Molecular Mechanisms Whereby Inter- Regulation Of Two Transcription Factors Nrf1 And Nrf2 Is Involved In The Pathology Of Nash And HCC

Hepatocellular carcinoma?HCC?,one of several malignant tumors,has poor prognosis in humans.The detailed molecular mechanism of its pathogenesis and treatment strategy need to be further studied and developed.Among the many factors leading to HCC,patients with nonalcoholic steatohepatitis?NASH?has become the main reason.The molecular mechanism of NASH and the pathological process from NASH to HCC will be an important research direction for chemoprevention and treatment research.The antioxidant transcription factor Nrf1 is a member of the CNC-bZIP transcription factor family and has important molecular functions such as regulating proteasome activity,redox homeostasis,substance and energy metabolism.Nrf1 knockout mice died at embryonic mesoderm formation,which indicates that Nrf1 is one of the essential genes for embryonic development and its important physiological functions.Specific knocking out transcription factor Nrf1 in mouse liver tissue spontaneously caused NASH and eventually deteriorated to HCC,which indicates that Nrf1 plays a critical role in regulating lipid metabolism,nonresolving inflammatory processes,and cell cancer transformation.However,there are few studies about the molecular function and pathological function of Nrf1.The molecular pathological mechanism of NASH and hepatic malignant transformation caused by Nrf1 deletion is still unclear.In this paper,we try to explore in the background of human genetic,the possible molecular mechanisms of NASH and HCC which induced by Nrf1 knockout,from tissue morphology,cell phenotype and molecular function three aspects.A series of experiments using genetically edited monoclonal cell lines as research models were performed to study the molecular processes of nonresolving inflammatory and malignant cell malignancy,and obtained results are as follows:?1?Knockout of the Nrf1 gene in human liver-derived cells can produce NASH-like phenotype such as lipid accumulation and high expression of inflammation-related factors at the cellular level.It indicates that Nrf1 may be related to human NASH and HCC,which has important research significance.?2?Nrf1 knockout-induced phenotypes such as non-controlled activation of the inflammatory marker gene COX2,loss of expression of the tumor suppressor gene PTEN,and malignant proliferation of subcutaneous tumors in nude mice,are all due to excessive activation of Nrf2.The Nrf1/2-COX1/2 axis mediates the cross-talk between oxidative stress homeostasis and the inflammatory response system,whereas the Nrf1/2-miR22-PTEN axis mediates the cross-talk between oxidative stress homeostasis and the PI3K-AKT signaling pathway.?3?In cells,Nrf1 and Nrf2 regulate each other to form a closely related binary system,which jointly regulates the expression of downstream genes.So overexpression Nrf1 or knock it out often produced the same effects.Among which the‘double-sidedness'of Nrf2 on tumors depends on the activity of Nrf1 in genetic background.?4?Deletion of Keap1 expression after Nrf1 knockout is the main cause of Nrf2transient activation.During the study of Keap1,we first discovered a novel splice variant of Keap1 and named it Keap1^?C.In summary,the experimental results in this paper indicated that Nrf1 may be a potential tumor suppressor gene and can be regarded as a target for chemoprevention and clinical treatment of NASH and HCC.The binary whole constituted by Nrf1 and Nrf2may be at the core position of the cross-talk of each signal pathway in the process of tumor development.And the selective regulation of Nrf1/2 will be a new direction for cancer prevention and treatment.