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

• Published in: Tumor biology Vol. 37; no. 7; pp. 8811 - 8824
• Main Authors: Lv, Lin, Liu, Hai-Guang, Dong, Si-Yang, Yang, Fan, Wang, Qing-Xuan, Guo, Gui-Long, Pan, Yi-Fei, Zhang, Xiao-Hua
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.07.2016; Springer Nature B.V
• Subjects: Apoptosis - drug effects; Apoptosis - genetics; Autophagy; Autophagy - drug effects; Autophagy - genetics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colorectal cancer; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Fluorouracil - pharmacology; Gene expression; Genes, ras - genetics; Humans; Hyaluronan Receptors - genetics; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Mitogen-Activated Protein Kinases - genetics; Organoplatinum Compounds - pharmacology; Original Article; Phosphatidylinositol 3-Kinases - genetics; Phosphorylation - drug effects; Phosphorylation - genetics; Proto-Oncogene Proteins c-akt - genetics; Retrospective Studies; Signal Transduction - drug effects; Signal Transduction - genetics; Up-Regulation - drug effects; Up-Regulation - genetics; CD44v6; Autophagy; Colorectal cancer; Chemoresistance
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1007/s13277-015-4755-6

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.