MFN1相关线粒体融合障碍促进混合型肝癌发生的作用机制研究
结题报告
批准号:
81972590
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
黄启超
学科分类:
肿瘤发生
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
黄启超
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中文摘要
混合型肝癌(cHC)兼具肝细胞肝癌和胆管细胞癌特征。多数研究表明cHC为单一肝脏细胞起源,但向两种表型癌细胞恶性转化的机制尚不明确。MFN1是线粒体融合关键分子,我们曾发现其在人肝细胞肝癌中表达降低,并促进肝癌进展。最近我们意外发现:Akt/β-catenin同时过表达在野生鼠诱发肝细胞肝癌,而在部分肝细胞敲除MFN1鼠中全部诱发cHC,且MFN1敲除细胞主要转化为胆管样细胞癌。进一步发现,Akt/β-catenin诱发鼠肝细胞肝癌组织中MFN1表达降低;人cHC组织中MFN1在肝细胞样肝癌中表达下降,而在胆管样细胞癌中几乎不表达。这些结果提示:MFN1可能介导线粒体融合障碍,参与cHC发生。基于此,本项目拟进一步系统研究MFN1相关线粒体融合障碍促进cHC发生的病理过程及其诱导肝细胞向肝细胞样肝癌和胆管样细胞癌两种表型转化的作用及机制,以期拓展对cHC发生的理解,也为其防治提供新思路。
英文摘要
Combined hepatocellular and cholanigocarcinoma (cHC) has both hepatocellular carcinoma and cholangiocarcinoma, with low survival rate and lack of effective treatment. Recent studies have shown that two types of tumor cells in cHC may be the same hepatocyte origin, but the mechanism of how liver cell transform into two types of tumor cells is still unclear. The mitochondrial fusion protein MFN1 is one of the most important effectors of mitochondrial fusion. We have previously demonstrated that downregulated MFN1 significantly promoted the progression of hepatocellular carcinoma. Recently, we unexpectedly found that Akt/beta-catenin overexpression induced hepatocellular carcinoma in wild mice. While, cHC was developed based on this mouse liver cancer model after knocking out MFN1 in a portion of hepatocyte. Importantly, we also found that MFN1 knockout cells were mainly transformed into cholangiocarcinoma-like cells. Moreover, Akt/beta-catenin overexpression decreased the expression of MFN1 in mouse hepatocellular carcinoma tissues. It was further confirmed that, in human cHC tissues, the expression of MFN1 was decreased in hepatocellular carcinoma-like cells, while the MFN1 expression was almost negative in cholangiocarcinoma-like cells. These results suggested that MFN1 mediated mitochondrial fusion disorder may play a key role in the oncogenesis of cHC. Based on these results, this project intends to further study the pathological process of cHC induced by MFN1-related mitochondrial fusion disorder and the mechanism of hepatocytes transform into hepatocellular carcinoma-like cells and cholangiocarcinoma-like cells. Our work might broaden the understanding of the occurrence of cHC and providing new ideas for its prevention and treatment in the further.
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DOI:10.1016/j.ymthe.2022.01.032
发表时间:2022-04-06
期刊:MOLECULAR THERAPY
影响因子:12.4
作者:Wang, Dalin;Tian, Jiming;Huang, Qichao
通讯作者:Huang, Qichao
DOI:10.1111/cas.15715
发表时间:2023-04
期刊:Cancer science
影响因子:5.7
作者:
通讯作者:
Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis
Akap1 缺陷通过 NDUFS1 介导的线粒体功能障碍和细胞凋亡加剧小鼠糖尿病心肌病
DOI:10.1007/s00125-020-05103-w
发表时间:2020-02-19
期刊:DIABETOLOGIA
影响因子:8.2
作者:Qi, Bingchao;He, Linjie;Ji, Lele
通讯作者:Ji, Lele
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