我校西南医院张雷达专家团队在《JOURNAL OF HEPATOLOGY》发表研究成果——p53功能不全伴mTOR过度活化促进肝细胞肝癌发生发展机制和治疗的研究
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p53功能不全伴mTOR过度活化促进肝细胞肝癌发生发展机制和治疗的研究

罗袁登,张雷达,别平, 谢传明

 

p53基因突变在人肝细胞癌(HCC)中频繁发生。雷帕霉素靶蛋白(mTOR)信号通路的高度活化也与肝癌密切相关。然而,目前尚不清楚这些变化是否协同诱发肝癌,并可作为一种潜在的治疗策略。

在本研究中,本研究团队从体内转基因小鼠水平,体外原代细胞及肿瘤细胞株实验证明:p53(haploinsufficicency)功能不全通过Pten/Akt/mTOR轴促进Tsc1缺失介导的mTOR活化,从而驱动HCC发生及肺转移。PI3K/Akt抑制剂能够显著降低mTOR活性,从而有效地增强mTOR抑制剂的抗癌作用。同时发现抑制mTOR激活是p53功能不全和Tsc1缺失导致肝癌发生的潜在治疗靶点。

该研究首次报道,肝癌亚群p53单倍型缺失(haplodeficiency)能够协同Tsc1缺失(mTOR过度激活)促进肝癌生成及肺转移。研究结果进一步证明Pten/PI3K/Akt/mTOR轴及其下游靶点Abcc4在p53和Tsc1缺失驱动的肝癌发生中起到关键作用。靶向mTOR是p53(haplo)缺陷型肝癌的一个意想不到的弱点,可用于治疗Abcc-4阳性HCC患者。

为进一步研究p53与Tsc1缺失诱导肝癌发生及转移的分子机制,研究者通过转录组学分析发现:Abcc4与p53/Tsc1缺失导致的肝癌发生密切相关。已有研究者发现Abcc4与多种肿瘤发生及转移相关,且多个潜在药物进入临床试用期。

研究者发现抑制或干扰Abcc4能够显著阻断p53突变和Tsc1缺失介导的细胞增殖。此外,在临床HCC样本中,Abcc4在高侵袭性p53突变的HCC中高表达且与HCC患者存活率呈负相关。研究表明,p53突变和Tsc1缺失的致癌活性依赖于Abcc4,它标志着人类肝癌的一种高侵袭性亚型。这一发现将为p53突变与Tsc1缺失(mTOR高度激活)的肝癌患者提供新的诊断理论依据与治疗新靶点。

上述研究成果于2020年7月19日在JOURNAL OF HEPATOLOGY(2020年SCI影响因子25.083)在线发表了题为“p53 haploinsufficiency and increased mTOR signaling define a subset of aggressive hepatocellular carcinoma”的工作(VOLUME 74, ISSUE 1, P96-108, JANUARY 01, 2021)。

 

附:英文摘要

 

p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma.

Background & aims: p53 mutations occur frequently in human HCC. Activation of the mammalian target of rapamycin (mTOR) pathway is also associated with HCC. However, it is still unknown whether these changes together initiate HCC and can be targeted as a potential therapeutic strategy.

Methods: We generated mouse models in which mTOR was hyperactivated by loss of tuberous sclerosis complex 1 (Tsc1) with or without p53 haplodeficiency. Primary cells were isolated from mouse livers. Oncogenic signalling was assessed in vitro and in vivo, with or without targeted inhibition of a single molecule or multiple molecules. Transcriptional profiling was used to identify biomarkers predictive of HCC. Human HCC materials were used to corroborate the findings from mouse models.

Results: p53 haploinsufficiency facilitates mTOR signalling via the PTEN/PI3K/Akt axis, promoting HCC tumorigenesis and lung metastasis. Inhibition of PI3K/Akt reduced mTOR activity, which effectively enhanced the anticancer effort of an mTOR inhibitor. ATP-binding cassette subfamily C member 4 (Abcc4) was found to be responsible for p53 haploinsufficiency- and Tsc1 loss-driven HCC tumorigenesis. Moreover, in clinical HCC samples, Abcc4 was specifically identified an aggressive subtype. The mTOR inhibitor rapamycin significantly reduced hepatocarcinogenesis triggered by Tsc1 loss and p53 haploinsufficiency in vivo, as well as the biomarker Abcc4.

Conclusions: Our data advance the current understanding of the activation of the PTEN/PI3K/Akt/mTOR axis and its downstream target Abcc4 in hepatocarcinogenesis driven by p53 reduction and Tsc1 loss. Targeting mTOR, an unexpected vulnerability in p53 (haplo)deficiency HCC, can be exploited therapeutically to treat Abcc4-positive patients with HCC.

 

 

 


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