Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, P.R. China.
Department of Orthopedic, The Second Hospital of Jilin University, Changchun, P.R. China.
DNA Cell Biol. 2022 Feb;41(2):215-224. doi: 10.1089/dna.2021.0769.
Hepatocellular carcinoma (HCC) is an aggressive disease with a high degree of tumor heterogeneity. Genetic lesions of mTOR-related genes, including and hyperactivation of mTOR signaling, are common in HCC. However, the association of genetic alterations with hepatocarcinogenesis remains unclear. In this study, continuous truncating mutations occurred within or upstream of the Rap_GAP domain in clinical HCC samples. To elucidate whether hyperactivation of mTOR signaling in HCC is caused by truncating mutations, HCC cell models carrying the deletion (CRISPR/Cas9) or the truncating mutation (mutagenesis) were established. Our findings showed that either deletion or mutant could lead to loss-of-function and hyperactivation of mTOR signaling. Furthermore, hyperactivation of mTOR signaling was relieved by rapamycin. Immunohistochemistry of clinical samples confirmed frequent loss in HCC. Thus, our study revealed that genetic alterations cause loss of function and result in the hyperactivation of mTOR, and high frequency of truncating mutations around RAP_GAP domain may be one of the reasons for the hyperactivation of mTOR in HCC patients.
肝细胞癌 (HCC) 是一种侵袭性疾病，具有高度的肿瘤异质性。mTOR 相关基因的遗传病变，包括 和 mTOR 信号的过度激活，在 HCC 中很常见。然而，遗传改变与肝癌发生的关系尚不清楚。在这项研究中，临床 HCC 样本中 Rap_GAP 结构域内或其上游发生连续截断突变。为了阐明 HCC 中 mTOR 信号的过度激活是否是由 截断突变引起的，建立了携带 缺失（CRISPR/Cas9）或 截断突变（诱变）的 HCC 细胞模型。我们的研究结果表明，无论是 缺失还是 突变都可能导致 功能丧失和 mTOR 信号的过度激活。此外，雷帕霉素可缓解 mTOR 信号的过度激活。临床样本的免疫组化证实 HCC 中 经常缺失。因此，我们的研究表明遗传改变导致 功能丧失，并导致 mTOR 的过度激活，而 RAP_GAP 结构域周围 截断突变的高频可能是 HCC 患者中 mTOR 过度激活的原因之一。
