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

Abstract

Background & 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 noninflammatory HCC remains unclear. Methods: Spontaneous noninflammatory 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 noninflammatory HCC, with molecular characteristics similar to those of diethylnitrosamine-mediated noncirrhotic 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 noninflammatory HCC. Conclusion: Our findings reveal the mechanisms of mTORC1-driven noninflammatory HCC and provide insight into further development of a protective strategy against noninflammatory HCC. Funding Statement: This work was supported by the National Key R&D Program of China (2018YFC1106400, 018YFA0108200), Science and Technology Planning Project of Guangdong Province (2015B020229002), the National Natural Science Foundation of China (81470875, 81701580, 81600489), the Natural Science Foundation of Guangdong Province (2014A030312013, 2018A030313128, 2018A030313214), Guangdong key research and development plan (2019B020234003), and Science and Technology Program of Guangzhou (201604020002, 201803010086). Declaration of Interests: The authors declare that they have no competing financial interest to disclose. Ethics Approval Statement: All of the animal experiments were approved by the Animal Ethics Committee of Southern Medical University (approval number SYXK 2011-0074) and performed in accordance with animal ethics guidelines and approved protocols.