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Upregulation of CD44v6 contributes to acquired chemoresistance via the modulation of autophagy in colon cancer SW480 cells

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Tumor Biology

Abstract

The CD44 isoform containing variant exon v6 (CD44v6) plays an important role in the progression, metastasis, and prognosis of colorectal cancer (CRC). Recently, it was found that CD44v6 is involved in acquired drug resistance. This study aimed to investigate the molecular mechanism of CD44v6 in the resistance of CRC cells to chemotherapy. A stable CD44v6 overexpression model in SW480 cells was established via lentiviral transduction. The chemosensitivity of cells to 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) was determined by cell counting kit (CCK)-8, lactate dehydrogenase (LDH) release, and colony formation assays. Immunohistochemical staining of CD44v6 was performed in human CRC tissues. The key components in cell apoptosis, drug efflux and metabolism, mismatch repair, autophagy, epithelial–mesenchymal transition (EMT), and the PI3K–Akt and MAPK–Ras–Erk1/2 pathways were assessed using flow cytometry, quantitative real-time polymerase chain reaction (PCR), and western blot assays. The CD44v6 overexpression cells showed a higher viability, a lower LDH release rate, and an increased clonogenicity than the control cells under drug treatment. Moreover, overexpression of CD44v6 resulted in enhanced autophagy flux, EMT, and phosphorylation of Akt and Erk in the presence of drugs. Furthermore, high CD44v6 expression in the primary tumor was closely associated with an early recurrence in CRC patients who underwent curative surgery and adjuvant chemotherapy. In conclusion, overexpression of CD44v6 contributes to chemoresistance in SW480 cells under cytotoxic stress via the modulation of autophagy, EMT, and activation of the PI3K–Akt and MAPK–Ras–Erk pathways.

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Acknowledgments

This work was supported by the Science Foundation from the Health Bureau of Wenzhou City of Zhejiang, China (Y20140713) and by the Incubation Program from The First Affiliated Hospital of Wenzhou Medical University (FHY2014013).

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    1. Department of Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

      Lin Lv, Hai-Guang Liu, Si-Yang Dong, Fan Yang, Qing-Xuan Wang, Gui-Long Guo, Yi-Fei Pan & Xiao-Hua Zhang

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    Lin Lv and Hai-Guang Liu contributed equally to this work.

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    Lv, L., Liu, HG., Dong, SY. et al. Upregulation of CD44v6 contributes to acquired chemoresistance via the modulation of autophagy in colon cancer SW480 cells. Tumor Biol. 37, 8811–8824 (2016). https://doi.org/10.1007/s13277-015-4755-6

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