Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment.

Tumor cells show deregulated metabolism leading to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment has been reported to impair effector T cells. However, T-regulatory cells (Tregs) show metabolic advantages in lactate-rich TME that maintain a strong suppression of effector T cells, which leads to tumor immune evasion. Therefore, the glycolytic process of tumors could represent a therapeutic target, and agents that modify the energy metabolism of tumor cells have therapeutic potential. Resveratrol is a naturally occurring polyphenol that has been confirmed to suppress tumor cells' glycolytic metabolism. In this study, we show that resveratrol induces metabolic reprogramming in ovarian cancer cells. Resveratrol increases oxidative and decreases glycolysis, in association with decreased lactate production both in vitro and in vivo. Lactate reduction in TME weakens the suppressive function of Tregs, and subsequently restores anti-tumor immunity. Significantly, combined resveratrol and PD-1 blockade promote anti-tumor efficacy. These data suggest that resveratrol's anti-tumor actions in ovarian cancer could be explained, in part, through modification of the anti-tumor immunity, and indicate a novel treatment strategy for improving immune checkpoint blockade therapy using resveratrol.

CPE overexpression is correlated with pelvic lymph node metastasis and poor prognosis in patients with early-stage cervical cancer.

PURPOSE: Elevated carboxypeptidase E (CPE) levels play crucial roles in tumorigenesis and metastasis. This study investigated the expression and clinicopathological significance of CPE in early-stage cervical cancer. METHODS: Elevated carboxypeptidase E expression was analyzed using quantitative polymerase chain reaction and western blotting in normal cervical tissue, cervical cancer cell lines, and in cervical cancer tissues and adjacent noncancerous tissues (ANTs) from the same patient. Immunohistochemistry (IHC) was used to examine CPE expression in tissue samples from 112 patients with early-stage cervical cancer (FIGO stages Ia2-IIa2), 60 patients with cervical intraepithelial neoplasia, and 19 patients with normal cervical tissues (NCTs). Associations between CPE expression and prognostic and diagnostic factors were evaluated statistically. RESULTS: CPE expression was significantly higher in cervical cancer cell lines and tissues than in normal tissues and ANTs. Semi-quantitative analysis of IHC indicated that CPE gradually increased from CIN I to cervical cancer, but was absent in NCTs. CPE expression was seen in 40.2 % (45/112) of the cervical cancer samples. CPE expression was significantly associated with FIGO stage (P = 0.003), tumor size (P = 0.012), stromal invasion (P < 0.001), lymphovascular space invasion (P = 0.016), parametrial infiltration (P = 0.027), vaginal involvement (P = 0.007), postoperative adjuvant therapy (P = 0.024), recurrence (P < 0.001), survival (P < 0.001), and pelvic lymph node metastasis (PLNM) (P < 0.001), and it was significantly higher in tissues from patients with PLNM than without PLNM. Logistic regression analysis identified high-level CPE expression as an independent risk factor for PLNM (P = 0.001). Patients with higher CPE expression had shorter overall survival duration than patients with lower CPE expression. Univariate and multivariate Cox-regression analyses suggested that high-level CPE expression is an independent prognostic factor for overall survival in early-stage cervical cancer. CONCLUSIONS: High-level CPE expression was associated with a poor prognosis in early-stage cervical cancer. CPE may serve as a biomarker for predicting PLNM and survival in these patients.

FOXM1 promotes tumor cell invasion and correlates with poor prognosis in early-stage cervical cancer.

OBJECTIVE: The forkhead box M1 (FOXM1) transcription factor plays crucial roles in regulating the proliferation, differentiation, and transformation of cells. Overexpression of FOXM1 is associated with a variety of aggressive solid carcinomas, including cervical cancer. However, the precise role and molecular mechanism responsible for the aggressive action of FOXM1 in cervical cancer remain unclear. This study investigated the cellular and molecular aggressive function of FOXM1 in cervical cancer. METHODS: The FOXM1 gene and protein expression profiles were determined by quantitative polymerase chain reaction, Western blotting and immunohistochemical staining, and other cellular and molecular approaches including gene transfection, short hairpin RNA interference (RNAi), and wound-healing, migration, and invasion assays. RESULTS: FOXM1 expression was significantly up-regulated at both mRNA and protein levels in early-stage cervical cancer, compared to cervical intraepithelial neoplasia and normal cervical tissues. High levels of FOXM1 expression were significantly associated with aggression in cervical cancer, and were an independent prognostic factor for poor survival in early-stage cervical cancer patients. Moreover, enforced expression of FOXM1 increased migration and invasion of cancer cells, whereas RNAi-mediated knockdown of FOXM1 had the opposite effect. In addition, up-regulation of FOXM1 increased the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 in vitro and in vivo, and activated the Akt/glycogen synthase kinase-3ß/Snail pathway, resulting in the promotion of migration and invasion of cervical cancer cells. CONCLUSIONS: These results suggest that FOXM1 up-regulation is associated with poor prognosis in early-stage cervical cancer, and therefore it may act as a prognostic marker and a new potential target for cervical cancer treatment.

Successful management of mucinous ovarian cancer by conservative surgery in week 6 of pregnancy: case report and literature review.

PURPOSE: The management of ovarian cancer during pregnancy is still a big challenge, mostly due to the reciprocal impacts between cancer and pregnancy. The objective of this article is to present a rare case of maternal ovarian adenocarcinoma and review published similar cases about this clinical condition. MATERIALS AND METHODS: Here we report a rare case of maternal ovarian adenocarcinoma detected during gestational week 6, with good pregnancy outcome treated with conservative surgery. RESULTS AND DISCUSSION: A case of maternal ovarian adenocarcinoma (stage I) was detected in week 6 of pregnancy receiving conservative surgery without chemotherapy. In week 39 of pregnancy, due to relapse of the cancer, the patient underwent excision of the isolated tumor, and gave birth to a healthy baby through cesarian section. After that, the patient received cytoreductive surgery associated with six chemotherapy. The patient was finally diagnosed as epithelial ovarian cancer stage IIIC, and had survived more than 5 years without relapse. The successful experience from this case suggested that pregnancy complicated with early ovarian cancer receiving conservative surgery could continue to pregnancy and the effect of cesarian section followed with cytoreductive surgery associated with six chemotherapy at full term was still satisfied.

PBOV1 correlates with progression of ovarian cancer and inhibits proliferation of ovarian cancer cells.

Prostate and breast cancer overexpressed 1 (PBOV1) is significantly upregulated in prostate, breast and bladder cancer, while its expression status in ovarian cancer and its clinical significance are unclear. We examined the expression levels of PBOV1 mRNA and protein in ovarian cancer cell lines and primary tissues using real-time PCR and western blotting. Immunohistochemistry was employed to analyze PBOV1 expression in 17 normal ovaries, 13 cystadenoma tissues, 14 borderline tumor tissues, and 165 clinicopathologically characterized ovarian cancers. There was negative PBOV1 expression in the 17 normal ovarian epithelial tissues. Compared to the normal ovarian epithelial cells, PBOV1 mRNA and protein were overexpressed in ovarian cancer cell lines. There was high PBOV1 protein expression in the ovarian cancer tissues from 59 of the 165 (35.8%) patients; PBOV1 expression was weak in 106 (64.2%) patients. Notably, there were significant negative associations between high PBOV1 expression and ascending histological grade, late pT/pN/pM, and International Federation of Gynecology and Obstetrics (FIGO) stage (P<0.05). Patients with high PBOV1 expression had longer overall survival; patients with low PBOV1 expression had shorter survival. Multivariate analysis revealed that PBOV1 upregulation is an independent prognostic indicator for ovarian cancer and might serve as a tumor-suppressor gene. Furthermore, PBOV1 overexpression inhibited ovarian cancer cell proliferation and tumorigenesis in vitro and in a tumor transplantation nude mouse model. In conclusion, our results suggest that PBOV1 may play an important role in suppressing ovarian cancer proliferation and carcinogenesis. PBOV1 may be a novel and useful prognostic marker and potential target for treating human ovarian cancer.

Bax-interacting factor-1 inhibits cell proliferation and promotes apoptosis in prostate cancer cells.

Prostate cancer (PCa) is one of the most common malignant tumors and the second leading cause of cancer-related death among males. Bax-interacting factor-1 (Bif-1) is a member of Endophilin family, which binds to and activates the BAX protein in response to the apoptosis signaling pathway. Loss of Bif-1 may suppress the intrinsic pathway of apoptosis and promote tumorigenesis, but there is also converse evidence that Bif-1 could in part be responsible for the tumorigenesis and the role of Bif-1 in PCa development is not clear. In the present study, we aimed to understand the relationships between Bif-1 expression and PCa development. The mRNA and protein expression levels of Bif-1 in PCa cell lines, benign prostatic hyperplasia (BPH) (n=100) and PCa tissues (n=100, including low Gleason-scored PCa n=43 and high Gleason-scored PCa n=57) were detected and the effects of Bif-1 overexpression on the apoptosis, proliferation and migration in LNCaP cells were explored. Bif-1 mRNA levels of PCa cell lines were analyzed by real-time PCR and the protein levels were detected by western blotting. Bif-1 expression in BPH and PCa samples was detected by immunohistochemistry. To build Bif-1 overexpression PCa cells, Bif-1 gene was transfected into LNCaP cells by pcDNA3.1(+)­Bif-1 vector. Cell apoptosis was detected by flow cytometric analysis, cell proliferation measured by 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide (MTT) assay and cell migration was analyzed by wound­healing assay. The results proved that Bif-1 is downregulated in both PCa cell lines (P<0.01) and clinical samples (P<0.05), and Bif-1 expression is suppressed with the cancer progression (BPH vs. PCa P<0.01, and low Gleason-scored PCa vs. high Gleason-scored PCa P<0.05). Overexpression of Bif-1 could significantly inhibit cell proliferation (P<0.05) and enhancing PCa cell apoptosis (P<0.05), but it did not affect the migration ability (P>0.05). Our findings give strong evidence that Bif-1 is involved in PCa tumorigenesis and acts as a suppressor in PCa progression, and may have significance in understanding the process of PCa development.

Predictive value of excision repair cross-complementing rodent repair deficiency complementation group 1 and ovarian cancer risk.

OBJECTIVE: We aimed to analyze the association between excision repair cross-complementing rodent repair deficiency complementation group 1 (XRCC1) and ovarian cancer risk. METHODS: We performed a hospital-based case-control study with 155 cases and 313 controls in China. All Chinese cases with newly diagnosed primary ovarian cancer between May 2005 to May 2010 in our hospital were invited to participate within 2 months of diagnosis. Controls were randomly selected from people who requested general health examinations in the same hospital during the same period. SNPs in EXCC1, ERCC1 C8092A and ERCC1 T19007C, were analyzed by PCR-RFLP method. RESULTS: We observed a non-significantly increased risk of ovarian cancer among individuals with ERCC1 8092TT compared with those with the 8092CC genotype (adjusted OR=1.55, 95% CI%=0.74-2.97). Moreover, 19007TT genotype carriers also showed a non-significant increased risk of ovarian cancer over those with the 19007CC genotype (adjusted OR=1.78, 95% CI%=0.91-3.64). CONCLUSION: Our firstly investigation of links between polymorphisms in the ERCC1 gene and the risk of ovarian cancer in Chinese population demonstrated no significant association. Further large sample studies in Chinese populations are needed.