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      Cisplatin resistance in gastric cancer cells is involved with GPR30‐mediated epithelial‐mesenchymal transition


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          Cisplatin is the major chemotherapeutic drug in gastric cancer, particularly in treating advanced gastric cancer. Tumour cells often develop resistance to chemotherapeutic drugs, which seriously affects the efficacy of chemotherapy. GPR30 is a novel oestrogen receptor that is involved in the invasion, metastasis and drug resistance of many tumours. Targeting GPR30 has been shown to increase the drug sensitivity of breast cancer cells. However, few studies have investigated the role of GPR30 in gastric cancer. Epithelial‐mesenchymal transition (EMT) has been shown to be associated with the development of chemotherapeutic drug resistance. In this study, we demonstrated that GPR30 is involved in cisplatin resistance by promoting EMT in gastric cancer. GPR30 knockdown resulted in increased sensitivity of different gastric cancer (GC) cells to cisplatin and alterations in the epithelial/mesenchymal markers. Furthermore, G15 significantly enhanced the cisplatin sensitivity of GC cells while G1 inhibited this phenomenon. In addition, EMT occurred when AGS and BGC‐823 were treated with cisplatin. Down‐regulation of GPR30 with G15 inhibited this transformation, while G1 promoted it. Taken together, these results revealed the role of GPR30 in the formation of cisplatin resistance, suggesting that targeting GPR30 signalling may be a potential strategy for improving the efficacy of chemotherapy in gastric cancer.

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          The epithelial to mesenchymal transition (EMT) and cancer stem cells: implication for treatment resistance in pancreatic cancer

          The mechanical properties of epithelial to mesenchymal transition (EMT) and a pancreatic cancer subpopulation with stem cell properties have been increasingly recognized as potent modulators of the effective of therapy. In particular, pancreatic cancer stem cells (PCSCs) are functionally important during tumor relapse and therapy resistance. In this review we have surveyed recent advances in the role of EMT and PCSCs in tumor progression, metastasis and treatment resistance, and the mechanisms of integrated with biochemical signals and the underlying pathways involved in treatment resistance of pancreatic cancer. These findings highlight the importance of confirming stem-cells markers and complex molecular signaling pathways controlling EMT and cancer stem cells in pancreatic cancer during tumor formation, progression, and response to therapy.
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            Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells.

            The aim of this study was to assess paclitaxel resistant-epithelial ovarian carcinoma (EOC) cells for cellular morphology, motility, and molecular changes consistent with epithelial-mesenchymal transition (EMT). The human EOC cell lines NOS-2, TAOV and SKOV-3 were continuously exposed to increasing doses of paclitaxel to establish three stable cell lines resistant to paclitaxel (NOS-PR, TAOV-PR, and SKOV-PR cells, respectively). Using these cell lines, cellular functions such as motility, invasive ability, and proliferative potential were assessed. Several molecules involved in EMT or cell invasiveness were assessed using Western blot analysis. In a peritoneal metastasis model using mice inoculated with NOS-2 or NOS-PR cells, we investigated the differences of peritoneal dissemination and survival time. NOS2-PR cells showed phenotypic changes consistent with EMT; with spindle-shaped morphology and enhanced pseudopodia formation. Western blot analysis revealed decreased expression of the epithelial adhesion molecule, E-cadherin and an increase in mesenchymal markers such as vimentin, fibronectin and smooth-muscle actin in NOS-PR cells compared to NOS-2 cells. The NOS2-PR cells displayed increased expression of Snail and Twist, EMT-regulatory transcription factors. Migratory potential in a wound assay and metastatic potential to the peritoneum of mice were markedly enhanced in NOS2-PR cells compared to NOS-2 cells. These data suggest that there is a possible link between chronic paclitaxel-resistance and induction of the EMT in EOC cells. It is possible that therapeutic benefits such as the restoration of chemosensitivity or suppression of metastasis will be enabled by gaining further insight into the mechanisms underlying chemoresistance and EMT.
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              Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer.

              Human epidermal growth factor receptor 2 (HER2)-directed treatment using trastuzumab has shown clinical benefit in HER2-positive gastric cancer. Clinical trials using lapatinib in HER2-positive gastric cancer are also currently underway. As with other molecularly targeted agents, the emergence of acquired resistance to HER2-directed treatment is an imminent therapeutic problem for HER2-positive gastric cancer. In order to investigate the mechanisms of acquired resistance to HER2-directed treatment in gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (SNU216 LR) in vitro by chronic exposure of a HER2-positive gastric cancer cell line (SNU216) to lapatinib. The resultant SNU216 LR cells were also resistant to gefitinib, cetuximab, trastuzumab, afatinib and dacomitinib. Interestingly, SNU216 LR cells displayed an epithelial-mesenchymal transition (EMT) phenotype and maintained the activation of MET, HER3, Stat3, Akt and mitogen-activated protein kinase signaling in the presence of lapatinib. Using gene expression arrays, we identified the upregulation of a variety of EMT-related genes and extracellular matrix molecules, such as Testican-1, in SNU216 LR cells. We showed that the inhibition of Testican-1 by small interfering RNA decreased Testican-1-induced, MET-dependent, downstream signaling, and restored sensitivity to lapatinib in these cells. Furthermore, treatment with XAV939 selectively inhibited β-catenin-mediated transcription and Testican-1-induced EMT signaling, leading to G1 arrest. Taken together, these data support the potential role of EMT in acquired resistance to HER2-directed treatment in HER2-positive gastric cancer, and provide insights into strategies for preventing and/or overcoming this resistance in patients.

                Author and article information

                J Cell Mol Med
                J. Cell. Mol. Med
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                12 February 2020
                March 2020
                : 24
                : 6 ( doiID: 10.1111/jcmm.v24.6 )
                : 3625-3633
                [ 1 ] First Clinical Medical College Zhejiang Chinese Medical University Hangzhou China
                [ 2 ] Department of Abdominal Surgery Zhejiang Cancer Hospital Hangzhou China
                [ 3 ] Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diagnosis and Treatment of Digestive System Tumor Hangzhou China
                [ 4 ] Department of Ultrasonics Zhejiang Cancer Hospital Hangzhou China
                [ 5 ] Cancer Institute of Integrated traditional Chinese and Western Medicine Key Laboratory of Cancer Prevention and Therapy Combining Traditional Chinese and Western Medicine Zhejiang Academy of Traditional Chinese Medicine Hangzhou China
                Author notes
                [*] [* ] Correspondence

                Xiangdong Cheng, Department of Abdominal Surgery, Zhejiang Cancer Hospital, East Banshan Road, Hangzhou, Zhejiang 310022, China.

                Email: chengxd@ 123456zcmu.edu.cn

                Wei Chen, Cancer Institute of Integrated traditional Chinese and Western Medicine, Key laboratory of cancer prevention and therapy combining traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Hangzhou, Zhejiang 310012, China.

                Email: wei_chen@ 123456zju.edu.cn

                Author information
                © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 26 September 2019
                : 27 January 2020
                Page count
                Figures: 6, Tables: 0, Pages: 9, Words: 4693
                Funded by: the Key Research Program of Traditional Chinese Medical Science and Technology Plan of Zhejiang Province
                Award ID: 2016ZZ012
                Funded by: the National Natural Science Foundation of China
                Award ID: 81573953
                Award ID: 81703753
                Funded by: the Medical Science and Technology Project of Zhejiang Province
                Award ID: WKJ‐ZJ‐1728
                Funded by: the Natural Science Foundation of Zhejiang Province
                Award ID: LY18H290006
                Original Article
                Original Articles
                Custom metadata
                March 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.9 mode:remove_FC converted:05.04.2020

                Molecular medicine
                cisplatin,epithelial‐mesenchymal transition (emt),g1,g15,gastric cancer,gpr30,resistance


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