Paired box 8 facilitates the c-MYC related cell cycle progress in TP53-mutation uterine corpus endometrial carcinoma through interaction with DDX5.

As a molecular marker of the female reproductive system, Paired Box 8 is widely used in pathological diagnosis of gynecological tumors, but it is not clear whether its expression level is related to the development of uterine corpus endometrial carcinoma and molecular subtype classifications. Here, we show that PAX8 is up-regulated in TP53 mutation category of UCEC, which is result from the low methylation level of PAX8 in UCEC. We have identified that genes connected to ribosome, lysosome, ribosome biogenesis and cell cycle as PAX8 targets and demonstrate that modulation of the PAX8-DDX5 interaction influences c-MYC related cell cycle and cell growth. Our work defines DDX5 as a critical PAX8 co-factor, places the PAX8-DDX5 interaction in biological context, and highlights PAX8 as a key point for development of novel anti-MYC therapies in TP53-mutation UCEC.

FoxM1 promotes the migration of ovarian cancer cell through KRT5 and KRT7.

Forkhead box M1(FoxM1) played an important role in the pathogenesis of ovarian cancer, but its downstream molecular network is mysterious. Here, we combined ChIP-seq with RNA-seq analysis and identified 687 FoxM1-binding regions and 182 genes regulated by FoxM1. The above data pointed out that KRT5 and KRT7 were downstream target genes of FoxM1. Next, we used qPCR and Western blot to verify that FoxM1 knockdown inhibited the expression levels of KRT5 and KRT7. We also demonstrated that FoxM1 regulated KRT5 and KRT7 genes expression through binding a consensus AP-2 cis element, and showed that KRT5 and KRT7 deficiency could prevent the migration but not proliferation of SK-OV-3 cells. Finally, tissue microarray results indicated that KRT5 and KRT7 were highly expressed in ovarian cancer and positively correlated with FoxM1 expression. TCGA database showed that high expression of KRT5 and KRT7 could significantly reduce the survival rate of patients with ovarian cancer. The above results clarify the specific downstream molecular network of FoxM1 to promote the pathogenesis of ovarian cancer, and provide a basis experiment for the judgment of ovarian cancer prognosis and the design of drug targets.

SND1 facilitates the invasion and migration of cervical cancer cells by Smurf1-mediated degradation of FOXA2.

Staphylococcal nuclease domain-containing protein 1 (SND1) is known to be involved in the progression of a variety of human cancers. However, the role of SND1 in cervical cancer remains unclear. Here, we found that the expression of SND1 in cervical cancer tissue was higher than that in normal cervical tissue. Importantly, high SND1 expression was closely associated with tumorigenic phenotype and shorter survival among cervical cancer patients. Functional assays demonstrated that SND1 knockdown inhibited the migration and invasion capabilities of cervical cancer cells in vitro. Additionally, a xenograft assay showed that silencing SND1 in cervical cancer cells suppressed lung metastasis in vivo. Further investigation revealed that knockdown of SND1 inhibited epithelial-to-mesenchymal transition (EMT) of cervical cancer cells by enhancing FOXA2 expression. Moreover, the pro-metastasis effect of SND1 in cervical cancer was at least in part dependent on FOXA2 inhibition. Mechanistically, we found that SND1-induced FOXA2 ubiquitination resulted in degradation, mediated by the E3 ligase enzyme Smurf1. In summary, SND1 plays a crucial role in cervical cancer metastasis, and we provide evidence that SND1 may serve as a prognostic and therapeutic target in cervical cancer.

Elevated plasma levels of lysophosphatidic acid and aberrant expression of lysophosphatidic acid receptors in adenomyosis.

BACKGROUND: Given the important roles of the receptor-mediated lysophosphatidic acid (LPA) signaling in both reproductive tract function and gynecological cancers, it will be informative to investigate the potential role of LPA in the development of adenomyosis. The objective of this study was to evaluate the levels of LPA in plasma and the expression of six LPA receptors in the endometrial tissue collected from women with and without adenomyosis. METHODS: Plasma and endometrial tissue samples were collected form women with and without adenomyosis. The levels of LPA in plasma were determined by using high-performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Immunohistochemistry was performed to evaluate the expression of six LPA receptors (LPA1-6) in endometrial tissue samples. The effects of LPA on IL-8 production, VEGF production and cell proliferation in human endometrial stromal cells (ESCs) were also assessed. RESULTS: LPA1 staining was localized to the cytoplasm, membrances of the epithelial cells of the endometrial glands, and there was little staining in the stromal cells. LPA2-5 staining were localized to the nuclei of stromal and glandular cells. Plasma levels of LPA were increased in adenomyosis. LPA1, LPA4 and LPA5 immunoreactivity were significantly higher in the adenomyosis group than in the control group, while LPA2 and LPA3 immunoreactivity were significantly lower in the adenomyosis group than in the control group. LPA6 was undetectable in the endometria. LPA induced the release of IL-8 from ESCs but did not affect cell proliferation and VEGF production. CONCLUSION: These results indicate that elevated plasma levels of LPA and aberrant expression of LPA receptors in the endometria may be associated with the development of adenomyosis.

Suppressor of fused (Sufu) promotes epithelial-mesenchymal transition (EMT) in cervical squamous cell carcinoma.

Suppressor of fused is essential for the maximal activation of Sonic Hedgehog signaling in development and tumorigenesis. However, the role of Sufu in cervical carcinoma remains unknown. Here, we report new findings of Sufu in regulating the epithelial-to-mesenchymal transition through the FoxM1 transcriptional modulation by 14-3-3ζ protein in cervical carcinoma. Sufu is overexpressed in cervical squamous cell carcinoma and its level in clinical tumor tissues is positively correlated with 14-3-3ζ. Functionanlly, siSufu remarkably prevents the cancer cell migration and invasion. We further demonstrate that the transcriptional activity of Sufu is increased by FoxM1, of which stability is promoted by 14-3-3ζ. Knockdown FoxM1 decreases the invasion of SiHa cells and reconstitution of Sufu rescues the invasion of these cells.Finally, overexpression of Sufu is significantly associated with differentiation grade, FIGO stage, Depth of stromal invasion and vascular cancer embolus. Our findings highlight a novel role for Sufu in cervical carcinogenesis.