The goal of this project is to delineate the molecular and cellular mechanisms that drive hepatocarcinogenesis, and the immediate focus is on deciphering dual roles of molecules in liver tumorigenesis. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, although the underlying mechanisms are poorly understood. In most recent experiments, we have found an unanticipated HCC- suppressing effect of Shp2, a tyrosine phosphatase previously known to be pro-oncogenic. Ablation of Shp2 promotes hepatic damage, inflammation, and spontaneous development of hepatocellular tumors in aged mice. Shp2 loss dramatically sensitizes the mice to chemical carcinogen-induced liver tumorigenesis. We have also found pro- and anti-oncogenic actions of Stat3 in HCC development. Consistent with our observations on Shp2 and Stat3, several other groups have identified HCC-inhibitory effects in genes previously identified as pro-tumorigenic. Although the underlying mechanisms remain to be elucidated, one common phenotype is the augmented HCC development following removal of a pro-survival molecule from hepatocytes. Of note, these mouse tumor models closely recapitulate many aspects of the pathogenic process in human HCCs, involving chronic hepatic injury-inflammation-compensatory proliferation-hepatocarcinogenesis. Therefore, we believe that common mechanisms are shared between the mouse models and human patients in HCC initiation and development. On this project, we will use the established animal models to dissect the molecular and cellular events in the liver at initial, early and late stages of hepatocarcinomas. Specifically, we propose the following 3 Aims: 1) to determine the nature of cell origin in HCC initiation and cell-cell communications driving tumor progression;2) to determine the tumorigenic properties and aberrant signaling pathways of isolated hepatoma cells;and 3) to decipher the dual functions of Stat3 in HCC development. Success of this project will illustrate a general mechanism underlying HCC initiation and progression, and will also facilitate design of novel diagnostic and therapeutic strategies for hepatocarcinoma.
Liver cancer is the third leading cause of cancer-related mortality in the world and the incidence is rising rapidly in the U.S. However, the molecular mechanisms underlying liver tumorigenesis are poorly understood. Success of this project will contribute to better understanding of liver cancer and will provide novel therapeutic strategies for this malignant disease.
|Liang, Yan; Feng, Yun; Zong, Min et al. (2017) ?-Catenin Deficiency in Hepatocytes Aggravates Hepatocarcinogenesis Driven by Oncogenic ?-Catenin and MET. Hepatology :|
|Lee, Jin; Liao, Rui; Wang, Gaowei et al. (2017) Preventive Inhibition of Liver Tumorigenesis by Systemic Activation of Innate Immune Functions. Cell Rep 21:1870-1882|
|Liu, Wen; Guo, Wenjie; Shen, Lihong et al. (2017) T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis-associated cancer in mice. Oncotarget 8:7586-7597|
|Gagné-Sansfaçon, Jessica; Coulombe, Geneviève; Langlois, Marie-Josée et al. (2016) SHP-2 phosphatase contributes to KRAS-driven intestinal oncogenesis but prevents colitis-associated cancer development. Oncotarget 7:65676-65695|
|Maeshima, Keisuke; Stanford, Stephanie M; Hammaker, Deepa et al. (2016) Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation. JCI Insight 1:|
|Chen, Wendy S; Zhu, Helen He; Feng, Gen-Sheng (2016) Treating leukemia at the risk of inducing severe anemia. Exp Hematol 44:329-31|
|Mathew, Grinu; Hannan, Abdul; Hertzler-Schaefer, Kristina et al. (2016) Targeting of Ras-mediated FGF signaling suppresses Pten-deficient skin tumor. Proc Natl Acad Sci U S A 113:13156-13161|
|Luo, Xiaolin; Liao, Rui; Hanley, Kaisa L et al. (2016) Dual Shp2 and Pten Deficiencies Promote Non-alcoholic Steatohepatitis and Genesis of Liver Tumor-Initiating Cells. Cell Rep 17:2979-2993|
|Coulombe, Geneviève; Langlois, Ariane; De Palma, Giada et al. (2016) SHP-2 Phosphatase Prevents Colonic Inflammation by Controlling Secretory Cell Differentiation and Maintaining Host-Microbiota Homeostasis. J Cell Physiol 231:2529-40|
|Hanley, Kaisa L; Feng, Gen-Sheng (2015) A new VETC in hepatocellular carcinoma metastasis. Hepatology 62:343-5|
Showing the most recent 10 out of 15 publications