Biliang Chen

Overexpression of CXCR4 is significantly associated with cisplatin-based chemotherapy resistance and can be a prognostic factor in epithelial ovarian cancer

The chemokine receptor 4 (CXCR4) plays an important role in the growth, angiogenesis and metastasis of various cancers, including epithelial ovarian cancer (EOC). However, the correlation between CXCR4 and the clinical response of EOC patients to chemotherapy remains unknown. 124 EOC patients were recruited to assess the relationship between CXCR4 and the response to cisplatin-based chemotherapy. The results showed that patients with a higher CXCR4 expression had a significantly lower chemosensitivity, a poorer progression-free survival and a lower overall survival than those with lower CXCR4 expression. In addition, knockdown of CXCR4 by small interfering RNA suppressed cell proliferation and resulted in G1/S arrest, increased apoptosis and chemosensitivity in both cisplatin-sensitive A2780 cells and cisplatin-resistant cell A2780/cis in vitro. Our data suggest that CXCR4 is one of the key molecules in cisplatin-based chemotherapy for EOC patients and that CXCR4 inhibition is a potential strategy to address the chemoresistance of EOC. [BMB Reports 2014; 47(1): 33-38]

Overexpressed active Notch1 induces cell growth arrest of HeLa cervical carcinoma cells

Human cervical carcinoma is one of the most common malignant tumors, but the mechanisms that orchestrate the multiple oncogenic insults required for initiation and progression are not clear. Notch signaling plays a critical role in maintaining the balance between cell proliferation, differentiation, and apoptosis, but perturbed Notch signaling may contribute to tumorigenesis. We now show that Notch1 is detected in all cervical cancer, including advanced diseases. We also constitutively overexpressed active Notch1 in human cervical carcinoma to explore the effects of Notch1 signaling on human cervical carcinoma cell growth and to investigate the underlying molecular mechanisms. The signaling may participate in the development of human cervical carcinoma cells, but overexpressed active Notch1 inhibits their growth through induction of cell cycle arrest. Increased Notch1 signaling induced a downmodulation of human papillomavirus transcription through suppression of activator protein (AP)-1 activity by upregulation of c-Jun and the decreased expression of c-Fos. Thus, Notch1 signaling plays a key role and exerts dual effects, functioning in context-specific manner

Overexpression of CD147 in ovarian cancer is initiated by the hypoxic microenvironment.

Ovarian cancer is a lethal malignant tumour characterised by activated invasion, distant metastasis, anti‐cancer drug resistance, angiogenesis and metabolism. CD147, an extracellular matrix metalloproteinase inducer, is overexpressed in most ovarian tumours and plays an important role in the progression of ovarian cancer and other malignant tumours. However, the factor(s) initiating this overexpression is unknown. Because of rapid reproduction and their hypoxic microenvironment, malignant tumours use glycolysis for energy, and lactic acid produced is harmful to the cells. For survival, excessive lactate needs to be transported by monocarboxylate transporters (MCTs). Functioning of MCT1 and MCT4 require the ancillary of CD147. The gene for CD147 possesses two hypoxia‐inducible factors binding sites in its 3′‐flank. It is logical to postulate that the hypoxic microenvironment is a major initiator of the overexpression of CD147, thus conferring on ovarian cancers their malignant properties. A model that can represent spontaneous ovarian cancer is necessary to verify this hypothesis.

Elevated growth differentiation factor 15 expression predicts poor prognosis in epithelial ovarian cancer patients

1 The State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 17 Changle West Road, 710032 Xi’an, Shaanxi, China 2 Department of Gynecology and Obstetrics, The People’s Liberation Army 323 Hospital, Xi’an, Shaanxi 710045, China 3 State Key Laboratory of Tumor Biology, Department of Pathology, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi 710033, China 4 Department of Health Service, School of Public Health, Fourth Military Medical University, Xi’an, Shaanxi 710033, China 5 Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, 169 Changle West Road, 710033 Xi’an, Shaanxi, China Tumor Biol. (2016) 37:8465 DOI 10.1007/s13277-016-5008-z

Galectin-3 induces ovarian cancer cell survival and chemoresistance via TLR4 signaling activation

Paclitaxel resistance becomes common in patients with aggressive ovarian cancer and results in recurrence after conventional therapy. Galectin-3 is a multifunctional lectin associated with cell migration, cell proliferation, cell adhesion, and cell-cell interaction in tumor cells. Whether circulating galectin-3 is involved in paclitaxel resistance in ovarian cancer remains unknown. The current study investigated the effect of galectin-3 on toll-like receptor 4 (TLR4) signaling and thus paclitaxel resistance. With blood and cancer tissue samples obtained from 102 patients, we identified associations between serum galectin-3 level or TLR4 expression and paclitaxel resistance phenotype. In vitro, treatment with exogenous galectin-3 restored cell survival and migration of SKOV-3 and ES-2 cells was decreased by galectin-3 silencing and paclitaxel treatment. Furthermore, exogenous galectin-3 boosted expression of TLR4, MyD88, and p-p65, as well as interleukin (IL)-6, IL-8, and vascular endothelial growth factor (VEGF) release induced by paclitaxel. Moreover, galectin-3 inhibited the interaction between TLR4 and caveolin-1 (Cav-1) in SKOV-3 and ES-2 cells. In addition, overexpression of Cav-1 dampened the expression of MyD88 and p-p65 stimulated by galectin-3 and enhanced apoptosis in SKOV-3 cells under paclitaxel exposure. In summary, our study elucidated that exogenous galectin-3 might induce paclitaxel resistance through TLR4 signaling activation by inhibiting TLR4-Cav-1 interaction, revealing a novel insight into paclitaxel resistance induction.

BRIP1 inhibits the tumorigenic properties of cervical cancer by regulating RhoA GTPase activity

Breast cancer 1, early onset (BRCA1)-interacting protein 1 (BRIP1), a DNA-dependent adenosine triphosphatase and DNA helicase, is required for BRCA-associated DNA damage repair functions, and may be associated with the tumorigenesis and aggressiveness of various cancers. The present study investigated the expression of BRIP1 in normal cervix tissues and cervical carcinoma via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry assays. BRIP1 expression was observed to be reduced in squamous cancer tissue and adenocarcinoma compared with normal cervix tissue, and there were significant correlations between the reduction in BRIP1 expression and unfavorable variables, including the International Federation of Gynecologists and Obstetricians stage and presence of lymph node metastases. In order to elucidate the role of BRIP1 in cervical cancer, a BRIP1 recombinant plasmid was constructed and overexpressed in a cervical cancer cell line (HeLa). The ectopic expression of BRIP1 markedly inhibited the tumorigenic properties of HeLa cells in vitro, as demonstrated by decreased cell growth, invasion and adhesion, and increased cell apoptosis. In addition, it was identified that the inhibitory tumorigenic properties of BRIP1 may be partly attributed to the attenuation of RhoA GTPase activity. The present study provides a novel insight into the essential role of BRIP1 in cervical cancer, and suggests that BRIP1 may be a useful therapeutic target for the treatment of this common malignancy.

MicroRNA-145 Negatively Regulates Cell Proliferation Through Targeting IRS1 in Isolated Ovarian Granulosa Cells From Patients With Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a complex, heterogeneous endocrine and metabolic disorder affecting 5% to 10% of reproductive-age women. A high rate of granulosa cell (GC) proliferation contributes to the abnormal folliculogenesis in patients with PCOS. Evidence has proved that dysregulation of microRNAs is involved in the pathogenesis of PCOS. In this study, we investigated the effect of miR-145 on cell proliferation and the underlying mechanism of miR-145 in isolated human GCs from the aspirated follicular fluid in women with PCOS. Our findings showed that miR-145 is downregulated in human GCs from PCOS. The miR-145 mimics suppress cell proliferation and promoted cell apoptosis in human GCs from PCOS. However, miR-145 inhibitor promotes cell proliferation and inhibited cell apoptosis. Moreover, using a dual-luciferase reporter assay, we confirmed that the insulin receptor substrate 1 (IRS1) gene is a direct target of miR-145. The miR-145 mimics inhibited messenger RNA and protein IRS1 expression levels, and silencing of IRS1 by small interfering RNA inhibits human GC proliferation, but IRS1 overexpression abrogates the suppressive effect of miR-145 mimics. Furthermore, miR-145 mimics can inhibit the activation of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). The IRS1 overexpression abrogates the suppressive effect of miR-145 mimics on MAPK/ERK signaling pathways. Together, miR-145 mimics suppress cell proliferation by targeting and inhibiting IRS1 expression to inhibit MAPK/ERK signaling pathways. Our study further found that high concentrations of insulin decreases the miR-145 expression, upregulates IRS1, and promotes cell proliferation. These observations showed that miR-145 is a novel and promising molecular target for improving the dysfunction of GCs in PCOS.Polycystic ovary syndrome (PCOS) is a complex, heterogeneous endocrine and metabolic disorder affecting 5% to 10% of reproductive-age women. A high rate of granulosa cell (GC) proliferation contributes to the abnormal folliculogenesis in patients with PCOS. Evidence has proved that dysregulation of microRNAs is involved in the pathogenesis of PCOS. In this study, we investigated the effect of miR-145 on cell proliferation and the underlying mechanism of miR-145 in isolated human GCs from the aspirated follicular fluid in women with PCOS. Our findings showed that miR-145 is downregulated in human GCs from PCOS. The miR-145 mimics suppress cell proliferation and promoted cell apoptosis in human GCs from PCOS. However, miR-145 inhibitor promotes cell proliferation and inhibited cell apoptosis. Moreover, using a dual-luciferase reporter assay, we confirmed that the insulin receptor substrate I (IRS1) gene is a direct target of miR-145. The miR-145 mimics inhibited messenger RNA and protein IRS1 expression levels, and silencing of IRS1 by small interfering RNA inhibits human GC proliferation, but IRS1 over-expression abrogates the suppressive effect of miR-145 mimics. Furthermore, miR-145 mimics can inhibit the activation of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). The IRS1 overexpression abrogates the suppressive effect of miR-145 mimics on MAPK/ERK signaling pathways. Together, miR-145 mimics suppress cell proliferation by targeting and inhibiting IRS1 expression to inhibit MAPK/ERK signaling pathways. Our study further found that high concentrations of insulin decreases the miR-145 expression, upregulates IRS1, and promotes cell proliferation. These observations showed that miR-145 is a novel and promising molecular target for improving the dysfunction of GCs in PCOS.

Elevated GrowthDifferentiation Factor 15 Expression Predict Poor Prognosis in EpithelialOvarian Cancer Patients

The purpose of this study was to determine the expression of growth differentiation factor 15 (GDF15) and explore its clinical significance in epithelial ovarian cancer (EOC) patients. The expression of GDF15 in EOC tissues and serum samples was evaluated using immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), respectively. The association of GDF15 expression with clinicopathologic parameters was analyzed. Survival time was assessed using the Kaplan–Meier technique and Cox regression model. Both in EOC tissues and serum, high GDF15 levels were obviously related with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, ascites, and chemoresistance. Kaplan–Meier analysis indicated that EOC patients with high GDF15 expression showed poorer progression-free survival (PFS) and overall survival (OS). Multivariate analysis demonstrated that GDF15 expression was an independent predictor of PFS in EOC patients. Our study shows that elevated GDF15 expression was associated with poor prognosis in EOC patients. We suggest that GDF15 is a novel biomarker for the early detection of EOC, prediction of the response to chemotherapy, and screening for recurrence in EOC patients.

Apurinic/apyrimidinic endonuclease 1 polymorphisms are associated with ovarian cancer susceptibility in a Chinese population.

Objective Apurinic/apyrimidinic endonuclease 1 (APE1) plays an essential role in the base excision repair pathway. Recent studies have shown that APE1 polymorphisms are associated with an increased risk for many types of cancers. This study investigated the association between APE1 polymorphisms and the susceptibility of ovarian cancer. Methods A case-control study was performed on 124 patients with ovarian cancer and 141 controls. We genotyped the rs1760944 and rs1130409 polymorphisms and assessed their associations with the risk for ovarian cancer. Results The rs1130409 polymorphism was significantly associated with a risk for ovarian cancer. The TG/GG genotype and the G allele were associated with a decreased risk for ovarian cancer (adjusted odds ratio [aOR], 0.495; 95% confidence interval [CI], 0.267–0.920 for TG vs TT; aOR, 0.263; 95% CI, 0.132–0.521 for GG vs TT; aOR, 0.486; 95% CI, 0.344–0.0.688 for the G allele vs the T allele). In the stratified analyses, we found that when comparing the TG/GG genotype versus the TT genotype, the lower risk was more evident in subgroups of patients 50 years or older (aOR, 0.753; 95% CI, 0.604–0.938), patients with menarche age of 15 years or older (aOR, 0.722; 95% CI, 0.573–0.910), patients with gravidity of 3 or more times (aOR, 0.732; 95% CI, 0.587–0.912), and postmenopausal women (aOR, 0.763; 95% CI, 0.615–0.947). Meanwhile, the rs1760944 polymorphism was not found to be associated with a risk for ovarian cancer. However, by haplotype analysis, we found that the T-G and G-G haplotypes were associated with a decreased risk for ovarian cancer. Conclusions Our results suggest that in a Han Chinese population, the APE1 rs1130409 polymorphism may correlate with ovarian cancer susceptibility.

High expression of Kruppel-like factor 4 as a predictor of poor prognosis for cervical cancer patient response to radiotherapy

Purpose: The aim of this study was to explore the associations of Kruppel-like factor 4 expression with sensitivity to radiation therapy in locally advanced cervical squamous cell carcinoma patients. Methods: The records of 117 locally advanced cervical squamous cell carcinoma patients were retrospectively reviewed, and Kruppel-like factor 4 expression in cervical carcinoma tissues was examined by immunohistochemical staining. The associations of Kruppel-like factor 4 expression with clinicopathological parameters were analyzed. Survival time was analyzed using Kaplan–Meier analysis and a Cox regression model. Results: Patients being resistant to radiation therapy were associated with advanced International Federation of Gynecology and Obstetrics stage, tumor diameter (>4 cm), and poor differentiation grade. The high Kruppel-like factor 4 expression level was significantly related to resistance to radiation therapy, including radiation therapy non-response, local recurrence, and distant metastasis. The high Kruppel-like factor 4 expression level was also significantly related to the advanced International Federation of Gynecology and Obstetrics stage and poor differentiation grade. Kaplan–Meier analysis indicates that locally advanced cervical squamous cell carcinoma patients with high Kruppel-like factor 4 expression showed worse progression-free survival and overall survival. Univariate and multivariate Cox regression model analyses suggest that the high Kruppel-like factor 4 expression was one of the high-risk factors associated with poor prognosis in locally advanced cervical squamous cell carcinoma patients after radiation therapy. Conclusion: Our results suggest that the high Kruppel-like factor 4 expression can be used as a novel biomarker to predict radiation therapy resistance and poor prognosis for locally advanced cervical squamous cell carcinoma.