Cellular Physiology and Biochemistry (Apr 2018)

RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways

  • Tianze Liu,
  • Xiaojun Wu,
  • Yizhuo Li,
  • Wenjing Lu,
  • Fufu Zheng,
  • Changlin Zhang,
  • Qian Long,
  • Huijuan Qiu,
  • Yixin Li,
  • Qin Ge,
  • Miao Chen,
  • Xinfa Yu,
  • Wangbing Chen,
  • Hongyang Zhang,
  • Wenlin Huang,
  • Meihua Luo,
  • Wuguo Deng,
  • Liren Li

DOI
https://doi.org/10.1159/000489153
Journal volume & issue
Vol. 46, no. 4
pp. 1365 – 1380

Abstract

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Background/Aims: RBFOX3, an RNA-binding fox protein, plays an important role in the differentiation of neuronal development, but its role in the chemosensitivity of hepatocellular carcinoma (HCC) to 5-FU is unknown. Methods: In this study, we examined the biological functions of RBFOX3 and its effect on the chemosensitivity of HCC cells to 5-FU in vitro and in a mouse xenograft model. Results: RBFOX3 was found to have elevated expression in HCC cell lines and tissue samples, and its knockdown inhibited HCC cell proliferation. Moreover, knockdown of RBFOX3 improved the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and enhanced the apoptosis induced by 5-FU. However, overexpression of RBFOX3 reduced the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and decreased the apoptosis induced by 5-FU. We further elucidated that RBFOX3 knockdown synergized with 5-FU to inhibit the growth and invasion of HCC cells through PI3K/AKT and epithelial-mesenchymal transition (EMT) signaling, and promote apoptosis by activating the cytochrome-c/caspase signaling pathway. Finally, we validated that RBFOX3 regulated 5-FU-mediated cytotoxicity in HCC in mouse xenograft models. Conclusions: The findings from this study indicate that RBFOX3 regulates the chemosensitivity of HCC to 5-FU in vitro and in vivo. Therefore, targeting RBFOX3 may improve the inhibition of HCC growth and progression by 5-FU, and provide a novel potential therapeutic strategy for HCC.

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