Chouhan , S. and Singh , S. and Athavale, D. and Ramteke , P. and Pandey , V. and Joseph, J. and Mohan , R. and Shetty , P.K. and Bhat , M.K. (2016) Glucose induced activation of canonical Wnt signaling pathway in hepatocellular carcinoma is regulated by DKK4. Scientific Report (27558 ).

Text 56-1.Dr. Bhat (Sci. Report).pdf Download (2372Kb)

Abstract

Elevated glycemic index, an important feature of diabetes is implicated in an increased risk of hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms of this association are relatively less explored. Present study investigates the effect of hyperglycemia over HCC proliferation. We observed that high glucose culture condition (HG) specifically activates canonical Wnt signaling in HCC cells, which is mediated by suppression of DKK4 (a Wnt antagonist) expression and enhanced β-catenin level. Functional assays demonstrated that a normoglycemic culture condition (NG) maintains constitutive expression of DKK4, which controls HCC proliferation rate by suppressing canonical Wnt signaling pathway. HG diminishes DKK4 expression leading to loss of check at G0/G1/S phases of the cell cycle thereby enhancing HCC proliferation, in a β-catenin dependent manner. Interestingly, in NOD/SCID mice supplemented with high glucose, HepG2 xenografted tumors grew rapidly in which elevated levels of β-catenin, c-Myc and decreased levels of DKK4 were detected. Knockdown of DKK4 by shRNA promotes proliferation of HCC cells in NG, which is suppressed by treating cells exogenously with recombinant DKK4 protein. Our in vitro and in vivo results indicate an important functional role of DKK4 in glucose facilitated HCC proliferation.

Item Type:	Article
Additional Information:	This is Open Access article for full text click above weblink
Subjects:	Cancer Biology
Depositing User:	Mr. Rameshwar Nema
Date Deposited:	01 Jul 2016 03:53
Last Modified:	01 Jul 2016 03:53
URI:	http://nccs.sciencecentral.in/id/eprint/289

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