Liu Tianze, Wu Xiaojun, Li Yizhuo, Lu Wenjing, Zheng Fufu, Zhang Changlin, Long Qian, Qiu Huijuan, Li Yixin, Ge Qin, Chen Miao, Yu Xinfa, Chen Wangbing, Zhang Hongyang, Huang Wenlin, Luo Meihua, Deng Wuguo, Li Liren
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.
Cell Physiol Biochem. 2018;46(4):1365-1380. doi: 10.1159/000489153. Epub 2018 Apr 18.
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.
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.
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.
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.
背景/目的：RBFOX3是一种RNA结合蛋白，在神经元发育分化中起重要作用，但其在肝细胞癌（HCC）对5-氟尿嘧啶（5-FU）化疗敏感性中的作用尚不清楚。
在本研究中，我们在体外和小鼠异种移植模型中检测了RBFOX3的生物学功能及其对HCC细胞对5-FU化疗敏感性的影响。
发现RBFOX3在HCC细胞系和组织样本中表达升高，其敲低可抑制HCC细胞增殖。此外，敲低RBFOX3可增强5-氟尿嘧啶（5-FU）对细胞增殖、迁移和侵袭的抑制作用，并增强5-FU诱导的细胞凋亡。然而，RBFOX3过表达则降低了5-氟尿嘧啶（5-FU）对细胞增殖、迁移和侵袭的抑制作用，并减少了5-FU诱导的细胞凋亡。我们进一步阐明，敲低RBFOX3与5-FU协同作用，通过PI3K/AKT和上皮-间质转化（EMT）信号通路抑制HCC细胞的生长和侵袭，并通过激活细胞色素c/半胱天冬酶信号通路促进细胞凋亡。最后，我们在小鼠异种移植模型中验证了RBFOX3调节HCC中5-FU介导的细胞毒性。
本研究结果表明，RBFOX3在体外和体内均调节HCC对5-FU的化疗敏感性。因此，靶向RBFOX3可能增强5-FU对HCC生长和进展的抑制作用，并为HCC提供一种新的潜在治疗策略。
