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Defects in mTORC1 Network and mTORC1-STAT3 Pathway Crosstalk Contributes to Non-inflammatory Hepatocellular Carcinoma

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Background and Aims Mammalian target of rapamycin complex 1 (mTORC1) is frequently hyperactivated in hepatocellular carcinoma (HCC). Cases of HCC without inflammation and cirrhosis are not rarely seen in clinics.… Click to show full abstract

Background and Aims Mammalian target of rapamycin complex 1 (mTORC1) is frequently hyperactivated in hepatocellular carcinoma (HCC). Cases of HCC without inflammation and cirrhosis are not rarely seen in clinics. However, the molecular basis of non-inflammatory HCC remains unclear. Methods Spontaneous non-inflammatory HCC in mice was triggered by constitutive elevation of mTORC1 by liver-specific TSC1 knockout (LTsc1KO). A multi-omics approach was utilized on tumor tissues to better understand the molecular basis for the development of HCC in the LTsc1KO model. Results We showed that LTsc1KO in mice triggered spontaneous non-inflammatory HCC, with molecular characteristics similar to those of diethylnitrosamine-mediated non-cirrhotic HCC. Mitochondrial and autophagy defects, as well as hepatic metabolic disorder were manifested in HCC development by LTsc1KO. mTORC1 activation on its own regulated an oncogenic network (DNA-damage-inducible transcript 4, nuclear protein 1, and fibroblast growth factor 21), and mTORC1–signal transducer and activator of transcription pathway crosstalk that altered specific metabolic pathways contributed to the development of non-inflammatory HCC. Conclusion Our findings reveal the mechanisms of mTORC1-driven non-inflammatory HCC and provide insight into further development of a protective strategy against non-inflammatory HCC.

Keywords: hepatocellular carcinoma; hcc; pathway crosstalk; mtorc1; non inflammatory; inflammatory hcc

Journal Title: Frontiers in Cell and Developmental Biology
Year Published: 2020

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