Hepatocellular carcinoma (HCC) is an aggressive disease with a high degree of tumor heterogeneity. Genetic lesions of mTOR-related genes, including TSC2 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 TSC2 Rap_GAP domain in clinical HCC samples. To elucidate whether hyperactivation of mTOR signaling in HCC is caused by TSC2 truncating mutations, HCC cell models carrying the TSC2 deletion (CRISPR/Cas9) or the TSC2 truncating mutation (mutagenesis) were established. Our findings showed that either TSC2 deletion or TSC2 mutant could lead to TSC2 loss-of-function and hyperactivation of mTOR signaling. Furthermore, hyperactivation of mTOR signaling was relieved by rapamycin. Immunohistochemistry of clinical samples confirmed frequent TSC2 loss in HCC. Thus, our study revealed that genetic alterations cause TSC2 loss of function and result in the hyperactivation of mTOR, and high frequency of TSC2 truncating mutations around RAP_GAP domain may be one of the reasons for the hyperactivation of mTOR in HCC patients.
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