Hepatocellular carcinoma (HCC), the fifth most common cancer worldwide and the third leading cause of cancer-related deaths, accounts for ~80% of primary liver cancer. Unlike the significant decline in mortality rate of other types of cancers, the mortality of HCC patients has been steadily increasing over the past 2~3 decades, largely owing to the incidence surge of obesity pandemic-related metabolic syndrome and liver metabolic diseases. HCC requires several decades to evolve and is often detected at a stage that is refractory to currently available therapeutics. Thus, prevention and treatment at its initiating stage is of particular importance for HCC patients, which are however impossible without in-depth understanding of molecular insights into how liver cancer initiates. My research interests are mainly focused on how p53 pathways control HCC initiation, and my current findings indicate that intact MDM2/MDMX-p53-MTHFD1L pathways are crucial for protecting chronically injured liver from HCC initiation. I will further determine the underlying mechanisms whereby p53-pathways regulate Mthfd1l and Mthfd1l promotes HCC initiation and development. My long-term goal is to help develop therapeutically specific molecules targeting aberrant signaling pathways for future treatment or prevention of HCC.
Myscientific interest focuses on the molecular dissection and translationalresearch of liver cancer initiation and development, fatty liver disease, particularlythe role of p53 family (including MDM2/MDMX-p53 pathways and p53’s targets, p63and its targets) in controlling liver steatosis, fibrosis and tumorigenesis, usingcell culture system and animal models. In my previous research, throughcell-culture based experiments I have found that metabolic stresses (such asglucose deprivation and anti-diabetes drug treatment) can activate p53 throughAMPK-mediated phosphorylation of MDMX, and subsequent binding of p-MDMX to14-3-3 and dissociation of MDMX with p53. To further understand thephysiological and pathological significance of this pathway in metabolism-associatedtumorigenesis, I have recently recruited MDMX3SA/3SA knock-in mouseline that contains 3 point mutations of phosphorylation sites in Mdmx gene,MDM2C305F/C305F knock-in mouse line (which contains a point mutationto disable the ribosomal stress caused binding of MDM2 to RPL11/L5) and MDMX3SA/3SA;MDM2C305F/C305F double knock-in (DKI) mouse line. My recent resultsindicate that in DKI mice on long-term high-fat-diet (HFD) feeding or treatedwith carcinogen, hepatocellular carcinoma (HCC) initiation is accelerated.Because of these observations, in the near future I will further specificallyinvestigate how dual defects of these p53 activation pathways accelerate HCCinitiation and development, using DEN-induced HCC mouse model and syngeneic mouseliver cancer model. Previously we have identified CCDC3 as a transcriptionaltarget of p63, a member of p53 family, and found that CCDC3 may take partialresponsibility for p63-mediated lipid metabolism and adipogenesis, byrecruiting cell culture system and mouse model ectopically expressing CCDC3.Recently I have created Ccdc3-knockout mouse line to investigate the role ofCCDC3 in obesity, metabolic homeostasis, NAFLD, liver tumorigenesis andlongevity in vivo. Very interestingly I have observed that high-fat-dietinduced obesity, glucose intolerance, insulin resistance and liver steatosis issignificantly compromised by deletion of CCDC3, mice lacking CCDC3 present ayounger metabolic pattern under HFD, and HFD-feeding enhanced liver cancerdevelopment is significantly ameliorated by CCDC3 deletion. To understand howCCDC3 regulates the progress of obesity, NAFLD, liver cancer and metabolicdisorders is one of my major scientific interests. In addition, I havedemonstrated that INZ (a small molecule identified by Lu lab specificallytargeting p53 pathway) can sensitize cancer cells to chemotherapy drugs such ascisplatin and doxorubicin. Hence, I am very experienced in developmentalbiology, mouse genetics, cellular and molecular biology, biochemistry, andpharmacology. Also, Tulane University School of Medicine as wellas Louisiana Cancer Research Center are well equipped with all the state-of-theart core facilities, including confocal imaging, proteomics, metabolomics, FACSand cell sorting, live animal imaging, animal facilities, and other infrastructuresas well as an intellectually interactive, academically cooperative,research-principally dynamic, colleague-friendly, and rapidly growing researchenvironment. Hence, I am highlyconfident about that I am well suited for executing my proposed and highlyinnovative projects.
Ongoing and recently completed projects that I would like to highlightinclude:
1) 555625 Mentoring Research Excellence in Aging andRegenerative Medicine Cobre-Pilot, Yiwei Zhang
Aug. 2017- May2018
Defects of p53-activatingpathways impair beige fat formation/function to exacerbate metabolic disordersand accelerate aging.
2) Tulane SOM Pilot Fund, Yiwei Zhang
Feb. 2021
Role ofp53-IMP2 axis in adipocyte browning.
3) 559422 Mentoring Research Excellence inAging and Regenerative Medicine COBRE-pilot, Yiwei Zhang
Aug.2021- May 2022
Roleof p53-IMP2 axis in adipocyte browning, obesity and aging
