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C‐Met And β‐catenin Co‐delivery By Hydrodynamic Tail Vein Injection Promotes HCC Development In Mice
Author(s) -
Tao Junyan,
Singh Sucha,
Monga Satdarshan
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.45.10
Subject(s) - hccs , catenin , hepatocellular carcinoma , mutant , carcinogenesis , wnt signaling pathway , cancer research , beta catenin , hepatocyte growth factor , medicine , cancer , biology , chemistry , receptor , microbiology and biotechnology , signal transduction , gene , genetics
Hepatocellular carcinoma (HCC) isthe fifth mostfrequently diagnosed type of cancer worldwide and second most frequent cause of cancer related deaths. Thus generation of a mouse model that mimics human HCC will improve understanding of biology and provide opportunity to test novel therapies. Hepatocyte growth factor receptor c‐Met is overexpressed in HCC. Also β‐catenin mutations affecting serine 33 (S33) and S45 but not N‐terminal deletions affecting exon‐3 are frequently observed in HCC patients. Intriguingly, expression of mutant forms of β‐catenin or c‐Met alone fail to induce HCC development in mice. Previous study has shown that co‐delivery of β‐catenin N‐terminal deletion mutant with c‐Met induced HCC, but there is no study on crosstalk of β‐catenin point mutants and c‐Met. We co‐delivered c‐Met and β‐catenin point mutants (S33Y and S45Y) by hydrodynamic tail vein injection to initiate liver tumorigenesis. Microscopic nodules were apparent at 4 weeks and large tumors were evident at 9 weeks post injection of c‐Met/S45Y‐β‐catenin. Microscopic nodules were apparent at 6 weeks while large tumors were evident at 12 weeks after c‐Met/S33Y‐β‐catenin injection. Tumors in both conditions were HCCs that displayed overexpression of several downstream targets of Wnt and HGF pathways. In summary, our results demonstrate that c‐Met cooperates with point‐mutant‐β‐catenin to promote growth and development of HCC.