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Although ovarian cancer usually responds well to platinum- and taxane-based first-line chemotherapy, most patients develop recurrence and chemoresistance. Regenerating gene 4 (REG4) is a secretory protein involved in cell differentiation and proliferation. We found higher REG4 expression in ovarian cancer than in normal tissues ( p  < .05). Regenerating gene 4 expression was negatively associated with overall, progression-free or post-progression survival rates of patients with ovarian cancer receiving platinum or paclitaxel treatment ( p  < .05) according to a Kaplan-Meier plotter. Regenerating gene 4 overexpression resulted in either cisplatin or paclitaxel resistance, and apoptosis resistance in CAOV3 ovarian cancer cells ( p  < .05). REG4-transfected ovarian cancer cells showed stronger migration and invasion treated with cisplatin or paclitaxel ( p  < .05). Additionally, cisplatin or paclitaxel exposure led to the overexpression of phosphorylated phosphoinositide 3-kinase (p-PI3K), p-Akt, phosphorylated mammalian target of rapamycin (p-mTOR), glutathione S-transferase-π, survivin, and B-cell lymphoma 2 in REG4 transfectants compared with control cells ( p  < .05). These findings suggested that REG4 expression was up-regulated in ovarian cancer, and associated with poor survival and chemotherapy resistance. REG4 promoted the occurrence, development, and chemotherapy resistance of ovarian cancer by regulating cell proliferation, apoptosis, migration, and invasion, and PI3K/Akt/m-TOR signalling pathways. IMPACT STATEMENT What is already known on this subject? REG4 mRNA expression is up-regulated in many digestive cancers. High REG4 expression was associated with an adverse prognosis, high tumour and nodal stages, poor differentiation, and hepatic and peritoneal metastases of digestive cancers. REG4 expression conferred cancer cells with increased resistance to chemoradiotherapy, especially 5-FU-based treatment, by activating the MAPK/Erk/Bim signalling pathway. What do the results of this study add? REG4 was highly expressed in ovarian cancer. The expression of p-PI3K, p-AKT, p-mTOR, GST-π, survivin, and Bcl-2 was increased in REG4-overexpressing cells. High REG4 expression was significantly associated with inferior OS, PFS, and PPS rates in patients with ovarian cancer receiving platinum chemotherapy. REG4 mediated cisplatin and paclitaxel resistance in CAOV3 ovarian cancer cells. The percentage of apoptotic cells was markedly lower in REG4-transfected compared to mock-transfected cells after cisplatin or paclitaxel treatment. What are the implications of these findings for clinical practice and/or further research? This study aimed to evaluate the prognostic significance of REG4 expression in ovarian cancer treated with platinum and paclitaxel, to explore REG4 chemoresistance mechanisms to platinum and paclitaxel, and to provide a scientific experimental basis for the clinical treatment and outcome evaluation of ovarian cancer. In order to provide comprehensive clinical treatment of ovarian cancer, it is helpful to improve our understanding of multi-drug resistance and identify new cancer diagnostic biomarkers.

Beclin 1, an important autophagy-related protein in human cells, is involved in autophagy, differentiation, anti-apoptosis, and cancer suppression, which is increased during periods of cell stress and extinguished during cell cycle. Human ovarian tumors display allelic loss of Beclin 1 with high frequency. To clarify Beclin 1's role in ovarian carcinogenesis and subsequent progression, its expression was examined by immunostaining on tissue microarrays containing ovarian normal tissue, benign and borderline tumors, and carcinomas. Beclin 1 mRNA and protein expression was examined in ovarian normal tissue, benign and borderline tumors, carcinoma tissue, and cell lines by reverse transcription polymerase chain reaction or Western blot, respectively. The results demonstrated that the higher Beclin 1 mRNA was observed in ovarian benign tumor than normal ovary and ovarian carcinoma (P < 0.05) and negatively correlated with the differentiation of ovarian carcinoma (P < 0.05). Beclin 1 protein expression was stronger in ovarian carcinoma than that in normal ovary and inversely related to the differentiation of ovarian carcinoma (P < 0.05) by Western blot. Immunohistochemically, Beclin 1 expression was statistically higher in ovarian borderline tumor and carcinoma than normal ovary and benign tumor (P < 0.05) and inversely linked to differentiation, lower ki-67 expression, and higher cumulative or relapse-free survival rate of ovarian carcinoma (P < 0.05). Cox proportional hazard model indicated that age and International Federation of Gynecology and Obstetrics staging (P < 0.05), but not pathological classification differentiation degree or Beclin 1 expression, were independent prognostic factors for overall and relapse-free ovarian carcinomas (P > 0.05). It was suggested that the aberrant Beclin 1 expression is closely linked to tumorigenesis and differentiation of ovarian carcinoma. Beclin 1 expression might be employed to indicate the worse prognosis of ovarian carcinomas, albeit not an independent factor.

Background: Ras homolog gene family member C (RhoC) is a small G protein/guanosine triphosphatase involved in tumor mobility, invasion, and metastasis., Methods: After RhoC siRNA transfection, we measured the changes in phenotypes and some relevant molecules in ovarian carcinoma cell, OVCAR3. The mRNA and protein expression of RhoC was detected in ovarian tumors., Results: RhoC siRNA transfection resulted in low growth, G1 arrest, and apoptotic induction in the OVCAR3 in comparison with the control and mock. Following RhoC knockdown, there was reduced mRNA or protein expression of protein kinase B (Akt), signal transducer and activator of transcription 3 (stat3), bcl-xL, surviving and phosphorylated p70S6 kinase (p-p70s6k), while the converse was true for Bax and caspase-3. Lovastatin induced apoptosis, suppressed proliferation, migration and invasion, and disrupted lamellipodia formation in OVCAR3. Lovastatin exposure induced lower RhoC, bcl-2, matrix metalloproteinase-9 (MMP-9), survivin, Akt, bcl-xL, vascular endothelial growth factor (VEGF), and p-p70s6k expression in OVCAR3 compared to the control, but higher caspase-3 and Bax expression. RhoC mRNA and protein expression was significantly higher in ovarian carcinoma than in benign tumors and normal ovary tissue (p<0.05) and was positively associated with dedifferentiation, FIGO staging and p-p70s6k expression of ovarian carcinoma (p<0.05)., Conclusions: The up-regulated RhoC expression may affect ovarian carcinogenesis and should be considered a good biomarker for the differentiation and progression of ovarian carcinoma. RhoC plays an important role in apoptosis by modulating the relevant genes and the phosphorylation of downstream p70s6k., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Extracellular matrix metalloproteinase inducer (EMMPRIN) was reported to involve in the invasion and metastasis of malignancies by regulating the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) in stromal and cancer cells. The study aimed to clarify the role of EMMPRIN expression in tumorigenesis and progression of ovarian epithelial carcinomas., Methods: EMMPRIN siRNA were transfected into ovarian carcinoma cells with the phenotypes and their related molecules examined. EMMPRIN expression was determined in ovarian normal tissue, benign and borderline tumors, and epithelial carcinomas by real-time PCR, western blot, and immunohistochemistry., Results: EMMPRIN siRNA treatment resulted in a lower growth, G 1 arrest, apoptotic induction, decreased migration, and invasion. The transfectants showed reduced expression of Wnt5a, Akt, p70s6k, Bcl-xL, survivin, VEGF, and MMP-9 than mock and control cells at both mRNA and protein levels. According to real-time PCR and western blot, EMMPRIN mRNA or protein level was higher in ovarian borderline tumor and carcinoma than normal ovary and benign tumors (P<0.05), and positively correlated with dedifferentiation and FIGO staging (P<0.05). Immunohistochemically, EMMPRIN expression was positively correlated with FIGO staging, dedifferentiation, Ki-67 expression, the lower cumulative and relapse-free survival rate (P<0.05)., Conclusions: Upregulated expression of EMMPRIN protein and mRNA might be involved in the pathogenesis, differentiation, and progression of ovarian carcinomas, possibly by modulating cellular events, such as proliferation, cell cycle, apoptosis, migration, and invasion.