A novel necroptosis-related lncRNA signature for predicting prognosis and anti-cancer treatment response in endometrial cancer.

Background: Necroptosis, a form of programmed cell death, underlies tumorigenesis and the progression of cancers. Anti-cancer strategies targeting necroptosis have increasingly been shown to present a potential cancer therapy. However, the predictive utility and anticancer sensitivity value of necroptosis-related lncRNAs (NRLs) for endometrial cancer (EC) are currently unknown. Methods: EC patient gene expression profiles and the corresponding clinical information collected from The Cancer Genome Atlas were used to identify NRLs that constituted a predictive signature for EC. The functional pathways, immune status, clinicopathological correlation, and anticancer drug sensitivity of the patients relative to the NRLs signatures were analyzed. Results: A signature composed of 7 NRLs (AC019080.5, BOLA3-AS1, AC022144.1, AP000345.2, LEF1-AS1, AC010503.4, and RPARP-AS1) was identified. The high-risk patient group with this signature exhibited a poorer prognosis and lower survival rate than low-risk group lacking this signature. This necroptosis-related lncRNA signature had a higher predictive accuracy compared with other clinicopathological variables (area under the receiver operating characteristic curve of the risk score: 0.717). Additionally, when patients were stratified based on other clinicopathological variables, the overall survival was significantly shorter in the high-risk versus low-risk group across all cohorts. Gene set enrichment analysis (GSEA) revealed that immune- and tumor-related signaling pathways and biological processes were enriched in the high-risk group compared to the low-risk group. Single-sample gene set enrichment analysis (ssGSEA) additionally showed that the resulting risk score was strongly correlated with EC patient immune status. Finally, patients with high-risk scores were more sensitive to the anti-cancer drugs such as Docetaxel, Mitomycin.C, Vinblastine, AZD.2281 (olaparib), AZD6244, and PD.0332991 (Palbociclib). Conclusion: These findings reveal a novel necroptosis-related lncRNA signature for predicting EC patient prognosis and shed new light on anticancer therapy strategies for EC.

Maelstrom promotes tumor metastasis through regulation of FGFR4 and epithelial-mesenchymal transition in epithelial ovarian cancer.

BACKGROUND: Increasing evidence has indicated that Maelstrom (MAEL) plays an oncogenic role in various human carcinomas. However, the exact function and mechanisms by which MAEL acts in epithelial ovarian cancer (EOC) remain unclear. RESULTS: This study demonstrated that MAEL was frequently overexpressed in EOC tissues and cell lines. Overexpression of MAEL was positively correlated with the histological grade of tumors, FIGO stage, and pT/pN/pM status (p < 0.05), and it also acted as an independent predictor of poor patient survival (p < 0.001). Ectopic overexpression of MAEL substantially promoted invasiveness/metastasis and induced epithelial-mesenchymal transition (EMT), whereas silencing MAEL by short hairpin RNA effectively inhibited its oncogenic function and attenuated EMT. Further study demonstrated that fibroblast growth factor receptor 4 (FGFR4) was a critical downstream target of MAEL in EOC, and the expression levels of FGFR4 were significantly associated with MAEL. (P < 0.05). CONCLUSION: Our findings suggest that overexpression of MAEL plays a crucial oncogenic role in the development and progression of EOC through the upregulation of FGFR4 and subsequent induction of EMT, and also provide new insights on its potential as a therapeutic target for EOC.

CHD1L promotes EOC cell invasiveness and metastasis via the regulation of METAP2.

Chromodomain helicase DNA binding protein 1-like (CHD1L) gene has been proposed to play an oncogenic role in human hepatocellular carcinoma. Previously we reported that CHD1L overexpression is significantly associated with the metastasis proceeding of epithelial ovarian cancer (EOC), and may predict a poor prognosis in EOC patients. However, the potential oncogenic mechanisms by which CHD1L acts in EOC remain unclear. To elucidate the oncogenic function of CHD1L, we carried out a series of in vitro assays, with effects of CHD1L ectogenic overexpression and silencing being determined in EOC cell lines (HO8910, A2780 and ES2). Real-time PCR and Western blotting analyses were used to identify potential downstream targets of CHD1L in the process of EOC invasion and metastasis. In ovarian carcinoma HO8910 cell lines, ectopic overexpression of CHD1L substantially induced the invasive and metastasis ability of the cancer cells in vitro. In contrast, knockdown of CHD1L using shRNA inhibited cell invasion in vitro in ovarian carcinoma A2780 and ES2 cell lines. We also demonstrated that methionyl aminopeptidase 2 (METAP2) was a downstream target of CHD1L in EOC, and we found a significant, positive correlation between the expression of CHD1L and METAP2 in EOC tissues (P<0.05). Our findings indicate that CHD1L plays a potential role in the inducement of EOC cancer cell invasion and/or metastasis via the regulation of METAP2 expression and suggests that CHD1L inhibition may provide a potential target for therapeutic intervention in human EOC.

High expression of AGBL2 is a novel prognostic factor of adverse outcome in patients with ovarian carcinoma.

The putative oncogenic role of ATP/GTP binding protein like 2 (AGBL2) in catalyzing α-tubulin detyrosination has recently been characterized in cancer. However, the status of AGBL2 expression in ovarian cancer and its potential clinical and prognostic significance remain unclear. In the present study, immunohistochemistry staining investigated the protein expression level of AGBL2 in paraffin-embedded pathological specimens from 30 normal ovaries, 35 ovarian cystadenomas, 38 borderline ovarian tumors and 165 invasive ovarian carcinomas. The association between AGBL2 expression and clinicopathological characteristics of patients was evaluated using the χ2 test or Fisher's exact test. The survival status of patients was assessed by receiver-operator curve analysis. The results demonstrated that high expression of AGBL2 was observed in 9% of cystadenomas cases, 21% of borderline tumors cases and 38% of ovarian carcinomas cases; however AGBL2 expression was not high in normal ovarian tissues (P<0.01). Furthermore, the results demonstrated that high expression of AGBL2 was associated with tumor histological grade, advanced pT/pN/pM and cancer stage according to the International Federation of Gynecology and Obstetrics (P<0.05). Following univariate survival analysis of the ovarian carcinoma groups, high expression of AGBL2 was significantly associated with shorter patient survival (P<0.001). In addition, multivariate analysis revealed that AGBL2 could be identified as a potential independent prognostic factor for overall survival in patients with ovarian carcinoma (P=0.004). Furthermore, the results demonstrated that AGBL2 expression was significantly associated with the expression of immunity related GTPase M (IRGM) (P=0.013) and LC3A/B (P=0.004). IRGM expression level was also significantly associated with LC3A/B expression level (P=0.023). These findings demonstrated that AGBL2 expression was high in ovarian carcinomas, which suggested that AGBL2 may participate in the acquisition of an aggressive phenotype and may therefore serve as an independent prognostic molecular marker.

Overexpression of SLC12A5 is associated with tumor progression and poor survival in ovarian carcinoma.

INTRODUCTION: The solute carrier family 12 member 5 (SLC12A5) gene is playing a putative oncogenic role in colorectal carcinoma. However, the status of SLC12A5 amplification and expression in ovarian carcinoma and its potential clinical and/or prognostic significance has not yet been investigated. METHODS: In the present study, semi-quantitative staining and fluorescence in situ hybridization were used to investigate SLC12A5 protein expression and gene amplification levels. Samples were obtained from archival, formalin-fixed, paraffin-embedded pathological specimens consisting of 30 normal ovaries, 30 ovarian cystadenomas, 30 borderline ovarian tumors, and 147 invasive ovarian carcinomas. SLC12A5 immunohistochemical staining results, pathological parameters, and patient prognosis were then evaluated using various statistical models. Patient survival rate was also assessed using receiver-operator curve analysis. RESULTS: Our results revealed no SLC12A5 protein overexpression in normal ovaries. However, 7% of cystadenomas had SLC12A5 protein overexpression along with 17% of borderline tumors and 37% of ovarian carcinomas (P<0.01). Amplification of SLC12A5 was detected in 10.3% of ovarian carcinomas. Further correlational analyses showed that SLC12A5 protein overexpression in ovarian carcinomas was significantly associated with ascending histological grade, pT/pN/pM status, as well as FIGO stage (P<0.05). A subsequent univariate survival analysis of our ovarian carcinoma cohorts resulted in a significant association between SLC12A5 protein overexpression and decreased patient survival (44.3 and 85.9 months for high and low SLC12A5 protein expression, respectively; P<0.001). Importantly, additional multivariate analysis revealed that SLC12A5 protein expression was a significant, independent prognostic factor for overall survival in ovarian carcinoma patients (P=0.003). CONCLUSIONS: Collectively, these findings support the conclusion that SLC12A5 protein overexpression could indicate an invasive and/or aggressive phenotype of ovarian carcinoma. Future work will need to investigate whether SLC12A5 protein can serve as an independent prognostic molecular marker in patients with ovarian carcinoma.

CHD1L protein is overexpressed in human ovarian carcinomas and is a novel predictive biomarker for patients survival.

BACKGROUND: Our recent studies suggested that the chromodomain helicase DNA binding protein 1-like (CHD1L) gene plays an oncogenic role in human hepatocellular carcinoma. However, the status of CHD1L protein expression in ovarian cancer and its clinical/prognostic significance are obscure. METHODS: In this study, immunohistochemistry (IHC) for CHD1L was performed on a tissue microarray (TMA) containing 102 primary ovarian carcinomas and 44 metastatic lesions (omental metastasis). Receiver-operator curve (ROC) analysis was used to evaluate patients' survival status. RESULTS: There is an augmented tendency of CHD1L expression in ovarian carcinoma metastasis than in primary lesions (P<0.05). A significant association was found between positive expression of CHD1L and tumors histological type (P <0.05). By univariate survival analysis of the ovarian carcinoma cohorts, positive expression of CHD1L was significantly correlated with shortened patient survival (mean 66.7 months versus 97.4 months, P<0.05). Moreover, CHD1L expression was evaluated to be a significant and independent prognostic factor in multivariate analysis (P<0.05). CONCLUSIONS: These findings provide evidence that positive expression of CHD1L protein is significantly correlated with the metastasis proceeding of ovarian carcinoma, and CHD1L protein expression, as examined by IHC, may act as a novel prognostic biomarker for patients with ovarian carcinoma.

Intensive expression of Bmi-1 is a new independent predictor of poor outcome in patients with ovarian carcinoma.

BACKGROUND: It has been suggested that the B-cell specific moloney leukemia virus insertion site 1 (Bmi-1) gene plays an oncogenic role in several types of human cancer, but the status of Bmi-1 amplification and expression in ovarian cancer and its clinical/prognostic significance are unclear. METHODS: The methods of immunohistochemistry and fluorescence in situ hybridization were utilized to examine protein expression and amplification of Bmi-1 in 30 normal ovaries, 30 ovarian cystadenomas, 40 borderline ovarian tumors and 179 ovarian carcinomas. RESULTS: Intensive expression of Bmi-1 was detected in none of the normal ovaries, 3% cystadenomas, 10% borderline tumors, and 37% ovarian carcinomas, respectively. Amplification of Bmi-1 was detected in 8% of ovarian carcinomas. In ovarian carcinomas, significant positive associations were found between intensive expression of Bmi-1 and the tumors ascending histological grade, later pT/pN/pM and FIGO stages (P < 0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of intensive expression of Bmi-1 with shortened patient survival (mean 49.3 months versus 100.3 months, p < 0.001) was demonstrated. Importantly, Bmi-1 expression provided significant independent prognostic parameters in multivariate analysis (p = 0.005). CONCLUSIONS: These findings provide evidence that intensive expression of Bmi-1 might be important in the acquisition of an invasive and/or aggressive phenotype of ovarian carcinoma, and serve as a independent biomarker for shortened survival time of patients.

Decreased expression of PinX1 protein is correlated with tumor development and is a new independent poor prognostic factor in ovarian carcinoma.

Human interacting protein X1 (PinX1) has been identified as a critical telomerase inhibitor and proposed to be a putative tumor suppressor gene. Loss of PinX1 has been found in a large variety of malignancies, but the expression status in epithelial ovarian tumors has not been investigated. In this study, immunohistochemistry for PinX1 protein was performed on a tissue microarray (TMA) of epithelial ovarian tumors (informatively containing 25 cystadenomas, 29 borderline tumors, and 157 invasive carcinomas) and 12 normal ovaries. Receiver-operator curve (ROC) analysis was used to determine cut-off scores for tumor positivity and to evaluate patients' survival status. The threshold for PinX1 positivity was determined to be above 60% (area under the curve = 0.856, P < 0.001) based on the area under the ROC. Positive expression of PinX1 was observed in 100% of normal ovarian tissues, in 84% of cystadenomas, in 75.9% borderline tumors, and 66.2% of ovarian carcinomas. Decreased expression of PinX1 was strongly related to patients with poor prognostic factors regarding presence of lymph node metastasis (P = 0.024), distant metastasis (P < 0.001), and late International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.001). In univariate survival analysis, a highly significant correlation between loss of PinX1 and shortened patient survival (mean, 48.2 months vs 99.2 months, P < 0.001) was displayed. Multivariate analysis demonstrated PinX1 expression (P = 0.027) was evaluated as an independent parameter. Our findings suggest that loss of PinX1 is an adverse independent molecular marker for epithelial ovarian carcinoma patients. PinX1 may be a novel target for telomerase-based anticancer therapy due to inhibiting telomerase activity.

Expression and clinical significance of YKL-40 protein in epithelial ovarian cancer tissues.

BACKGROUND AND OBJECTIVE: Overexpression of YKL-40 has been detected in the sera from patients with various kinds of malignant tumors, including epithelial ovarian cancer. Moreover, YKL-40 expression is closely related to clinical phenotypes of some malignant tumors. This study was to investigate the expression and clinical significance of YKL-40 protein in epithelial ovarian cancer tissues. METHODS: Protein expression of YKL-40 was detected by immunohistochemistry (IHC) using tissue microarray (TMA) consisting of 86 specimens of epithelial ovarian cancer and 20 specimens of normal ovarian tissues. The correlations of YKL-40 expression to clinical features and prognosis, as well as to the expression of clusterin protein in epithelial ovarian cancer were evaluated. RESULTS: The expression of YKL-40 in all normal ovarian tissues was negative or at low levels. In 74 evaluable specimens of epithelial ovarian cancer, overexpression of YKL-40 was detected in 42 cases (56.8%). YKL-40 expression was closely associated with the clinical stage of epithelial ovarian cancer (p < 0.0001). The overall survival time in patients with overexpression of YKL-40 was significantly shorter than that in patients with normal expression of YKL-40 (p = 0.0389). Moreover, expression of YKL-40 protein was positively correlated with that of clusterin protein in epithelial ovarian cancer (p < 0.0001). CONCLUSION: YKL-40 may be used as a new molecular marker to predict the prognosis of epithelial ovarian cancer.