ARID1A-mutated cervical cancer depends on the activation of YAP signaling.

BACKGROUND: Cervical cancer is a prevalent female malignancy with poor survival rates. ARID1A is frequently mutated or deleted in a variety of tumors and YAP signaling is widely activated in human malignancies. Nevertheless, the mechanism of YAP signaling in ARID1A-mutated cervical cancer remains unknown. METHODS: The cell viability was determined by MTT assay. The expression of ARID1A, YAP1 and CTGF were evaluated by western blot. The cell proliferation was detected by colony formation. RESULTS: The bioinformatics analysis suggested that mutation of ARID1A was associated with the activation of YAP1 signaling. In addition, knockdown of YAP1 inhibited ARID1A-mutated cervical cancer cells growth. Verteporfin is an inhibition of YAP1 signaling. Interestingly, knockdown of ARID1A decreased ARID1A-wildtype cervical cancer cells resistance to verteporfin. Meanwhile, overexpression of ARID1A increased ARID1A-mutated cervical cancer cells resistance to verteporfin. Similarly, blocking YAP1 signaling inhibited the tumor formation caused by ARID1A-mutated cervical cancer cells in vivo. CONCLUSION: Inhibition of YAP1 signaling suppresses ARID1A-mutated-induced tumorigenesis of cervical cancer, providing a novel therapeutic strategy for cervical cancer.

lncRNA MIAT Regulates Cell Growth, Migration, and Invasion Through Sponging miR-150-5p in Ovarian Cancer.

Background: MIAT (myocardial infarction-associated transcript) regulates cell proliferation, apoptosis, and metastasis in several cancers. In this study, the authors aimed to explore the role of MIAT in ovarian cancer. Materials and Methods: The expression of MIAT in ovarian cancer subtypes, normal human ovarian surface epithelial and ovarian cancer cell lines was measured by qualitative real-time polymerase chain reaction (qRT-PCR). OVCAR3 and SKOV3 cells were transfected with MIAT overexpression plasmid or siMIAT. The cell growth ability was then evaluated by CCK-8 and colony formation assays. The cell migration and invasion rate were separately measured by wound-healing and transwell assays. The levels of epithelial-mesenchymal transition (EMT)-associated markers were evaluated by Western blotting. MIAT sponging miR-150-5p was predicted by starBase and confirmed by dual-luciferase reporter assays. The expression of miR-150-5p in OVCAR3 and SKOV3 cells with MIAT overexpression or knockdown, and in ovarian cancer subtypes was also measured by qRT-PCR. Further analyses confirmed the role of MIAT sponging miR-150-5p in ovarian cancer cells. Results: MIAT was highly expressed in mesenchymal subtype ovarian cancer tissues and ovarian cancer cells. In OVCAR3 and SKOV3 cells, overexpression of MIAT promoted, and knockdown of MIAT suppressed the cell growth, migration, invasion, and EMT. miR-150-5p was sponged and regulated by MIAT. miR-150-5p was downregulated in mesenchymal subtype ovarian cancer. Suppression of cell migration, invasion, and EMT caused by miR-150-5p overexpression was rescued by MIAT overexpression. Conclusions: MIAT acts as an oncogene in ovarian cancer cells through sponging miR-150-5p. MIAT or miR-150-5p expression might be a potential prognostic biomarker for ovarian cancer patients. MIAT and miR-150-5p are potential therapeutic targets in treatment of ovarian cancer.

YAP promotes the malignancy of endometrial cancer cells via regulation of IL-6 and IL-11.

BACKGROUND: Emerging evidence shows that Hippo signal pathways can regulate the progression of various cancer. While the roles of Yes-associated protein (YAP), the key transducer of Hippo signals, in the development of endometrial cancer (EC) are rarely investigated. METHODS: The expression of YAP in endometrial cancer cells and tissues was measured. Its roles in proliferation and expression of interleukins (ILs) were investigated by use of its specific siRNA or inhibitor (verteporfin, VP). RESULTS: YAP was upregulated in endometrial cancer cells and tissues. Knockdown of YAP or VP can suppress the proliferation while increase its chemo-sensitivity of EC cells. We found that targeted inhibition of YAP can decrease the expression of interleukin-6 (IL-6) and IL-11 in EC cells. Recombinant IL-6 or IL-11 can attenuate si-YAP suppressed proliferation of EC cells. Chromatin immunoprecipitation (ChIP) assay suggested that YAP can directly bind with the promoter of IL-6 and induce its transcription. As to IL-11, inhibitor of NF-κB (BAY 11-7082) can significantly down regulate the mRNA expression of IL-11. Over expression of p65 abolished si-YAP suppressed transcription of IL-11. It suggested that NF-κB was involved in the YAP regulated expression of IL-11. CONCLUSIONS: YAP can regulate the proliferation and progression of EC cells. It suggested that targeted inhibition of YAP might be a potent potential approach for EC therapy.

NEDD9 overexpression is associated with the progression of and an unfavorable prognosis in epithelial ovarian cancer.

Neural precursor cell-expressed, developmentally down-regulated 9 (NEDD9), a scaffolding protein, has been identified as a prometastatic and poor prognostic gene in multiple malignant tumors. However, the potential role of the NEDD9 protein in epithelial ovarian cancer (EOC) remains unclear. In the present study, we investigated the expression of NEDD9 and the correlation between NEDD9 expression and prognosis in EOC. NEDD9 expression was detected in 129 archived EOC specimens by immunohistochemical staining and in 28 freshly frozen EOC specimens by Western blotting. The expression of NEDD9 was evaluated in ovarian cancer cell lines by Western blotting and immunofluorescence. The association between the expression of NEDD9 and prognosis was determined by survival analysis. Results suggested that NEDD9 was overexpressed in EOC specimens compared with noninvasive epithelial ovarian tumors and normal ovarian specimens. A high level of NEDD9 expression significantly correlated with advanced-stage tumors (International Federation of Gynecology and Obstetrics classes III-IV, P < .001), high-grade carcinoma (grades 2-3, P < .001), and suboptimal primary cytoreductive surgery (residual disease <1cm, P = .021). The expression level of NEDD9 varied in ovarian cancer cell lines. Multivariate analysis indicated that NEDD9 overexpression (P = .033), advanced stage (P < .001), and high-grade carcinoma (P = .01) were independent predictors of poor survival. In conclusion, NEDD9 is overexpressed and associated with an unfavorable prognosis in EOC. NEDD9 overexpression is an independent factor of poor prognosis and may serve as a potential biomarker in EOC.

Overexpression of c-Abl predicts unfavorable outcome in epithelial ovarian cancer.

OBJECTIVES: Abelson tyrosine kinase (c-Abl) has been shown to promote solid tumor invasion and metastasis. However, little is known regarding whether c-Abl contributes to the development or progression of epithelial ovarian cancer (EOC). The aims of this study are to determine the expression of c-Abl and investigate a possible relationship between c-Abl and prognosis in EOC. METHODS: c-Abl protein level was evaluated in 137 EOC specimens by immunohistochemical staining and 32 EOC specimens by Western blot analysis. Expression of c-Abl in ovarian cancer cell lines was measured by Western blot analysis and immunofluorescence. Survival analysis was performed to assess the correlation between c-Abl expression and survival. RESULTS: Immunohistochemical staining and Western blot analysis revealed that c-Abl was overexpressed in EOC compared with samples from a non-invasive ovarian tumor and normal ovaries (P<0.05). Furthermore, expression of c-Abl was significantly associated with advanced FIGO stage, poor grade, serum Ca-125 and residual tumor size (P<0.05). By Western blot analysis, c-Abl expression was examined in four ovarian cancer cell lines. Meanwhile, immunofluorescence was performed to show c-Abl expression in SKOV3 and 3AO cell lines. Survival analysis demonstrated that patients with low c-Abl staining had a significantly better survival compared to patients with high c-Abl staining (P<0.05). In multivariate analysis, c-Abl overexpression, poor grade, advanced stage and suboptimal surgical debulking were independent prognostic factors of poor survival. CONCLUSIONS: Our present study finds that c-Abl overexpression is associated with an unfavorable outcome. c-Abl may be a crucial predictor for EOC metastasis.

WAVE1 gene silencing via RNA interference reduces ovarian cancer cell invasion, migration and proliferation.

OBJECTIVE: Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) has been implicated in cancer cell migration and invasion. We have previously shown that the overexpression of WAVE1 in epithelial ovarian cancer (EOC) tissues is associated with a poor prognosis. However, the mechanism of WAVE1 regulating the malignant behaviors in EOC remains unclear. METHODS: In the present study, we knocked down WAVE1 expression in SKOV3 and OVCAR-3 cells through RNA interference to detect the cell biology and molecular biology changes. Moreover, western-blot was used to investigate the underlying mechanism of WAVE1 regulating the proliferative and invasive malignant behaviors in ovarian cancer cells. RESULTS: The down-regulation of WAVE1 had a significant effect on cell morphological changes. WAVE1 silencing decreased cell migration, cell invasion, cell adhesion, colony formation and cell proliferation in vitro. In addition, we found that down-regulation of WAVE1 inhibited malignant behaviors in vivo. Furthermore, our study also indicated that the PI3K/AKT and p38MAPK signaling pathways might contribute to WAVE1 promotion of ovarian cancer cell proliferation, migration, and invasion. CONCLUSIONS: WAVE1 might promote the proliferative and invasive malignant behaviors through the activation of the PI3K/AKT and p38MAPK signaling pathways in EOC.

High level of WAVE1 expression is associated with tumor aggressiveness and unfavorable prognosis of epithelial ovarian cancer.

OBJECTIVES: Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) has been shown to promote cancer invasion and metastasis. However, no evidence has been found to identify the role of WAVE1 in epithelial ovarian cancer (EOC). This study aims to determine the effect of WAVE1 expression and investigate a possible relationship between WAVE1 and prognosis in EOC. METHODS: WAVE1 protein level was measured in 223 EOC specimens by immunohistochemical staining and 46 EOC specimens by Western blot analysis. Expression of WAVE1 in ovarian cancer cell lines was evaluated by Western blot analysis and immunofluorescence. Survival analysis was performed to assess the correlation between WAVE1 expression and survival. RESULTS: Immunohistochemical staining and Western blot analysis showed that WAVE1 was overexpressed in EOC compared with samples from a non-invasive ovarian tumor and normal ovaries (P<0.05). Furthermore, expression of WAVE1 was significantly associated with advanced FIGO stage, poor grade, serum Ca-125 and residual tumor size (P<0.05). By Western blot analysis, WAVE1 expression was detected in four ovarian cancer cell lines. Immunofluorescence was performed to demonstrate WAVE1 expression in SKOV3 and 3AO cell lines. Survival analysis showed that patients with low WAVE1 staining had a significantly better survival compared to patients with high WAVE1 staining (P<0.05). In multivariate analysis, WAVE1 overexpression, advanced stage and suboptimal surgical debulking were independent prognostic factors of poor survival. CONCLUSIONS: Our present study finds that WAVE1 overexpression is associated with an unfavorable prognosis. WAVE1 is an independent prognostic factor for EOC, which suggests that it is a novel and crucial predictor for EOC metastasis.