Glucose induced activation of canonical Wnt signaling pathway in hepatocellular carcinoma is regulated by DKK4.
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.
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411 007, India.
Surbhi
S
Chouhan
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411 007, India.
Snahlata
S
Singh
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411 007, India.
Dipti
D
Athavale
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411 007, India.
Pranay
P
Ramteke
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411 007, India.|Laboratory of Neuroscience, Department of Biotechnology and Bioinformatics, Hyderabad Central University, Hyderabad-500 046, India.
Vimal
V
Pandey
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411 007, India.
Jomon
J
Joseph
Sri Dharmasthala Manjunatheshwara Medical Sciences and Hospital, Dharwad-580009, Karnataka, India.
Rajashekar
R
Mohan
Sri Dharmasthala Manjunatheshwara Medical Sciences and Hospital, Dharwad-580009, Karnataka, India.
Praveen Kumar
PK
Shetty
National Centre for Cell Science, Savitribai Phule Pune University Campus, Ganeshkhind, Pune-411 007, India.
Manoj Kumar
MK
Bhat
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D038321:Glycemic Index; D056945:Hep G2 Cells; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C495270:CTNNB1 protein, human; C442333:DKK4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D051176:beta Catenin; D005947:Glucose