Department of Pharmacy, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai 200240, China.
Math Biosci Eng. 2019 Jul 8;16(6):6319-6334. doi: 10.3934/mbe.2019315.
Hepatocellular carcinoma (HCC) is increasingly known as a serious, worldwide public health concern. Sorafenib resistance is the main challenge faced by many advanced HCC patients. The specific mechanisms of sorafenib resistance remind unclear. In the current study, GEO2R was conducted to identify differentially expressed genes (DEGs) between sorafenib-resistant samples and the control group by using RNA-sequence analysis and analyzing dataset GSE109211. Next, protein-protein interaction (PPI) network was built to explore key targets proteins in sorafenib-resistant HCC. Furthermore, gene ontology (GO) analysis was used to research the underlying roles of key proteins. Moreover, the Kaplan-Meier survival analysis was performed to display the effect of key proteins on overall survival in HCC. Western blotting was performed to detected resistance-related proteins and CCK-8 assay was employed to measured cell viability. In the present research, 164 sorafenib resistance-related DEGs in HCC were identified by using RNA-sequence analysis and analyzing the dataset GSE109211. GO analysis revealed DEGs were involved in regulating multiple biological processes and molecular functions. DYNLL2, H2AFJ, SHANK2, ZWILCH, CDC14A, IFT20, MTA3, SERPINA1 and TCF4 were confirmed as key genes in this process. Moreover, our study showed Akt signaling was aberrantly activated and inhibition of Akt signaling enhanced anti-tumor capacity of sorafenib in sorafenib-resistant HCC cells. Identification of the DEGs in sorafenib resistant HCC cells may further provide the new insights of underlying sorafenib-resistant mechanisms and offer latent targets for early diagnosis and new therapies to improve clinical efficacy for sorafenib-resistant HCC patients.
肝细胞癌（HCC）日益成为全球严重的公共卫生问题。索拉非尼耐药是许多晚期 HCC 患者面临的主要挑战。索拉非尼耐药的确切机制尚不清楚。在本研究中，通过 RNA 测序分析和分析数据集 GSE109211，使用 GEO2R 鉴定索拉非尼耐药样本和对照组之间的差异表达基因（DEGs）。接下来，构建蛋白质-蛋白质相互作用（PPI）网络，以探索索拉非尼耐药 HCC 中的关键靶蛋白。此外，进行基因本体论（GO）分析以研究关键蛋白的潜在作用。此外，进行 Kaplan-Meier 生存分析以显示关键蛋白对 HCC 总生存的影响。进行 Western blot 检测以检测耐药相关蛋白，进行 CCK-8 测定以测量细胞活力。在本研究中，通过 RNA 测序分析和分析数据集 GSE109211，确定了 164 个 HCC 中与索拉非尼耐药相关的 DEGs。GO 分析表明，DEGs 参与调节多种生物过程和分子功能。DYNLL2、H2AFJ、SHANK2、ZWILCH、CDC14A、IFT20、MTA3、SERPINA1 和 TCF4 被确认为该过程中的关键基因。此外，我们的研究表明 Akt 信号通路异常激活，抑制 Akt 信号通路增强了索拉非尼在索拉非尼耐药 HCC 细胞中的抗肿瘤能力。鉴定索拉非尼耐药 HCC 细胞中的 DEGs 可能进一步提供索拉非尼耐药机制的新见解，并为早期诊断和新疗法提供潜在靶点，以提高索拉非尼耐药 HCC 患者的临床疗效。
