Loss of p53 and Ink4a/Arf cooperate in a cell autonomous fashion to induce metastasis of hepatocellular carcinoma cells
Program in Gene Function and Expression; Program in Molecular Medicine
Animals; Cyclin-Dependent Kinase Inhibitor p16; Gene Deletion; Liver Neoplasms, Experimental; Lung Neoplasms; Mice; Mice, Transgenic; Tumor Suppressor Protein p53
Genetics and Genomics
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. HCC patients frequently present with disease that has metastasized to other regions of the liver, the portal vein, lymph nodes, or lungs, leading to poor prognoses. Therefore, model systems that allow exploration of the molecular mechanisms underlying metastasis in this disease are greatly needed. We describe here a metastatic HCC model generated after the somatic introduction of the mouse polyoma virus middle T antigen to mice with liver-specific deletion of the Trp53 tumor suppressor locus and show the cell autonomous effect of p53 loss of function on HCC metastasis. We additionally find that cholangiocarcinoma also develops in these mice, and some tumors display features of both HCC and cholangiocarcinoma, suggestive of origin from liver progenitor cells. Concomitant loss of the Ink4a/Arf tumor suppressor locus accelerates tumor formation and metastasis, suggesting potential roles for the p16 and p19 tumor suppressors in this process. Significantly, tumor cell lines isolated from tumors lacking both Trp53 and Ink4a/Arf display enhanced invasion activity in vitro relative to those lacking Trp53 alone. Thus, our data illustrate a new model system amenable for the analysis of HCC metastasis.
DOI of Published Version
Cancer Res. 2007 Aug 15;67(16):7589-96. Link to article on publisher's site
Chen Y, Klimstra DS, Mongeau ME, Tatem JL, Boyartchuk VL, Lewis BC. (2007). Loss of p53 and Ink4a/Arf cooperate in a cell autonomous fashion to induce metastasis of hepatocellular carcinoma cells. Program in Gene Function and Expression Publications. https://doi.org/10.1158/0008-5472.CAN-07-0381. Retrieved from https://escholarship.umassmed.edu/pgfe_pp/100