Xuemei Jia

LncRNAs as new biomarkers to differentiate triple negative breast cancer from non-triple negative breast cancer.

Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with high heterogeneity. To date, there is no efficient therapy for TNBC patients and the prognosis is poor. It is urgent to find new biomarkers for the diagnosis of TNBC or efficient therapy targets. As an area of focus in the post-genome period, long non-coding RNAs (lncRNAs) have been found to play critical roles in many cancers, including TNBC. However, there is little information on differentially expressed lncRNAs between TNBC and non-TNBC. We detected the expression levels of lncRNAs in TNBC and non-TNBC tissues separately. Then we analyzed the lncRNA expression signature of TNBC relative to non-TNBC, and found dysregulated lncRNAs participated in important biological processes though Gene Ontology and Pathway analysis. Finally, we validated these lncRNA expression levels in breast cancer tissues and cells, and then confirmed that 4 lncRNAs (RP11-434D9.1, LINC00052, BC016831, and IGKV) were correlated with TNBC occurrence through receiver operating characteristic curve analysis. This study offers helpful information to understand the initiation and development mechanisms of TNBC comprehensively and suggests potential biomarkers for diagnosis or therapy targets for clinical treatment.

LncRNAs expression profiling in normal ovary, benign ovarian cyst and malignant epithelial ovarian cancer

Long noncoding RNA (lncRNA) has been recognized as a regulator of gene expression, and the dysregulation of lncRNAs is involved in the progression of many types of cancer, including epithelial ovarian cancer (EOC). To explore the potential roles of lncRNAs in EOC, we performed lncRNA and mRNA microarray profiling in malignant EOC, benign ovarian cyst and healthy control tissues. In this study, 663 transcripts of lncRNAs were found to be differentially expressed in malignant EOC compared with benign and normal control tissues. We also selected 18 altered lncRNAs to confirm the validity of the microarray analysis using quantitative real-time PCR (qPCR). Pathway and Gene Ontology (GO) analyses demonstrated that these altered transcripts were involved in multiple biological processes, especially the cell cycle. Furthermore, Series Test of Cluster (STC) and lncRNA-mRNA co-expression network analyses were conducted to predict lncRNA expression trends and the potential target genes of lncRNAs. We also determined that two antisense lncRNAs (RP11-597D13.9 and ADAMTS9-AS1) were associated with their nearby coding genes (FAM198B, ADAMTS9), which participated in cancer progression. This study offers helpful information to understand the initiation and development mechanisms of EOC.

Progesterone protects ovarian cancer cells from cisplatin-induced inhibitory effects through progesterone receptor membrane component 1/2 as well as AKT signaling

Progesterone, also known as P4 (pregn-4-ene-3, 20-dione), is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Despite the physiological effects, P4 is also effective for the treatment of numerous pathological states, such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus as well as cancer. Considering the hormone microenvironment of gynecological cancers, P4 should be particularly noted in ovarian cancer. The present study demonstrated that P4 protected the ovarian cancer cell line HO-8910 from cisplatin (CDDP)-induced cell cycle arrest and restored the cell migratory capability following treatment of CDDP. Mechanistically, both progesterone receptor membrane component 1 (PGRMC1) and the progesterone receptor (PGR) were decreased in the cells treated with CDDP plus P4, while the level of progesterone receptor membrane component 2 (PGRMC2) was significantly elevated. Reversely, in the HO-8910 cells treated with CDDP alone, levels of both PGRMC1 and PGR were increased while the level of PGRMC2 was decreased. In addition to the receptor expression profile, the PI3K/AKT signaling pathway was also involved in the action of P4 in the CDDP-resistant HO-8910 cells, and a chemical inhibitor for PI3K, LY294002, significantly abolished the anti-apoptotic effect of P4. Consequently, the addition of a PI3K inhibitor to CDDP-based chemotherapy may have a more beneficial application for ovarian cancer therapy.

Clinical significance of plasma D-dimer in ovarian cancer: A meta-analysis

Background: D-dimer has been widely used for the diagnosis and prognosis of ovarian cancer, but there is still controversy on its prediction value of ovarian cancer. Objectives: To explore the clinical significance of plasma D-dimer level on ovarian cancer systematically. Methods: Using PubMed, Cochrane Library, and Web of Science libraries, all the relevant studies for the diagnostic and prognostic value of plasma D-dimer for ovarian cancer and the relationship between elevated D-dimer level and venous thromboembolism (VTE) risk of ovarian cancer were searched till May 30, 2016. Standardized mean difference (SMD), odds ratio (OR), hazard ratio (HR), and 95% confidence interval (CI) were appropriately pooled. Results: A total of 15 eligible studies involving a total of 1437 cancer patients were included. No significant association was found between high D-dimer level and overall survival of patients with ovarian cancer (HR 1.32, 95% CI: 0.90–1.95, P  =  .044). However, subgroup analysis indicated that the sample sizes could explain the heterogeneity between studies. And elevated D-dimer could predict increased risk of mortality when the sample sizes were >100 (HR 1.800, 95% CI: 1.283–2.523, P  =  .845). Besides, plasma D-dimer level was significantly higher in malignant ovarian cancer patients compared with benign controls (SMD 0.774, 95% CI: 0.597–0.951, P  =  .39), higher in advanced ovarian cancer patients (International Federation of Gynecology and Obstetrics [FIGO] classification III and IV) than in early stage ovarian cancer patients (FIGO classification I and II, SMD 0.611, 95% CI: 0.373–0.849, P  =  .442). And high D-dimer level indicated high VTE risk (OR 4.068, 95% CI: 2.423–6.829, P  =  .629) of ovarian cancer patients. Conclusion: The plasma D-dimer level in ovarian cancer patients can predict the changes that correlated with disease progression and the VTE risk. But its predictive value for the prognosis of ovarian cancer was significantly dependent on the sample sizes. More well-designed studies with large sample sizes are needed to validate and update the findings of present study.

Distinct expression profile of lncRNA in endometrial carcinoma.

Endometrial carcinoma (EC) is the most common malignancy in women. Dispite its prevalence, the prognosis of endometrial carcinoma still relies on conventional histological type, grade and invasion information. Its morbidity is still increasing and the outcome is very poor. To the best of our knowledge, hormonal imbalance and/or molecular genetic alterations are the main cause of EC. However, the alterations of lncRNAs which accounts for approximately 4/5 of human transcripts are still poorly understood. In the present study, using the RiboArray™ Custom Array, we studied the expression profiles of lncRNA in EC as compared to normal endometrium (NE) to find potential core lncRNAs for the diagnosis of EC. We found the potential core lncRNA by GO, KEGG, lncRNA and mRNA co-expression network. The potential functional lncRNAs were further detected by qPCR to validate the microarray results. A total of 172 lncRNAs and 188 mRNAs were found to be differentially expressed between type Ⅰ EC and the NE samples (fold change >1.5). qPCR validation showed good consistency with the microarray data. GO, pathway analysis, the lncRNA and mRNA co-expression network as well as the TCGA data revealed that 6 lncRNAs (KIAA0087, RP11-501O2, FAM212B-AS1, LOC102723552, RP11-140I24 and RP11-600K151) may be the core regulators of endometrial carcinogenesis. The potential core lncRNAs revealed by the mRNA and lncRNA co-expression network might be helpful to explore potential early diagnostic and therapeutic targets for EC.

Multidrug resistant lncRNA profile in chemotherapeutic sensitive and resistant ovarian cancer cells

Most ovarian cancer patients are chemosensitive initially, but finally relapse with acquired chemoresistance. Multidrug‐resistance is the extremely terrible situation. The mechanism for the acquired chemoresistance of ovarian cancer patients is still not clear. LncRNAs have been recognized as the important regulator of a variety of biological processes, including the multidrug‐resistant process. Here, we carried out the lncRNA sequencing of the ovarian cancer cell line A2780 and the paxitaxel resistant cell line A2780/PTX which is also cross resistant to the cisplatin and epirubicin. Through integrating the published data with the cisplatin resistant lncRNAs in ovarian cancer cell line or ovarian cancer patients, 5 up‐regulated and 21 down‐regulated lncRNAs are considered as the multidrug‐resistant lncRNAs. By real‐time PCR analysis, we confirmed the 5 up‐regulated and 4 down‐regulated multidrug resistant lncRNAs were similarly changed in both the multidrug resistant ovarian cancer cell lines and the multidrug resistant colon cancer cell lines. Furthermore, we conducted the lncRNA‐mRNA co‐expression network to predict the potential multidrug resistant lncRNAs’ targets. Interestingly, the multidrug resistant genes ABCB1, ABCB4, ABCC3, and ABCG2 are all co‐expressed with lncRNA CTD‐2589M5.4. Our results provide the valuable information for the understanding of the lncRNA function in the multidrug resistant process.

E-cadherin expression as a prognostic factor in patients with ovarian cancer: a meta-analysis

The prognostic role of epithelial cadherin (E-cadherin) downregulation in ovarian cancer has been assessed for years while the results remain inconclusive. The aim of our study was to assess this issue. Eligible studies were identified through searches of PubMed, EMBASE and Cochrane Database. In total, 1562 patients from 17 studies were included to assess the association between E-cadherin expression and overall survival/progression-free survival and clinicopathological characteristics of ovarian cancer patients. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were calculated to estimate the effect. The quality of 17 studies was evaluated using the Newcastle Ottawa Quality Assessment Scale. We also performed subgroup analysis, publication bias and sensitivity analysis in this meta-analysis. The results showed that negative E-cadherin expression significantly predicted poor overall survival of ovarian cancer patients (HR = 1.90, 95% CI = 1.50–2.40). However, negative E-cadherin was not associated with poor progression-free survival (HR = 1.19, 95% CI = 0.86–1.64). Moreover, Negative E-cadherin expression was distinctly associated with FIGO stage (OR = 0.42, 95% CI = 0.31–0.57), tumor grade (OR = 0.48, 95% CI = 0.34–0.67), metastasis (OR = 0.13, 95% CI = 0.07–0.26) and recurrence (OR = 0.48, 95% CI = 0.29–0.79). This meta-analysis revealed that negative E-cadherin expression might be a predicative factor of poor prognosis in ovarian cancer patients.The prognostic role of epithelial cadherin (E-cadherin) downregulation in ovarian cancer has been assessed for years while the results remain inconclusive. The aim of our study was to assess this issue. Eligible studies were identified through searches of PubMed, EMBASE and Cochrane Database. In total, 1562 patients from 17 studies were included to assess the association between E-cadherin expression and overall survival/progression-free survival and clinicopathological characteristics of ovarian cancer patients. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were calculated to estimate the effect. The quality of 17 studies was evaluated using the Newcastle Ottawa Quality Assessment Scale. We also performed subgroup analysis, publication bias and sensitivity analysis in this meta-analysis. The results showed that negative E-cadherin expression significantly predicted poor overall survival of ovarian cancer patients (HR = 1.90, 95% CI = 1.50-2.40). However, negative E-cadherin was not associated with poor progression-free survival (HR = 1.19, 95% CI = 0.86-1.64). Moreover, Negative E-cadherin expression was distinctly associated with FIGO stage (OR = 0.42, 95% CI = 0.31-0.57), tumor grade (OR = 0.48, 95% CI = 0.34-0.67), metastasis (OR = 0.13, 95% CI = 0.07-0.26) and recurrence (OR = 0.48, 95% CI = 0.29-0.79). This meta-analysis revealed that negative E-cadherin expression might be a predicative factor of poor prognosis in ovarian cancer patients.

Prognostic and Clinicopathological significance of ARID1A in endometrium‐related gynecological cancers: A meta‐analysis

The tumor suppressor gene, AT Rich Interactive Domain 1A (ARID1A) mutation has been reported in a variety of cancers, especially the endometrium‐related gynecological cancers, including the ovarian clear cell carcinoma, ovarian endometrioid carcinoma, and uterine endometrioid carcinoma. However, the prognostic value of ARID1A in endometrium‐related gynecological cancers is still inconclusive. Therefore, we performed this meta‐analysis to evaluate the clinical significance of ARID1A in endometrium‐related gynecological cancers. By systematically searching all the relevant studies from Pubmed, Cochrane Library, and Web of Science up to September 2016, 11 studies with 1,432 patients were included. All the study characteristics and the prognostic data were extracted. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled using the fixed‐effect or random‐effect model. Our results indicated that negative ARID1A expression predicted shorter Progression free survival (PFS, HR, 1.84; 95%CI, 1.32–2.57, P = 0.000) of patients with endometrium related gynecological cancers, especially the patiently with OCCC and the patients in Japan. Besides, a marginal trend towards the same direction was found in the Overall analysis (OS, HR, 1.34; 95%CI, 0.93–1.93, P = 0.112). Furthermore, the significant correlation was achieved between the negative ARID1A expression and the FIGO stage of endometrium‐related gynecological cancers, but not the other characteristics. J. Cell. Biochem. 118: 4517–4525, 2017.

Benzotriazole Enhances Cell Invasive Potency in Endometrial Carcinoma Through CTBP1-Mediated Epithelial-Mesenchymal Transition

Background/Aims: Benzotriazole (BTR) and its derivatives, such as intermediates and UV stabilizers, are important man-made organic chemicals found in everyday life that have been recently identified as environmental toxins and a threat to female reproductive health. Previous studies have shown that BTR could act as a carcinogen by mimicking estrogen. Environmental estrogen mimics could promote the initiation and development of female cancers, such as endometrial carcinoma, a type of estrogenic-sensitive malignancy. However, there is little information on the relationship between BTR and endometrial carcinoma. In this study, we aimed to demonstrate the biological function of BTR in endometrial carcinoma and explored the underlying mechanism. Methods: The CCK-8 assay was performed to detect cell viability; transwell-filter assay was used to assess cell invasion; gene microarray analysis was employed to determine gene expression patterns in response to BTR treatment; western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were carried out to detect the expression levels of BTR-related genes. Results: Our data showed that BTR could induce the invasion and migration of endometrial carcinoma cells (Ishikawa and HEC-1-B). In addition, BTR increased the expression level of CTBP1, which could enhance the epithelial-mesenchymal transition (EMT) in cancer cells. Moreover, CTBP1 silencing reversed the effect of BTR on EMT progression in endometrial carcinoma cells. Conclusion: This study indicates that BTR could act as a carcinogen to promote the development of endometrial carcinoma mainly through CTBP1-mediated EMT, which deserves more attention.