MSX2 is an oncogenic downstream target of activated WNT signaling in ovarian endometrioid adenocarcinoma

Abstract

Ovarian endometrioid adenocarcinomas (OEAs) frequently exhibit constitutive activation of canonical WNT signaling, usually as a result of oncogenic mutations that stabilize and dysregulate the b-catenin protein. In previous work, we used microarray-based methods to compare gene expression in OEAs with and without dysregulated b-catenin as a strategy for identifying novel b-catenin/TCF target genes with important roles in ovarian cancer pathogenesis. Among the genes highlighted by the microarray studies was MSX2, which encodes a homeobox transcription factor. We found MSX2 expression was markedly increased in primary human and murine OEAs with dysregulated b-catenin compared with OEAs with intact b-catenin regulation. WNT pathway activation by WNT3a ligand or GSK3b inhibitor treatment potently induced MSX2 and ectopic expression of a dominant negative form of TCF4 inhibited MSX2 expression in ovarian cancer cells. Chromatin immunoprecipitation studies demonstrated that b-catenin/ TCF directly regulates MSX2 expression via binding to TCF binding elements in multiple regions of the MSX2 gene. Notably, ectopic MSX2 expression was found to promote neoplastic transformation of the rodent RK3E model epithelial cell line and to enhance the invasiveness of immortalized human ovarian epithelial cells in vitro and ovarian carcinoma cells in vivo. Inhibition of endogenous MSX2 expression in ovarian endometrioid cancer cells carrying a b-catenin mutation using shRNA approaches inhibited neoplastic properties of the cells in vitro and in vivo. Expression of MSX2 in selected ovarian carcinoma cells induced changes suggestive of epithelial-mesenchymal transition (EMT), but based on analysis of ovarian cell lines and primary tumor tissues, effects of MSX2 on EMT appear to be complex and context-dependent. Our findings indicate MSX2 is a direct downstream transcriptional target of b-catenin/TCF and has a key contributing role in the cancer phenotype of OEAs carrying WNT/b-catenin pathway defects.

RETRACTED: Silencing of Prrx1b suppresses cellular proliferation, migration, invasion and epithelial–mesenchymal transition in triple‐negative breast cancer

“…In particular, ZEB1 expression was reported to be closely linked with EMT in various cancer cells, including breast cancer. Increasing studies have demonstrated that the Wnt is the major signaling pathway that involved in EMT [26,27]. It is a critical developmental pathway involved in differentiation, migration, invasion and adhesion; these cellular processes are key components of tumorigenesis and metastasis [28].…”

Cessation of Epithelial Bmp Signaling Switches the Differentiation of Crown Epithelia to the Root Lineage in a β-Catenin-Dependent Manner

“…S5B in the supplemental material). Dlx3 and Msx2 are transcription factors required for amelogenesis (47) and regulated by the Wnt/␤-catenin pathway (48,49). ISH of serial sections indicated that the expression of these two factors and Amelx was significantly downregulated in Ctnnb1-negative epithelia in both molars and incisors ( Fig.…”

Homeobox Genes and Their Functional Significance in Ovarian Tumorigenesis

“…For example, both DLX4 and DLX5 induce c-Myc expression (Xu and Testa 2009;Trinh et al, 2011). On the other hand, MSX1 induces expression of growth arrest genes such as GADD153 and inhibits proliferation of ovarian cancer cells (Park et al, 2001), whereas MSX2 promotes ovarian cancer growth (Zhai et al, 2011). As discussed earlier, diversity in amino acid residues in the homeodomain and other motifs of family members gives rise to different DNA-binding specificities and can result in different phenotypes.…”

“…There is considerable evidence that patterning of the reproductive tract is controlled by a regulatory network of distinct sets of Wnts and homeobox genes (Kobayashi & Behringer, 2003). MSX2 is a transcriptional target of -catenin/TCF and MSX2 expression is increased in endometrioid ovarian carcinomas with deregulated -catenin (Zhai et al, 2011). Expression of AbdB HOX genes in the endometrium is also tightly regulated by estrogen and progesterone .…”