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线粒体分裂因子促进肝癌顺铂耐药。

Mitochondrial fission factor promotes cisplatin resistancein hepatocellular carcinoma.

机构信息

Department of Digestive Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.

Department of Digestive Surgery, Xi'an International Medical Center Hospital, Xi'an 710010, China.

出版信息

Acta Biochim Biophys Sin (Shanghai). 2022 Mar 25;54(3):301-310. doi: 10.3724/abbs.2022007.

DOI:10.3724/abbs.2022007
PMID:35538029
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9828151/
Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and one of the leading causes of cancer-related death worldwide. Chemotherapeutic agents/regimens such as cisplatin (DDP) are frequently used for advanced HCC treatment. However, drug resistance remains a major hindrance and the underline mechanisms are not fully understood. In this study, we investigated the expression pattern and function of mitochondrial fission factor (Mff) in cisplatin-resistant HCC. We found that Mff is highly expressed in cisplatin-resistant HCC tissues and cell lines. Knockdown of Mff suppresses cell proliferation and promotes cell apoptosis of HCC/DDP cells. In addition, knockdown of Mff sensitizes Huh-7/DDP cells to cisplatin treatment, inhibits cell proliferation, migration and invasion, and enhances cell apoptosis. Confocal imaging showed that knockdown of Mff inhibits the mitochondrial fission and downregulates the expression of GTPase dynamin-related protein 1 (Drp1) in cisplatin-resistant Huh-7/DDP cells. Moreover, xenograft tumor model revealed that knockdown of Mff sensitizes Huh-7/DDP xenograft tumor to cisplatin treatment . In summary, our findings suggest that Mff regulates mitochondrial Drp1 expression and promotes cisplatin resistance in HCC, which provides a potential therapeutic target for the treatment of resistant HCC.

摘要

肝细胞癌 (HCC) 是最常见的原发性肝脏肿瘤，也是全球癌症相关死亡的主要原因之一。顺铂 (DDP) 等化疗药物/方案常用于晚期 HCC 的治疗。然而，耐药性仍然是一个主要障碍，其潜在机制尚未完全阐明。在这项研究中，我们研究了线粒体分裂因子 (Mff) 在顺铂耐药 HCC 中的表达模式和功能。我们发现 Mff 在顺铂耐药 HCC 组织和细胞系中高表达。敲低 Mff 可抑制 HCC/DDP 细胞的增殖并促进细胞凋亡。此外，敲低 Mff 可增加 Huh-7/DDP 细胞对顺铂的敏感性，抑制细胞增殖、迁移和侵袭，并增强细胞凋亡。共聚焦成像显示，敲低 Mff 抑制线粒体分裂并下调顺铂耐药 Huh-7/DDP 细胞中 GTPase 动力相关蛋白 1 (Drp1) 的表达。此外，异种移植肿瘤模型表明，敲低 Mff 可增加 Huh-7/DDP 异种移植肿瘤对顺铂治疗的敏感性。总之，我们的研究结果表明，Mff 调节线粒体 Drp1 的表达并促进 HCC 对顺铂的耐药性，为治疗耐药性 HCC 提供了一个潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/6a415c7a1a18/abbs-2021-433-t6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/d8691b3e8808/abbs-2021-433-t1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/bb799df52f05/abbs-2021-433-t2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/b425a3dd8281/abbs-2021-433-t3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/6cfc0be27b8c/abbs-2021-433-t4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/22b394f08681/abbs-2021-433-t5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/6a415c7a1a18/abbs-2021-433-t6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/d8691b3e8808/abbs-2021-433-t1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/bb799df52f05/abbs-2021-433-t2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/b425a3dd8281/abbs-2021-433-t3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/6cfc0be27b8c/abbs-2021-433-t4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fc02/9828151/22b394f08681/abbs-2021-433-t5.jpg
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