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Title: RUNX3 acts as an ocogene through a hedgehog-dependent pathway in selected human neoplasms
Keywords: RUNX3 , ocogene, hedgehog, human neoplasms
Issue Date: 26-Jan-2011
Citation: PEH BEE KEOW (2011-01-26). RUNX3 acts as an ocogene through a hedgehog-dependent pathway in selected human neoplasms. ScholarBank@NUS Repository.
Abstract: RUNX3 is a cellular transcription factor and, as such is active in the nucleus (Katinka et al 1980, Tanaka et al 1982). In all adult solid cancers analyzed before the start of our work, RUNX3 acts as a tumor suppressor gene (Bae and Choi 2004) (downregulation is associated with tumorigenesis). RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization (Ito et al 2005) and promoter hypermethylation (Kim et al 2005). Since RUNX3 is a relatively new gene discovered in the 1990s, its different roles in human pathology are not fully explored. Hence, I explored the effect of RUNX3 overexpression in Sonic Hedgehog (SHH) - related neoplasms. Through my screening, RUNX3 was up-regulated and active in basal cell carcinoma and desmoplastic medulloblastoma. Although SHH has a minimal role in most adult tissues, it is known to be activated in basal cell carcinoma (Botchkarev and Fessing 2005) and medulloblastoma (Goodrich et al 1997). Silencing of RUNX3 with lentiviral shRNAs reduced cell proliferation and tumorigenesis in vitro and in vivo. In nude mice experiments, knockdown of endogenous RUNX3 in desmoplastic medulloblastoma cells significantly suppress tumorigenicity in nude mice. GLI1 was immunoprecipitated with RUNX3, indicating that endogenous RUNX3 interacts with endogenous GLI1 of the SHH signaling pathway. There are four RUNX consensus binding sequences in GLI1 promoter. Chromatin immunoprecipitation assay showed that RUNX3 is bound to the cognate RUNX3 binding site in the promoter region of GLI1. Altogether, these results showed that RUNX3 has an oncogenic activity in basal cell carcinoma and desmoplastic medulloblastoma. For the first time, GLI1 was identified as a novel downstream target of RUNX3 in the SHH signaling pathway. Strong evidence showed that RUNX3 transcriptionally regulates the expression of GLI1.
Appears in Collections:Ph.D Theses (Open)

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