Department of Geriatric Medicine, Shengli Clinical Medical College of Fujian Medical University, Fujian Key Laboratory of Geriatrics Diseases, Fujian Provincial Center for Geriatrics, Fujian Provincial Hospital, Fuzhou, 350001, China.
Department of Rehabilitation, Shengli Clinical Medical College of Fujian Medical University; Fujian Provincial Hospital, Fuzhou, 350001, China.
Curr Med Sci. 2024 Aug;44(4):789-798. doi: 10.1007/s11596-024-2879-x. Epub 2024 Jun 27.
Mitofusin-2 (MFN2) is a mitochondrial membrane protein that plays a critical role in regulating mitochondrial fusion and cellular metabolism. To further elucidate the impact of MFN2, this study aimed to investigate its significance on hepatocellular carcinoma (HCC) cell function and its potential role in mediating chemosensitivity.
This study investigated the effects of silencing and overexpressing MFN2 on the survival, proliferation, invasion and migration abilities, and sorafenib resistance of MHCC97-L HCC cells. Additional experiments were conducted using XAV939 (a β-catenin inhibitor) and HLY78 (a β-catenin activator) to further validate these findings.
Silencing MFN2 significantly promoted the survival and proliferation of MHCC97-L cells, enhanced their invasion and migration capacities, increased the IC of sorafenib, reduced the percentage of TUNEL-positive cells, and decreased the expression of proapoptotic proteins. Additionally, silencing MFN2 markedly induced the nuclear translocation of β-catenin, increased β-catenin acetylation levels and enhanced the expression of the downstream regulatory proteins Snail1 and Vimentin while inhibiting E-cadherin expression. Conversely, overexpressing MFN2 reversed the effects observed in MHCC97-L cells mentioned above. The results confirmed that silencing MFN2 activated the β-catenin/epithelial-mesenchymal transition (EMT) pathway and reduced the sensitivity of cells to sorafenib, which could be reversed by XAV939 treatment. Conversely, overexpression of MFN2 inhibited the β-catenin/EMT pathway and increased the sensitivity of cells to sorafenib, which could be altered by HLY78.
Low expression of MFN2 in HCC cells promotes the nuclear translocation of β-catenin, thereby activating the EMT pathway and mediating resistance to sorafenib.
线粒体融合蛋白 2（MFN2）是一种线粒体膜蛋白，在调节线粒体融合和细胞代谢中起着关键作用。为了进一步阐明 MFN2 的影响，本研究旨在探讨其对肝癌（HCC）细胞功能的意义及其在介导化疗敏感性中的潜在作用。
本研究研究了沉默和过表达 MFN2 对 MHCC97-L HCC 细胞存活、增殖、侵袭和迁移能力以及索拉非尼耐药性的影响。使用 XAV939（β-连环蛋白抑制剂）和 HLY78（β-连环蛋白激活剂）进行了额外的实验，以进一步验证这些发现。
沉默 MFN2 显著促进了 MHCC97-L 细胞的存活和增殖，增强了它们的侵袭和迁移能力，增加了索拉非尼的 IC，减少了 TUNEL 阳性细胞的百分比，并降低了促凋亡蛋白的表达。此外，沉默 MFN2 显著诱导了β-连环蛋白的核转位，增加了β-连环蛋白的乙酰化水平，并增强了下游调节蛋白 Snail1 和 Vimentin 的表达，同时抑制了 E-钙粘蛋白的表达。相反，过表达 MFN2 逆转了上述 MHCC97-L 细胞的作用。结果证实，沉默 MFN2 激活了β-连环蛋白/上皮间质转化（EMT）途径，并降低了细胞对索拉非尼的敏感性，XAV939 处理可逆转这一结果。相反，过表达 MFN2 抑制了β-连环蛋白/EMT 途径，并增加了细胞对索拉非尼的敏感性，HLY78 可改变这一结果。
HCC 细胞中 MFN2 的低表达促进了β-连环蛋白的核转位，从而激活了 EMT 途径，并介导了对索拉非尼的耐药性。
