Premium
Loss of desmocollin‐2 confers a tumorigenic phenotype to colonic epithelial cells through activation of Akt/β‐catenin signaling
Author(s) -
Kolegraff Keli,
Nava Porfirio,
Helms My N,
Parkos Charles,
Nusrat Asma
Publication year - 2011
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.25.1_supplement.242.3
Subject(s) - cancer research , carcinogenesis , gene knockdown , cell growth , protein kinase b , downregulation and upregulation , biology , microbiology and biotechnology , signal transduction , cell culture , cancer , gene , genetics
Reduced expression of the desmosomal cadherin desmocollin‐2 (Dsc2) has been reported in colorectal carcinomas, suggesting that Dsc2 may play a role in the development and/or progression of these cancers. However, no studies to date have examined the mechanistic contribution of Dsc2‐deficiency to tumorigenesis. Here, we report that loss of Dsc2 promotes cell proliferation and enables tumor growth in vivo through the activation of Akt/β‐catenin signaling. We found that down‐regulation of Dsc2 in the non‐tumorigenic colonic epithelial cell line SK‐CO15 led to enhanced β‐catenin signaling, an increase in cell proliferation, acquisition of invasive properties, and expression of CD44, a known β‐catenin target gene that is upregulated in colon cancers. Consistent with the in vitro findings that loss of Dsc2 promotes cell transformation, cells lacking Dsc2 formed tumors in immunodeficient mice, an effect that was not observed for Dsc2‐expressing parental cell lines. Importantly, inhibition of Akt prevented the increase in β‐catenin signaling and proliferation following Dsc2 knockdown and attenuated the in vivo growth of Dsc2‐deficient cells. Taken together, our results provide evidence that loss of Dsc2 may directly contribute to the growth of colon cancer cells. This work is supported by CCFA Fellowship and AGA Research Scholar Awards (PN) and NIH grants DK61739 (CP), DK55679 and DK59888 (AN).