线粒体蛋白LRPPRC经微管结合蛋白MAP1S介导调控自噬和肝细胞癌变

Hepatocellular carcinoma (HCC) is the most common form of liver cancer。Most HCC patients develop liver fibrosis-induced liver cirrhosis. Autophagy defects trigger oxidative stress that induces different types of cell death including apoptosis, necrosis and pyroptosis. Cells died of pyroptosis induce the death of other cells in the environment and promote liver fibrosis. Liver fibrosis-induced liver regeneration accelerates HCC by generatiing oxidative stress to induce genome instability and by reactivating cell division to amplify genome instability. Based on our preliminary results, we hypothesize that LRPPRC promotes the development of liver fibrosis and HCC and reduces survivals of mice with HCC through regulating MAP1S-mediated autophagy. We plan to objectively test our central hypothesis by pursuing specific aims: 1) Characterize the mechanisms by which LRPPRC suppresses autophagy flux and promotes pyroptosis; and 2) Determine that a depletion of LRPPRC causes a suppression of liver fibrosis and HCC and an improvement of survivals of mice with HCC in mouse models. We predict that the deletion of LRPPRC in mice will lead to an activation of autophagy, a suppression of pyroptosis and a reduction in intensity of liver fibrosis and incidence and malignancy of HCC. Successfully completing these aims will lead to deciphering novel mechanisms by which autophagy regulates pyroptosis to impact human closely related liver diseases including liver fibrosis, liver cirrhosis and HCC.

肝细胞癌(HCC)是肝癌的最常见类型。大多数HCC患者并发肝纤维化和肝硬化。自噬缺陷诱发氧化应激和包括凋亡坏死和焦亡不同类型的细胞死亡。死于焦亡的细胞诱导周围其他细胞的死亡并促进肝纤维化。肝纤维化诱导的氧化应激而随后的肝再生将增强扩增基因组不稳定性和HCC的发展。根据我们的研究基础，我们假定LRPPRC调控MAP1S介导的自噬促进肝纤维化和肝癌发生发展及影响癌患生存。我们设定以下目标来测试我们的中心假设：1）表征LRPPRC抑制自噬通量和促进焦亡的机制。我们假定LRPPRC敲除将稳定MAP1S促进自噬抑制焦亡。2）确定LRPPRC的敲除将抑制小鼠肝纤维化和HCC并改善生存。将小鼠的LRPPRC基因敲除会促进自噬抑制焦亡并减少小鼠的肝纤维化和HCC的病变程度及延长癌患寿命。目标的成功完成将揭示通过自噬调节焦亡来影响人类肝纤维化，肝硬化和HCC等密切相关的疾病的新机制。

肝细胞癌是肝癌的最常见类型。自噬缺陷诱发氧化应激和包括凋亡坏死和焦亡不同类型的细胞死亡。死于焦亡的细胞诱导周围其他细胞的死亡。肝纤维化诱导的氧化应激而随后的肝再生将增强扩增基因组不稳定性和HCC的发展。我们假定LRPPRC调控MAP1S介导的自噬促进肝纤维化和肝癌发生发展及影响癌患生存。我们的研究目标是1）阐明LRPPRC如何抑制自噬通量和促进焦亡的机制，2）揭示LRPPRC敲除如何遏制小鼠肝纤维化和肝细胞癌的发生发展而改善其生存。我们发现1）将小鼠LRPPRC基因敲除导致自噬底物受体P62的减少和Hippo信号通路关键调节蛋白YAP和细胞周期G1/S抑制蛋白P27增加；2）LRPPRC敲除通过P62-HDAC6影响微管乙酰化程度和稳定性而引起的自噬成熟阻断；3）通过YAP-P27促进肝细胞多倍体的发生而导致DNA损伤和基因组不稳定性扩展和进一步促进肿瘤发生发展从而使敲除小鼠产生更多更大的肝细胞癌存活更短。这些结论揭示了一个完全不同于预期的LRPPRC自噬和肝细胞癌的调节机制。此外，LRPPRC互作蛋白RASSF1A通过Hippo信号通路调节蛋白MST1抑制PI3K-AKT-mTOR来增强自噬启动并通过MAP1S促进自噬成熟。RASSF1A敲除小鼠同样加速肝细胞癌的发生发展和缩短存活时间。我们另外发现在前列腺癌中P62通过激活Keap1/Nrf2/ARE通路增强氧化应激而促进前列腺癌的发展。另一个线粒体相关的E3泛素连接酶Mul1促进自噬通量以促进 P62 相关蛋白聚集体和脂肪分化相关蛋白ADFP相关脂滴的降解并抑制肾透明细胞癌细胞的生长和迁移。结合从前我们的研究成果进一步证实促进自噬有利于抑制肿瘤发生也有利于抑制肿瘤发展改善患者生存。这项成果不仅导正了自噬和癌症研究领域的错误认知，也为将来在临床实践中利用不同自噬促进途径来预防治疗癌症并改善患者预后。