Biomarker For Human Ovarian Cancer Research Articles

Mitochondrial AAA protease gene associated with immune infiltration is a prognostic biomarker in human ovarian cancer.

Early diagnosis and identification of prognostic markers for ovarian cancer can significantly improve survival and reduce mortality. The role of the YME1L1 signaling axis in genetic alterations and immune infiltration of the tumor microenvironment remains unclear. Bioinformatics web resources, including GEPIA2, cBioPortal, Oncomine, Kaplan-Meier Plotter, and TIMER, were used to analyze the expression profile, prognostic value, and immune infiltration of YME1L1. We further performed a tissue microarray analysis of paraffin-embedded tissues from 60 patients with ovarian cancer, recorded at the FIGO/TNM cancer staging. Here, we used multi-omics analysis of multiple histological datasets to map the role of epigenetic and genetic alterations of YME1L1 in tumor immune infiltration and the prognosis of cancer patients. We explored YME1L1 gene expression profiles by systematically analyzing the association between YME1L1 expression and the prognosis of patients with ovarian cancer confirmed in multiple databases. High expression levels of YME1L1 were associated with poor overall and disease-free survival. Together, our studies suggest that YME1L1 may modulate tumor survival and immune features and contribute to tumor immune invasion, poor prognosis, and immunotherapy failure. Our findings may have clinical implications for the design of treatment strategies, prognosis assessment, and follow-up management of patients receiving immunotherapy for various cancers.

Serum MicroRNA-21 Negatively Relates to Expression of Programmed Cell Death-4 in Patients with Epithelial Ovarian Cancer

Background:Ovarian cancer is the third most common cancer of the female genital tract and the leading cause of cancer death associated with gynecologic tumors. MicroRNAs regulate at least 60% of human genes, including tumor suppressor genes and oncogenes and, thereby, can affect cancer risk.Aim of the work:We aimed to assess any diagnostic role for serum miR-21 as a biomarker in human ovarian cancer and to study relations with programmed cell death-4 (PDCD4), one of its target proteins, hoping to help explain heterogeneity of this cancer type and facilitate stratification of regimens for therapy.Subjects and Methods:A total of 60 newly diagnosed ovarian cancer cases and 30 apparently healthy females were recruited. Serum microRNA-21 levels were measured by TaqMan- Real time PCR assay and PDCD4 by ELISA.Results:Significant over-expression of serum miR-21 and lower serum PDCD4 levels were observed in ovarian cancer patients as compared to the control group. A statistically significant inverse correlation was also evident between miR-21 and PDCD4. However, no significant links were noted observed between miR-21 and tumor grade, stage or histopathological type.Conclusion:The present work showed significantly up-regulation of serum miR21 in the recruited group of patients and a significant inverse relation association between miR-21and PDCD4. These findings suggest that miR-21 may be used as a diagnostic biomarker for human ovarian cancer.

Overexpression of microRNA-497 suppresses cell proliferation and induces apoptosis through targeting paired box 2 in human ovarian cancer.

MicroRNAs are a class of endogenous, small non-coding RNAs which are tightly involved in evolution and progression of human cancers. MicroRNA-497 has been reported as tumor-suppressor in various human cancer. However, the role of miR-497 in ovarian cancer is still poorly known. We investigated the expression level and cellular function of miR-497 in human ovarian cancer. In this study, the expression of miR-497 in ovarian cancer tissues and SKOV3 cells was detected by quantitative reverse‑transcription polymerase chain reaction (qRT-PCR). CCK-8 assay was used to analysis the cell proliferation. Transwell assay was performed to analysis cell migration and invasion. Cell apoptosis was evaluated by flow cytometry. Luciferase assay was performed to verify a putative target site of miR-497 in the 3'UTR of PAX2 mRNA. The results showed that miR-497 was markedly decreased in ovarian cancer tissues and SKOV3 cells. Moreover, overexpression of miR-497 in SKOV3 cells induced PAX2 protein expression and resulted in inhibition of cell proliferation, migration and invasion, and induction of cell apoptosis. In addition, we confirmed that PAX2 is a direct target gene of miR-497. Furthermore, Silencing of PAX2 by RNA interference suppressed cell proliferation and promoted cell apoptosis invitro. Taken together, our study rationally present that miR-497 has a potential role as a useful diagnostic and therapeutic biomarker for human ovarian cancer.

Serum microRNA-145 as a novel biomarker in human ovarian cancer.

Ovarian cancer is one of the most threatening diseases among women in the world. Current detection methods are expensive and lack accuracy. Thus, a fast, non-invasive biomarker for detecting ovarian cancer is urgently needed. Compelling evidences have been demonstrated that microRNAs, a large family of single-stranded and non-protein-coding RNA molecules, can serve as useful biomarkers in cancer detection. In this study, the relative expressions of microRNA-145 (miR-145) in the serum of patients with ovarian cancer and healthy controls were investigated in an independent study. Subsequently, the diagnosis and prognosis value of miR-145 as a biomarker for ovarian cancer were examined. Furthermore, we performed a meta-analysis to summarize all the results from published studies and this study. Relative expressions of miR-145 were investigated in three independent groups (malignant ovarian cancer, benign ovarian tumor, and healthy controls), comprising a total of 270 participants. Receiver operating characteristic (ROC) curves and overall survival (OS) curves were conducted to compare miR-145 level and clinical characteristics among the three groups. The results showed that relative expressions of the serum miR-145 were significantly down-regulated in patients with malignant ovarian cancer and benign ovarian cancer, compared to healthy controls (P < 0.01). Serum miR-145 levels could discriminate patients with malignant ovarian cancer from healthy controls, with a power area under the curve (AUC) of 0.82 (95 % confidence interval (CI) = 0.77-0.88). Furthermore, patients with low serum levels of miR-145 had a significantly shorter median overall survival rate (hazard ratio (HR) = 1.81, 95 % CI = 1.03-3.17, P = 0.039). The meta-analysis yields good diagnostic performances of miR-145 in various cancers, with an AUC of 0.82 (95 % CI, 0.78-0.85). In conclusion, the present study suggested that miR-145 can potentially serve as an outstanding biomarker for ovarian and other human cancers detection.

Abstract 1421: Interleukin-22, a protective factor for ovarian cancer during TNFa-induced apoptosis.

Abstract Ovarian cancer is the 5th leading cause of death from cancer in women. Overall, only 10% of patients with advanced ovarian cancer are curable; despite the advances in chemotherapy the 5-year survival is still less than 30%. Interleukin-22 (IL-22), a member of the IL-10 family of cytokines is part of the innate immune system and is expressed by the Th17 cells. IL-22 has been shown to regulate several processes such as the acute-phase response, activation of the innate immune system, cell migration, differentiation and gene expression. However, its role in cancer immunology, especially in ovarian cancer has not been studied. The aim of this study is to investigate the expression and the role IL-22 in human ovarian cancer. In our work, we analyzed the expression of IL-22 protein in human ovarian cancer tissues and ascites samples using immunohistochemistry and ELISA; we tested the expression of IL-22 receptor on human ovarian cancer cells via Western Blot, and determined the association between disease outcome and IL-22 gene expression (Affymetrix)in patients with human ovarian cancer. We evaluated the effect of IL-22 on cellular proliferation using MTT assay and we assessed the effect of IL-22 on TNF-a induced apoptosis using caspase 3/7 activity (Caspase Glo) assay and 7AAD staining on multiple human ovarian cancer cell lines. Here we demonstrate that IL-22 was expressed in human ovarian cancer tissue (mostly in the stroma) and that the receptor for IL-22 was expressed on human ovarian cancer cells. We found that high expression of IL-22, as well as the IL-22-receptor in the tumor tissue leads to poor disease outcome in ovarian cancer patients. On the contrary, high expression of IL-22-binding protein (antagonist of IL-22) was associated with better survival in ovarian cancer patients. We showed that treatment with human recombinant (hr) IL-22 protein induced the activation of Stat-3, as well as increased the proliferation of human ovarian cancer cell lines. We also found that treatment with hr IL-22 at 100, 50 or even at 10 ng/mL concentrations inhibited TNF-a induced apoptosis in OVCAR-5 ovarian cancer cell line, and these results were reversed by the addition of IL22 binding protein to the culture. We conclude that interleukin-22 is an important factor in the tumor microenvironment of ovarian cancer; it promotes tumor growth by increasing proliferation and serves as a protective factor for ovarian cancer during TNF-s induced apoptosis. These data suggest that IL-22 is a potential therapeutical target and/or biomarker in human ovarian cancer. Citation Format: Klara Balint, Tamara Seedial, Phyllis Gimotty, George Coukos, Andrea Facciabene. Interleukin-22, a protective factor for ovarian cancer during TNFa-induced apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1421. doi:10.1158/1538-7445.AM2013-1421

Tumor Stress-Induced Phosphoprotein1 (STIP1) as a Prognostic Biomarker in Ovarian Cancer

Stress-induced phosphoprotein 1 (STIP1) has been recently identified as a released biomarker in human ovarian cancer. In addition, STIP1 secreted by human ovarian cancer cells has been shown to promote tumor cell proliferation by binding to ALK2 (activin A receptor, type II-like kinase 2) and activating the SMAD-ID3 signaling pathways. In this study, a total of 330 ovarian cancer tumor samples were evaluated for STIP1 expression by immunohistochemistry and analyzed for a possible correlation with patient characteristics and survival. The quantification of immunoreactivity was accomplished by applying an immunohistochemical scoring system (histoscore). Patients with high-level STIP1 expression (histoscore ≥169) had a significantly worse survival (high STIP1, mean survival time = 76 months; low STIP1, mean survival time = 112 months; P<0.0001). Moreover, STIP1 histoscores were significantly higher in high-grade tumors (grade 3) than in low-grade (grade 1–2) malignancies (P<0.0001), suggesting that STIP1 may be a proxy for tumor aggressiveness. The results of multivariable analysis revealed that high STIP1 histoscores, advanced stages, histologic types, and the presence of residual disease (≥2 cm) were independent predictors of poor prognosis. The addition of STIP1 histoscores improved the prediction of overall and progression-free survival rates in the multivariable Cox proportional hazard model. The treatment of ovarian cancer cells with recombinant STIP1 stimulated cell proliferation and migration, but co-treatment with anti-STIP1 antibodies abrogated this effect. Our findings suggest that STIP1 expression may be related to prognosis and that the STIP1 pathway may represent a novel therapeutic target for human ovarian cancer.

RETRACTED: High-mobility group protein B1 (HMGB1) is a novel biomarker for human ovarian cancer

High mobility group box l (HMGB1), a nuclear and extracellular protein, is implicated in some physiologic and pathologic conditions. In this study, we investigated the expression and function of HMGB1 in ovarian cancer. cDNA microarray analysis was performed to compare gene expression profiles of the highly invasive and the low invasive subclones derived from the SKOV3 human ovarian cancer cell line. Immunohistochemistry (IHC) staining was performed to investigate HMGB1 expression in a total of 100 ovarian tissue specimens. In functional assays, effects of HMGB1 knockdown on the biological behavior of ovarian cancer cells were investigated. HMGB1 was overexpressed in the highly invasive subclone compared with the low invasive subclone. High HMGB1 expression was associated with poor clinicopathologic features. Knockdown of HMGB1 expression significantly suppressed ovarian cancer cell proliferation accompanied by decreased cyclin D1 and PCNA expression, and inhibited cell migration and invasion accompanied by decreased MMP2 and MMP9 activities. HMGB1 is a newly identified gene overexpressed in ovarian cancer and associated with poor clinicopathologic features. HMGB1 may serve as a new biomarker and a therapeutic target for ovarian cancer in the future.

Stress-induced Phosphoprotein 1 as a Secreted Biomarker for Human Ovarian Cancer Promotes Cancer Cell Proliferation

Ovarian cancers are frequently not diagnosed until advanced stages, resulting in a high case fatality rate. Because of this, more tumor markers, in addition to CA125, for detecting and monitoring ovarian cancer are needed. During a systematic search for potential biomarkers of ovarian cancer, we compared the protein profiles between tumor interstitial fluid and normal interstitial fluid of ovaries, rationalizing that abnormal levels of proteins in tumor interstitial fluid may be detected in peripheral blood and thus serve as easily accessible tumor markers. Here, we show that stress-induced phosphoprotein 1 (STIP1) was secreted by ovarian cancer tissues into the peripheral blood of patients, resulting in a significant increase of serum levels of STIP1 in cancer patients compared with those in age-matched normal controls. Our results further indicated that combined use of CA125 and STIP1 may increase early detection of ovarian cancer. Functionally, recombinant STIP1 significantly induced ERK phosphorylation, promoted DNA synthesis, and increased Ki-67 immunoreactivity in ovarian cancer cells, suggesting that STIP1 in vitro promotes cell proliferation. Colocalization of STIP1 and phospho-ERK in human ovarian cancer tissues also supports an in vivo activation of ERK by STIP1. Further understanding of molecular roles of STIP1 in human ovarian cancer may shed light on its pathophysiology and development of novel therapeutic strategies.

Proteomics identification of stress-induced phosphoprotein (STIP1) as a potential biomarker for human ovarian cancer

16533 Patients with ovarian cancers are often associated with poor prognosis and limited survival rates because their cancers were not detected at earlier stages. Currently, CA125 is the most commonly used tumor marker for ovarian cancer, but it only results in 78% sensitivity, 82 to 95% specificity, and 82% positive predictive value. Therefore, discovery of new tumor markers for detecting ovarian cancer is warranted. Peripheral blood is a convenient source of tumor markers. However, screening for new tumor markers from blood is difficult because tumor markers, usually at low concentrations in blood, are easily obscured by serum abundant common proteins. Alternatively, tumor interstitial fluid (TIF) represents a rich source for secreted proteins from both cancer cells and neighboring stromal tissues, and the contents of TIF are eventually drained into blood circulation. In this study, we attempted to identify cancer-specific proteins from TIF derived from human ovarian cancer with proteomics approaches. Using statistical analysis of 596 protein spots in two-dimensional gels between the TIF of ovarian cancer and normal interstitial fluid (NIF) of normal ovaries, we identified several differentially expressed proteins, including stress-induced phosphoprotein 1 (STIP1). Specific elevations of STIP1 in TIF and ovarian cancer tissues were confirmed with Western blot analysis and immunohistochemistry, respectively. Subsequent enzyme-linked immunosorbent assay (ELISA) experiments revealed serum levels of STIP1 were significantly higher in ovarian cancer patients than in healthy controls. Receiver operating characteristics (ROC) curve analysis suggested the value of STIP1 to be comparable to CA125. These results suggest STIP1 has the potential as a biomarker for human ovarian cancer. No significant financial relationships to disclose.