S100A4/Nonmuscle Myosin IIA/p53 Axis Contributes to Aggressive Features in Ovarian High-Grade Serous Carcinoma.

S100A4 is a small calcium-binding protein that exerts its biological functions by interacting with nonmuscle myosin IIA (NMIIA) and p53. Although S100A4 promotes metastasis in several tumors, little is known about its involvement in the progression of ovarian high-grade serous carcinomas (HGSCs). Herein, we focused on functional roles of the S100A4/NMIIA/p53 axis in these tumors. In HGSC cell lines harboring mutant p53, knockdown (KD) of S100A4 reduced the expression of several epithelial-mesenchymal transition/cancer stem cell markers and the ALDH1high population, consistent with an inhibition of stemness features. S100A4-KD also increased apoptosis, decreased cell proliferation, and accelerated cell mobility. This was accompanied by increased Snail expression, which, in turn, was likely due to loss of p53 function. In contrast, specific inhibition of NMIIA by blebbistatin induced phenotypes that-with the exception of cell proliferation and mobility-were opposite to those observed in S100A4-KD cells. In clinical samples, cytoplasmic and/or nuclear interactions between S100A4, NMIIA, and mutant p53 were observed. In addition, high expression of S100A4, but not NMIIA or p53, was a significant and independent unfavorable prognostic factor in HGSC patients. These findings suggest that, via its interaction with NMIIA and p53, overexpressed S100A4 may induce epithelial-mesenchymal transition/cancer stem cell properties in HGSC and elicit several other tumor-associated phenotypes.

Alterations in ß-catenin, microsatellite instability, and HNF-1ß levels are independently associated with ovarian endometriosis-associated tumorigenesis.

We focused on specific molecular events during the development of endometriosis-associated ovarian endometrioid carcinoma (OEmCa) and ovarian clear cell carcinoma (OCCCa). Alterations in ß-catenin (encoded by CTNNB1) and microsatellite instability (MSI), as well as changes in the expression levels of HNF-1ß and DNA mismatch repair (MMR) proteins were investigated in 50 OEmCas and 21 OCCCas with endometriotic lesions. Mutations of CTNNB1 were identified in 28 (56%) of the 50 OEmCa cases and 26 (41.9%) of the 62 coexisting endometriosis lesions. MSI-high (H) was observed in 7 (14.6%) of the 48 OEmCa and 14 (23.3%) of the 60 coexisting endometriosis, and was significantly associated with loss of MMR protein expression, but not CTNNB1 mutations. Nonidentical CTNNB1 status between 2 different epithelial lesions within endometriosis was observed in 8 of 10 informative endometriosis cases that had adjacent OEmCa. Similar findings for MSI features were also found in 2 of 3 informative cases, suggesting that endometriotic lesions may predominantly consist of polyclonal cells. In contrast, high HNF-1ß expression was significantly associated with SLC3A1 expression, which plays a major role in HNF-1ß-triggered induction of reactive oxygen species in OCCCas, independent of abnormalities in both ß-catenin and MSI/MMR status. Finally, 4 inflammatory parameters associated with repeated hemorrhaging in endometriosis were significantly higher in endometriosis with MSI-high when compared with that with MSS, independent of both ß-catenin and HNF-1ß status. In conclusion, different molecular pathways including alterations in ß-catenin, MSI, and HNF-1ß levels may contribute to tumorigenesis in endometriosis-associated carcinoma.