WNT10B Functional Dualism: β-Catenin/Tcf-dependent Growth Promotion or Independent Suppression with Deregulated Expression in Cancer

Abstract

We found aberrant DNA methylation of the WNT10B promoter region in 46% of primary hepatocellular carcinoma (HCC) and 15% of colon cancer samples. Three of 10 HCC and one of two colon cancer cell lines demonstrated low or no expression, and 5-aza-2'deoxycytidine reactivated WNT10B expression with the induction of demethylation, indicating that WNT10B is silenced by DNA methylation in some cancers, whereas WNT10B expression is up-regulated in seven of the 10 HCC cell lines and a colon cancer cell line. These results indicate that WNT10B can be deregulated by either overexpression or silencing in cancer. We found that WNT10B up-regulated beta-catenin/Tcf activity. However, WNT10B-overexpressing cells demonstrated a reduced growth rate and anchorage-independent growth that is independent of the beta-catenin/Tcf activation, because mutant beta-catenin-transduced cells did not suppress growth, and dominant-negative hTcf-4 failed to alleviate the growth suppression by WNT10B. Although WNT10B expression alone inhibits cell growth, it acts synergistically with the fibroblast growth factor (FGF) to stimulate cell growth. WNT10B is bifunctional, one function of which is involved in beta-catenin/Tcf activation, and the other function is related to the down-regulation of cell growth through a different mechanism. We suggest that FGF switches WNT10B from a negative to a positive cell growth regulator.

Revealing ETC-1922159 Affected Unknown 3<em>^rd</em> order WNT10B-X-X Combinations, in Silico

“…However, the over-expression of WNT10B has lead to reduced cell growth in cancer, indicating a β-catenin independent component to be behind such a phenomena. Methylation of over-expressed WNT10B and synergistic work with FGF family of proteins later indicate the promotion of oncogenesis, as has been demonstrated in 29 .…”

“…However, the over-expression of WNT10B has lead to reduced cell growth in cancer, indicating a β-catenin independent component to be behind such a phenomena. Methylation of over-expressed WNT10B and synergistic work with FGF family of proteins later indicate the promotion of oncogenesis, as has been demonstrated in 29 .In a more recent work, ASCL2 has been found to play a major role in stemness in colon crypts and is implicated in colon cancer 30 . Switching off the ASCL2 leads to a literal blockage of the stemness process and vice versa.…”

“…In colorectal cancer, WNT10B has shown to play a dual function of both oncogenesis promotion via β-catenin/TCF pathway and the inhibition of cell growth, possibly via FGF family of proteins 29 . Methylation of WNT10B has been found in the some of the cancer cell lines while its reversal has lead to over-expression of the WNT10B.…”

“…This is further confirmed by wet lab experiments in 33 , which show BVES deletion results in amplified stem cell activity and Wnt signaling after radiation. WNT10B has been implicated in colorectal cancer 29 .…”

“…On the other hand, WNT10B is also involved in the formation of bone mass and progenitor maintenance of various kinds of tissue, while deletion of the same leads to loss of bone mass and mesenchymal progenitor cells 21 . Their contribution is also reported in axonal regeneration in injured CNS 22 In colorectal cancer, WNT10B has shown to play a dual function of both oncogenesis promotion via β-catenin/TCF pathway and the inhibition of cell growth, possibly via FGF family of proteins 29 . Methylation of WNT10B has been found in the some of the cancer cell lines while its reversal has lead to over-expression of the WNT10B.…”