1,2 , Yunlu Jia 1,2 , Cong Chen 1,2 , Jianguo Shen 1,2 , Linbo Wang 1,2 , Xinbing Sui 2,5 and Jichun Zhou 1,2 1 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China 2 Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China 3 USF Health Morsani College of Medicine, Tampa, FL, USA 4 Cancer Institute (Key Laboratory of Cancer Prevention & Intervention, National Ministry of Education), Second Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, China 5 Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China * These authors have contributed equally to this work Correspondence to: Linbo Wang, email: // Xinbing Sui, email: // Jichun Zhou, email: // Keywords : Lin28; Let-7; breast cancer; metastasis; drug resistance Received : November 09, 2016 Accepted : January 11, 2017 Published : January 29, 2017 Abstract The RNA binding protein Lin28 is best known for the critical role in cell development, recent researches also have implied its oncogenic function in various human cancers, including breast cancer. Specifically, aberrant Lin28 participates in multiple pathological processes, such as proliferation, metastasis, radiotherapy and chemotherapy resistance, metabolism, immunity and inflammation as well as stemness. In this review, we summarize the let-7-dependent and let-7-independent mechanism regulated by Lin28, focusing on its relation with tumor hallmarks in breast cancer, and subsequently discuss our present knowledge of Lin28 to develop a molecular-based therapeutic strategy against breast cancer.

Background Tamoxifen resistance remains a clinical challenge for hormone receptor-positive breast cancer. Recently, dysregulations in autophagy have been suggested as a potential mechanism for tamoxifen resistance. Although the long noncoding RNA H19 is involved in various stages of tumorigenesis, its role in tamoxifen resistance remains unknown. Here, we assessed the role of H19 in the development of tamoxifen-resistant breast cancer. Methods Quantitative real-time PCR analyzed expression of H19 in tamoxifen-resistant breast cancer tissues. Knockdown of H19 was used to assess the sensitivity to tamoxifen in vitro and in vivo. Both knockdown and overexpression of H19 were used to analyze the status of autophagy. Real-time quantitative methylation-specific polymerase chain reaction, chromatin immunoprecipitation, immunofluorescence, and Western blot were used to explore the tamoxifen resistance mechanism of H19. Results In this study, we observed that the expression of H19 was substantially upregulated in tamoxifen-resistant breast cancer cell line and tumor tissues, and knockdown of H19 enhanced the sensitivity to tamoxifen both in vitro and in vivo. Furthermore, knockdown of H19 significantly inhibited autophagy in MCF7 tamoxifen-resistant (MCF7/TAMR) cells. Conversely, overexpression of H19 promoted autophagy. Interestingly, overexpression of H19 in MCF7 tamoxifen-sensitive cells could recapitulate tamoxifen resistance. Moreover, an increase in methylation in the promoter region of Beclin1 was observed in MCF7/TAMR-shH19 cells. In the double knockdown groups, both shH19+shSAHH and shH19+shDNMT3B rescued the Beclin1 promoter region methylation levels and reactivated autophagy functions. A chromatin immunoprecipitation assay further validated that DNMT3B binds to the Beclin1 promoter region and the knockdown of H19 increases this binding. Conclusions Our findings demonstrate that H19 induces autophagy activation via the H19/SAHH/DNMT3B axis, which could contribute to tamoxifen resistance in breast cancer. Electronic supplementary material The online version of this article (10.1186/s13045-019-0747-0) contains supplementary material, which is available to authorized users.

Adjuvant chemotherapy(AC) plays a substantial role in the treatment of locally advanced gastric cancer (LAGC), but the response remains poor. We aims to improve its efficacy in LAGC. Therefore, we identified the expression of eight genes closely associated with platinum and fluorouracil metabolism (RRM1, RRM2, RRM2B, POLH, DUT, TYMS, TYMP, MKI67) in the discovery cohort (N=291). And we further validated the findings in TCGA (N=279) and GEO. Overall survival (OS) was used as an endpoint. Univariate and multivariate Cox models were applied. A multivariate Cox regression model was simulated to predict the OS. In the discovery cohort, the univariate Cox model indicated that AC was beneficial to high-RRM1, high-DUT, low-RRM2, low-RRM2B, low-POLH, low-KI67, low-TYMS or low-TYMP patients, the results were validated in the TCGA cohort. The multivariate Cox model showed consistent results. Cumulative analysis indicated that patients with low C-Score respond poorly to the AC, whereas the high and medium C-Score patients significantly benefit from AC. A risk model based on the above variables successfully predicted the OS in both cohorts (AUC=0.75 and 0.67, respectively). Further validation in a panel of gastric cancer cell (GC) lines (N=37) indicated that C-Score is significantly associated with IC50 value to fluorouracil. Mutation profiling showed that C-Score was associated with the number and types of mutations. In conclusion, we successfully simulated a predictive signature for the efficacy of AC in LAGC patients and further explored the potential mechanisms. Our findings could promote precision medicine and improve the prognosis of LAGC patients., Highlights • We successfully simulated a predictive signature for the efficacy of chemotherapy in LAGC patients and a GC cell line panel. • We further explored the potential mechanisms that it may be associated with the number and type of mutations. • Our findings could promote precision medicine and improve the prognosis of LAGC patients.

Long non-coding RNAs (lncRNAs), which occupy nearly 98% of genome, have crucial roles in cancer development, including breast cancer. Breast cancer is a disease with high incidence. Despite of recent progress in understanding the molecular mechanisms and combined therapy strategies, the functions and mechanisms of lncRNAs in breast cancer remains unclear. This review presents the currently basic knowledge and research approaches of lncRNAs. We also highlight the latest advances of seven classic lncRNAs and three novel lncRNAs in breast cancer, elucidating their mechanisms and possible therapeutic targets. Additionally, association between lncRNA and specific molecular subtype of breast cancer is reported. Lastly, we briefly delineate the potential roles of lncRNAs in clinical applications as biomarkers and treatment targets.

// Zhao Jing 1, 2, * , Weiqiang Fei 2, * , Jichun Zhou 3, * , Lumin Zhang 2 , Liuxi Chen 1 , Xiaomin Zhang 1 , Xiao Liang 4 , Jiansheng Xie 2 , Yong Fang 1, 2 , Xinbing Sui 1, 2 , Weidong Han 1, 2 , Hongming Pan 1, 2 1 Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 2 Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 3 Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China 4 Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China * These authors contributed equally to this work Correspondence to: Xinbing Sui, email: hzzju@aliyun.com Weidong Han, email: hanwd@126.com Hongming Pan, email: drpanhm@aliyun.com Keywords: salvianolic acid B, natural compound, autophagy, cell death, colorectal cancer Received: April 25, 2016 Accepted: August 13, 2016 Published: August 19, 2016 ABSTRACT Salvianolic Acid B (Sal B), an active compound extracted from the Chinese herb Salvia miltiorrhiza , is attracting more and more attention due to its biological activities, including antioxidant, anticoagulant and antitumor effects. However, autophagy induction in cancer cells by Sal B has never been recognized. In this study, we demonstrated that Sal B induced cell death and triggered autophagy in HCT116 and HT29 cells in a dose-dependent manner. Specific inhibition of autophagy by 3-MA or shRNA targeting Atg5 rescued Sal B-induced cell death in vitro and in vivo , suggesting that Sal B-induced autophagy may play a pro-death role and contribute to the cell death of colorectal cancer cell lines. Furthermore, AKT/mTOR signaling pathway was demonstrated to be a critical mediator in regulating Sal B-induced cell death. Overexpression of AKT by the transfection with AKT plasmid or pretreatment with insulin decreased Sal B-induced autophagy and cell death. Inversely, inhibition of AKT by LY294002 treatment markedly enhanced Sal B-induced autophagy and cell death. Taken together, our results demonstrate, for the first time, that Sal B is a novel autophagy inducer and exerts its antitumor activity as a single agent in colorectal cancer cells through the suppression of AKT/mTOR pathway.

Ji-Chun Zhou,1 Ju-Feng Guo,1,2 Rong-Yue Teng,1 Qin-Chuan Wang,1 Ji Wang,1 Qun Wei,1,3 Zi-Duo Li,1,4 Jian-Guo Shen,1 Lin-Bo Wang1,5 1Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 2Department of Surgical Oncology, Hangzhou First People’s Hospital, Hangzhou, People’s Republic of China; 3Department of International Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 4Dendritic Cell Biology and Therapeutic Group, ANZAC Research Institute, University of Sydney, Sydney, NSW, Australia; 5Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, People’s Republic of China Background: Although the correlation between metabolic abnormality and gastric cancer has been extensively investigated, the question of whether metabolic parameters might influence the efficacy of chemotherapy in locally advanced gastric cancer is still unanswered. In our present study, we investigated the relationship between serum fasting glucose, lipid levels, and histopathological response of neoadjuvant chemotherapy (NAC) in locally advanced gastric cancers. Patients and methods: A total of 128 patients were identified from a prospectively maintained database of patients with locally advanced gastric cancer who received NAC between July 2004 and December 2012. Histopathological response after NAC was analyzed according to Becker’s tumor-regression grade. Univariate analyses and multivariable regression analyses were performed to determine the correlation between tumor size, differentiation, fasting glucose, lipid levels, and tumor histopathological response after NAC. Results: Univariate analysis revealed that low-density lipoprotein level and total cholesterol, as well as tumor size and differentiation, correlated significantly with histopathological response. Low-density lipoprotein levels and tumor size were found to be independent predictors for histopathological response, according to multivariable regression analyses. Conclusion: In this observational, hypothesis-generating study, serum low-density lipoprotein measurement was found to be useful in predicting chemosensitivity to locally advanced gastric cancer patients undergoing NAC. Incorporation of serum low-density lipoprotein levels into individualized treatment protocols could be considered in clinical practice. Keywords: gastric cancer, neoadjuvant chemotherapy, low-density lipoprotein, histopathological response, predictive biomarker

Cong Chen,1,2 Shumin Huang,3 Aihua Huang,2,4 Yunlu Jia,1,2 Ji Wang,1,2 Zeqin Zhang,1,2 Misha Mao,1,2 Linbo Wang,1,2 Jichun Zhou1,2 1Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China; 3The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China; 4Department of Pathology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China Background: Ductal carcinoma in situ with microinvasion (DCISM) represents ~1% of all breast cancer cases. Risk factors for lymph node (LN) metastasis and appropriate adjuvant therapy for DCISM are still widely debated. Methods: We retrieved DCISM data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results registry database (1998–2013). Chi-squared tests and logistic regression models were applied to investigate the potential risks of LN metastasis. Univariate and multivariate Cox proportional hazards regressions were performed to estimate the prognostic factors of DCISM. Survival outcomes were estimated using the Kaplan–Meier method. A 1:1 propensity score matching was used to minimize potential bias. Results: Overall, 6,219 patients with DCISM met our inclusion criteria. Younger age and higher grade disease were identified as risk factors for LN metastasis. In the multivariable analysis, LN metastasis and chemotherapy were prognostic factors for worse overall survival and breast cancer-specific survival. Furthermore, propensity score matching and subgroup analysis showed that chemotherapy may not be effective for DCISM patients. Conclusion: Younger patients with high-grade disease tend to have LN involved in DCISM. Adjuvant chemotherapy might not be necessary for patients with DCISM. Keywords: SEER database, breast cancer, ductal carcinoma in situ with microinvasion, adjuvant chemotherapy, lymphatic metastasis

Cong Chen,1,2 Shumin Huang,3 Aihua Huang,1,2 Yunlu Jia,1,2 Ji Wang,1,2 Misha Mao,1,2 Jichun Zhou,1,2 Linbo Wang1,2 1Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, China; 3Department of Pediatric Health Care, The Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China Background: Despite the considerable experience gained thus far using endoscopic technologies, the role of total endoscopic thyroidectomy (ET) for papillary thyroid cancer (PTC) remains controversial. We conducted a systematic review and meta-analysis to investigate the safety and effectiveness of total ET compared with conventional open thyroidectomy (OT) in PTC. Methods: A systematic search was conducted using the PubMed, Embase and Cochrane Library electronic databases up to March 2018. The quality of included studies was evaluated using the Newcastle–Ottawa Scale. Review Manager software version 5.3 was used for the meta-analysis. Results: Twelve studies including 2,672 patients were ultimately included in the systematic review and meta-analysis. ET was associated with longer operative time (P

Accumulating evidence suggests that placenta-specific 8 (PLAC8) plays an important role in normal cellular process and human diseases, including multiple types of human tumors, and its role is highly relied upon in cellular and physiologic contexts. However, there are no reports on its expression profile and biological roles during lung cancer development. In the current study, both the clinical implications and biological effects of PLAC8 in lung cancer (LC) progression were investigated, and we identified and described the novel Krüppel-like factor 4 (KLF4)/PLAC8 regulatory pathway in cancer progression. Elevated PLAC8 levels were positively correlated with tumor size, histological grade, and tumor node metasis (TNM) stage, and LC patients with high PLAC8 expression suffered poor outcomes. In vitro and in vivo assays further revealed that endogenous PLAC8 promoted cell proliferation and tumor formation. We also found downregulated PLAC8 protein in several LC cell lines following the induction of KLF4, and immunohistochemistry analysis of LC tissues by microarray indicated a potential inverse correlation between PLAC8 and KLF4 expression. Luciferase reporter analysis and chromatin immunoprecipitation assays determined that KLF4 negatively regulated PLAC8 promoter activity via directly binding to the promoter region. Furthermore, the growth inhibition resulting from KLF4 overexpression was partially rescued by ectopic PLAC8 expression. Together, our data uncovered a previously unidentified role of PLAC8 as a central mediator in LC progression. PLAC8 was transcriptionally repressed by KLF4, and the novel KLF4/PLAC8 axis may act as a promising candidate target for LC diagnosis and therapy.

Lingmin Xie,1 Xiaolei Li,2 Qinchuan Wang,1 Jichun Zhou,1 Jun Shen,1 Lixi Luo,1 Yi Lu,1 Linbo Wang1 1Division of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, 2Division of Surgical Oncology, The First People’s Hospital of Wenling, Zhejiang, China Objectives: The aim of our study is to evaluate the effect of core needle biopsy (CNB) and subsequent neoadjuvant chemotherapy (NAC) on the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth hormone receptor 2 (HER2) and Ki67 in breast cancer, and the associated influencing factors.Materials and methods: In this retrospective cohort study, 143 patients with primary operable breast cancer who received NAC were included. ER, PR, HER2 and Ki67 statuses were compared between pretreatment and posttreatment residual samples. A control group of paired core and excision tumors from 123 patients who did not receive NAC within the same study period was also assessed. Data on patients’ clinicopathologic features were collected to identify associated influencing factors.Results: Ki67 value significantly increased in excision tumors compared with paired core samples in controls without presurgery treatment (P

Autophagy is a conserved catabolic process for the degradation and recycling of cytosolic components or organelles through a lysosome-dependent pathway. Autophagy can be induced in response to multiple stress conditions, such as nutrient deprivation, hypoxia, energy depletion, etc. As a result, autophagy can regulate many biological processes, including cell survival, metabolism, differentiation, senescence, and cell death. MicroRNAs (MiRNAs) are small noncoding molecules that regulate gene expression by silencing mRNA targets. MiRNA dysregulation exhibits great regulatory potential during organismal development, hematopoiesis, immunity, cell proliferation and death, and autophagy. Recently, increasing studies have linked MiRNAs to autophagic regulation during cancer initiation and development. Although the relationship between MiRNAs and autophagy is quite complicated and has not been well elucidated, MiRNAs may underlie key aspects of autophagy and cancer biology. Increasing evidence shows that MiRNAs play important roles as both oncogenic MiRNAs and tumor suppressive MiRNAs in cancer initiation and development. Thus, understanding the novel relationship between MiRNAs and autophagy may allow us to develop promising cancer biomarkers and therapeutic targets.

The contemporary surgery has reported the safety of laparoscopic surgery (LAP) for patients with gastrointestinal stromal tumors (GISTs). However, its use is still debated due to suspicion of the oncologic equivalence to open surgery (OPEN). We conducted a systematic review and meta-analysis of updated original articles to investigate the short- and long-term clinical outcomes of LAP compared with OPEN for GISTs.A systematic search was performed in PubMed, Embase, Web of Science, Cochrane Library and CNKI. Comparative studies of laparoscopic and open surgery for GISTs were published before November 2016. The Newcastle-Ottawa scale was utilized to conduct quality assessment. The Review Manager (RevMan) software version 5.0 was used for meta-analysis.Twenty-four studies involving 2140 patients were included for the meta-analysis. The meta-analysis results showed that, compared with OPEN, LAP indicated potentially favorable outcomes in terms of operative time (WMD, -30.71; 95% CI, -58.48 to -2.95; P = 0.03); intraoperative blood loss (WMD, -60.90; 95% CI, -91.53 to -30.28; P 0.0001); time to flatus (WMD, -1.10; 95% CI, -1.41 to -0.79; P 0.00001); time to oral intake (WMD, -1.25; 95% CI, -1.64 to -0.86; P 0.00001); length of hospital stay (WMD, -3.42; 95% CI, -4.37 to -2.46; P 0.00001); overall complications (OR, 0.38; 95% CI, 0.27 to 0.54; P 0.00001); and recurrence (OR, 0.45; 95% CI, 0.30 to 0.66; P 0.0001).Laparoscopic surgery is safe and feasible for the treatment of GISTs including less operative time and intraoperative blood loss, earlier postoperative recovery, shorter hospital stay, and lower rate of overall complications and recurrence.

The molecular mechanisms underlying the antineoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. Here we report that metformin induces genome-wide alterations in DNA methylation by modulating the activity of S-adenosylhomocysteine hydrolase (SAHH). Exposing cancer cells to metformin leads to hypermethylation of tumor-promoting pathway genes and concomitant inhibition of cell proliferation. Metformin acts by upregulating microRNA let-7 through AMPK activation, leading to degradation of H19 long noncoding RNA, which normally binds to and inactivates SAHH. H19 knockdown activates SAHH, enabling DNA methyltransferase 3B to methylate a subset of genes. This metformin-induced H19 repression and alteration of gene methylation are recapitulated in endometrial cancer tissue samples obtained from patients treated with antidiabetic doses of metformin. Our findings unveil a novel mechanism of action for the drug metformin with implications for the molecular basis of epigenetic dysregulation in cancer. This novel mechanism of action also may be occurring in normal cells.

// Jichun Zhou 1,2 , Jianguo Shen 1,2 , Benjamin J. Seifer 3 , Shaojie Jiang 4 , Ji Wang 1,2 , Hanchu Xiong 1,2 , Lingmin Xie 1,2 , Linbo Wang 1,2 and Xinbing Sui 2,5 1 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China 2 Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou, Zhejiang, China 3 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA 4 Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China 5 Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China Correspondence to: Linbo Wang, email: // Xinbing Sui, email: // Keywords : neoadjuvant chemotherapy, gastric cancer, predictive biomarker, histopathological response, chemosensitivity Received : December 13, 2015 Accepted : October 18, 2016 Published : October 27, 2016 Abstract Gastric cancer remains a major health burden worldwide. There is near-universal agreement that neoadjuvant chemotherapy (NAC) is a preferred management for locally advanced gastric cancer (LAGC). However, the optimal approach for an individual patient is still not clear and remains controversial, which could be at least partly explained by the lack of predictive tools. The ability to predict chemosensitivity from NAC in routine clinical practice is difficult and is an area of intense investigation, especially in the Precision-Medicine Era. Available consistent evidence suggests that a favorable tumor histopathological response to NAC may be a useful positive prognostic marker in gastric cancer. Hence, it is reasonable to speculate that making the histopathological response from NAC predictable will dramatically facility the NAC and improve patients’ outcome. This review provides an overview on the current status of predictive biomarkers for histopathological response from NAC in LAGC, including clinicopathological variables, imaging and molecular testing. Furthermore, limitations and future perspectives are also discussed.

International audience; The H19 lncRNA has been implicated in develop-ment and growth control and is associated with human genetic disorders and cancer. Acting as a molecular sponge, H19 inhibits microRNA (miRNA) let-7. Here we report that H19 is significantly de-creased in muscle of human subjects with type-2 di-abetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is re-capitulated in vitro where H19 depletion results in impaired insulin signaling and decreased glucose uptake. Furthermore, acute hyperinsulinemia down-regulates H19, a phenomenon that occurs through PI3K/AKT-dependent phosphorylation of the miRNA processing factor KSRP, which promotes biogen-esis of let-7 and its mediated H19 destabilization. Our results reveal a previously undescribed double-negative feedback loop between sponge lncRNA and target miRNA that contributes to glucose regulation in muscle cells.

ObjectivesWe aimed to investigate the prognostic value of RRM1 in GC patients.MethodsA total of assessable 389 GC patients with clinicopathological and survival information were enrolled from City of Hope (COH, n = 67) and Zhejiang University (ZJU, n = 322). RRM1 protein expression was determined by immunohistochemistry on FFPE tissue samples. Kaplan-Meier and Cox analyses were used to measure survival. Ras/Raf activity and invasion assays were used to evaluate the role of RRM1 in GC cell lines.ResultsIn vitro experiments demonstrated RRM1 activated Ras/Raf/MAPK signal transduction and promoted GC cell proliferation. Meanwhile, RRM1 expression was significantly associated with lymph node involvement, tumor size, Ki67 expression, histological subtype and histological grade in the GC tissue samples (pConclusionsRRM1 overexpression predicts poor survival in GC patients with advanced TNM stage. RRM1 could potentially serve as prognostic biomarker and therapeutic target for GCs.