SIRT3 and SIRT4 double-genes remodeled the mitochondrial network to induce hepatocellular carcinoma cell line differentiation and suppress malignant phenotypes

作者全名：Zhang, Lijun; Dai, Zhenning; Shi, Shanshan; Yan, Zi; Yang, Jiaxin; Xue, Wanting; He, Yunhao; Mi, Siqi; Cheng, Cheng; Wang, Liangxu; Li, Nanxiang; Tan, Wei; Jiang, Zhenyou; Sun, Hanxiao; Li, Shiyu

作者地址：[Zhang, Lijun; Dai, Zhenning; He, Yunhao; Cheng, Cheng; Sun, Hanxiao; Li, Shiyu] Jinan Univ, Inst Genom Med, Coll Pharm, Guangzhou 511436, Peoples R China; [Dai, Zhenning] Guangdong Second Tradit Chinese Med Hosp, Dept Stomatol, Guangdong Prov Key Lab Res & Dev Tradit Chinese Me, Guangzhou 510095, Peoples R China; [Shi, Shanshan; Jiang, Zhenyou; Li, Shiyu] Jinan Univ, Coll Basic Med & Publ Hyg, Dept Microbiol & Immunol, Guangzhou 510632, Peoples R China; [Yan, Zi; Yang, Jiaxin; Xue, Wanting; Li, Shiyu] Southern Med Univ, Affiliated Hosp 3, Guangdong Med Innovat Platform Translat 3D Printin, Guangzhou 510630, Peoples R China; [Mi, Siqi] Southern Med Univ, Guangdong Engn Res Ctr Translat Med 3DPrinting App, Guangdong Prov Key Lab Digital Med & Biomech, Sch Basic Med Sci,Natl Key Discipline Human Anat, Guangzhou 510515, Peoples R China; [Wang, Liangxu] Chongqing Med Univ, Dept Hepatobiliary Surg, Affiliated Hosp 1, Chongqing 400042, Peoples R China; [Li, Nanxiang] Shenzhen Univ, Dept Neurosurg, South China Hosp, Shenzhen 518111, Peoples R China; [Tan, Wei] Jinan Univ, Guangzhou Overseas Chinese Hosp, Dept Pediat Orthoped, Affiliated Hosp 1, Guangzhou 510632, Peoples R China

通信作者：Sun, HX; Li, SY (通讯作者)，Jinan Univ, Inst Genom Med, Coll Pharm, Guangzhou 511436, Peoples R China.; Jiang, ZY; Li, SY (通讯作者)，Jinan Univ, Coll Basic Med & Publ Hyg, Dept Microbiol & Immunol, Guangzhou 510632, Peoples R China.

来源：BIOCHEMICAL PHARMACOLOGY

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001217439300001

JCR分区：Q1

影响因子：5.3

年份：2024

卷号：223

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Hepatocellular carcinoma; Mitochondria; Sirtuin; Plasmid; Metabolic reprogramming

摘要：Tumor cells with damaged mitochondria undergo metabolic reprogramming, but gene therapy targeting mitochondria has not been comprehensively reported. In this study, plasmids targeting the normal hepatocyte cell line (L-O2) and hepatocellular carcinoma cell line were generated using three genes SIRT3, SIRT4, and SIRT5. These deacetylases play a variety of regulatory roles in cancer and are related to mitochondrial function. Compared with L-O2, SIRT3 and SIRT4 significantly ameliorated mitochondrial damage in HCCLM3, Hep3B and HepG2 cell lines and regulated mitochondrial biogenesis and mitophagy, respectively. We constructed doublegene plasmid for co-express SIRT3 and SIRT4 using the internal ribosome entry site (IRES). The results indicated that the double-gene plasmid effectively expressed SIRT3 and SIRT4, significantly improved mitochondrial quality and function, and reduced mtDNA level and oxidative stress in HCC cells. MitoTracker analysis revealed that the mitochondrial network was restored. The proliferation, migration capabilities of HCC cells were reduced, whereas their differentiation abilities were enhanced. This study demonstrated that the use of IRES-linked SIRT3 and SIRT4 double-gene vectors induced the differentiation of HCC cells and inhibited their development by ameliorating mitochondrial dysfunction. This intervention helped reverse metabolic reprogramming, and may provide a groundbreaking new framework for HCC treatment.

基金机构：SuYuan Biotechnology co. LTD.; National Natural Science Foundation of China [82073747, 82074133, 82300018]; Guangdong Basic and Applied Basic Research Foundation [2021A1515111074]; China Postdoctoral Science Foundation [2021M701620]; Scientific research project of Traditional Chinese Medicine Bureau of Guangdong Province [20232007]; President Foundation of The Third Affiliated Hospital of Southern Medical University [YQ2021001, YP202223]; Guangxi Key Laboratory of Birth Defects Research and Prevention [GXWCHZDKF-2022-21]

基金资助正文：Thanks for the technical support provided by SuYuan Biotechnology co. LTD. This work was supported by the National Natural Science Foundation of China (82073747, 82074133 and 82300018) , Guangdong Basic and Applied Basic Research Foundation (2021A1515111074) , the fellowship of China Postdoctoral Science Foundation (2021M701620) , Scientific research project of Traditional Chinese Medicine Bureau of Guangdong Province (20232007) , President Foundation of The Third Affiliated Hospital of Southern Medical University (YQ2021001, YP202223) , Guangxi Key Laboratory of Birth Defects Research and Prevention (GXWCHZDKF-2022-21) .