Yincheng Teng

Weighted Gene Co-expression Network Analysis in Identification of Endometrial Cancer Prognosis Markers

OBJECTIVE Endometrial cancer (EC) is the most common gynecologic malignancy. Identification of potential biomarkers of EC would be helpful for the detection and monitoring of malignancy, improving clinical outcomes. METHODS The Weighted Gene Co-expression Network Analysis method was used to identify prognostic markers for EC in this study. Moreover, underlying molecular mechanisms were characterized by KEGG pathway enrichment and transcriptional regulation analyses. RESULTS Seven gene co-expression modules were obtained, but only the turquoise module was positively related with EC stage. Among the genes in the turquoise module, COL5A2 (collagen, type V, alpha 2) could be regulated by PBX (pre-B-cell leukemia homeobox 1)1/2 and HOXB1(homeobox B1) transcription factors to be involved in the focal adhesion pathway; CENP-E (centromere protein E, 312kDa) by E2F4 (E2F transcription factor 4, p107/p130-binding); MYCN (v-myc myelocytomatosis viral related oncogene, neuroblastoma derived [avian]) by PAX5 (paired box 5); and BCL-2 (B-cell CLL/ lymphoma 2) and IGFBP-6 (insulin-like growth factor binding protein 6) by GLI1. They were predicted to be associated with EC progression via Hedgehog signaling and other cancer related-pathways. CONCLUSIONS These data on transcriptional regulation may provide a better understanding of molecular mechanisms and clues to potential therapeutic targets in the treatment of EC.

Overexpressed epidermal growth factor receptor (EGFR)‐induced progestin insensitivity in human endometrial carcinoma cells by the EGFR/mitogen‐activated protein kinase signaling pathway

Fertility‐sparing management is an important treatment for young women who have endometrial carcinoma (EC). Many patients with EC exhibit insensitivity or resistance to progestin therapy, and the molecular mechanisms of that insensitivity and resistance have been elusive. Epidermal growth factor receptor (EGFR) overexpression has been observed in EC, but the roles of EGFR in progestin resistance have not been investigated.

Correlation between the overexpression of epidermal growth factor receptor and mesenchymal makers in endometrial carcinoma

Objective The objective of this study was to evaluate the effect of overexpression of epidermal growth factor receptor (EGFR) on the expression of epithelial cell markers (E-cadherin and α-catenin) and mesenchymal cell markers (N-cadherin and vimentin) in endometrial carcinoma. Methods The expression of all 4 markers was evaluated in EGFR overexpressing Ishikawa cells, control Ishikawa cells, and KLE cells using reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. The expression of these 4 markers was also determined in cancerous tissues of patients with endometrial carcinoma using immunohistochemical staining. Results Ishikawa cells transfected with EGFR showed decreased expression of E-cadherin and α-catenin and increased expression of N-cadherin and vimentin compared with control Ishikawa cells (p<0.01 for all). The expression of N-cadherin and vimentin was higher and the expression of E-cadherin and α-catenin was lower in stage II-III than stage I and in grade II-III than grade I endometrial carcinoma tissue (p<0.01 for all). Conclusion Decreased expression of epithelial markers (E-cadherin and α-catenin) and increased expression of mesenchymal markers (N-cadherin and vimentin) were observed in human endometrial carcinoma tissue. These findings correlate with high EGFR expression in cultured endometrial carcinoma cells.

Human chorionic gonadotropin ratio of hemoperitoneum versus venous serum improves early diagnosis of ectopic pregnancy.

OBJECTIVE To analyze the value of the hCG ratio of peritoneal serum versus venous serum (R(P/V)) for early diagnosis and prognostic evaluation of ectopic pregnancy (EP). DESIGN Retrospective clinical study. SETTING University hospital. PATIENT(S) One hundred three women with hemoperitoneum and positive urine hCG tests underwent laparoscopy or laparotomy. INTERVENTION(S) Venous serum and peritoneal serum samples were obtained; ultrasound was performed in all the patients; dilatation and curettage was used in 28 patients. MAIN OUTCOME MEASURE(S) Quantitative hCG and R(P/V). RESULT(S) The R(P/V) in EP (5.55 +/- 4.32) is apparently greater than that in hemoperitoneum with intrauterine pregnancy (hIUP; 0.61 +/- 0.18). The median R(P/V) is 4.07 in the EP group versus 0.60 in the hIUP group, with a suggested threshold value of 1.0 for their differential diagnosis. Moreover, the R(P/V) of EP shows the dominant difference between the patients with active bleeding (8.03 +/- 3.29, n = 24) and the patients without active bleeding (4.59 +/- 3.88, n = 16) when the hCG level of venous serum is more than 1500 U/L. CONCLUSION(S) R(P/V) could instantly diagnose ectopic pregnancy and differentiate it from hIUP.

Influence of epidermal growth factor receptor inhibitor AG1478 on epithelial-mesenchymal transition in endometrial carcinoma cells.

Objective To analyze the influence of epidermal growth factor receptor inhibitor AG1478 on the proliferation and epithelial-mesenchymal transition in endometrial carcinoma cells. Materials and Methods The inhibitory effect of different concentrations of AG1478 on the proliferation of endometrial carcinoma cells was detected by tetrazolium-based assay. Western blot was applied to investigate the influence of AG1478 on expressions of epithelium-cadherin, &agr;-catenin, neural cadherin, vimentin, matrix metalloproteinase 9 (MMP9), and MMP2 protein in endometrial carcinoma cells. The influence of AG1478 on migration and invasion of endometrial carcinoma cells was examined by Transwell migration and invasion assay, respectively. Results AG1478 could suppress the proliferation of different endometrial carcinoma cells, and cells transfected with epidermal growth factor receptor were more sensitive (P < 0.05). The expression of an increase in epithelial marker proteins and a decrease in mesenchymal marker proteins, MMP9, MMP2 were observed in endometrial carcinoma cells after AG1478 treated. This effect was more obvious in cells transfected with epidermal growth factor receptor (P < 0.05). The migration and invasion ability of endometrial carcinoma cells were suppressed by AG1478, and Ishikawa cells transfected with epidermal growth factor receptor were demonstrated to be more sensitive to AG1478 (P < 0.05). Conclusions Epidermal growth factor receptor inhibitor AG1478 could effectively inhibit the proliferation and epithelial-mesenchymal transition of endometrial carcinoma cells.

Epidermal growth factor receptor signaling pathway involved in progestin‐resistance of human endometrial carcinoma: In a mouse model

Aim:  The aim of these investigations was to study the role of gefitinib (a specific oral epidermal growth factor receptor‐tyrosine kinase inhibitor) on reversing progestin‐resistance in a human endometrial carcinoma xenograft model.

Proteomic identification of PKM2 and HSPA5 as potential biomarkers for predicting high‐risk endometrial carcinoma

Aim:  Endometrial carcinoma (EC) is a common gynecologic malignancy. EC has a favorable prognosis because it is usually diagnosed at an early stage. However, the recurrence rate is high and the prognosis is poor for high‐risk EC. Identification of new biomarkers for the prediction of high‐risk features will help to guide the treatment and improve the prognosis of patients with EC.

Medical methods for cervical ripening before the removal of intrauterine devices in postmenopausal women: a systematic review

In China, most women with intrauterine devices (IUDs) ask to have them removed following the menopause. As the cervix is stenotic after the menopause and most IUDs do not have a thread attached, various medical methods are used for cervical ripening prior to IUD removal. A systematic review of the relevant literature was conducted to compare different medical methods for cervical priming with no treatment, or with other methods, prior to IUD removal in postmenopausal women. Multiple electronic databases including the Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, the WHO Reproductive Health Library (2011) and the Chinese Biomedical Literature Database were searched systematically. Reference lists of articles published in English or Chinese between 1980 and 2011 were searched. All randomized controlled trials (RCTs) on IUD removal following the menopause using medical agents compared with no treatment, or with other treatments, were included. Outcomes were the ease of IUD removal, need for forced cervical dilatation, cervical width, procedure time, severe pain and any side-effects. Data were processed using RevMan 5 software. Thirty original RCTs were eligible for inclusion. Most medical agents such as oestrogens, mifepristone, misoprostol and methyl carboprost were highly effective for facilitating IUD removal, and reduced the need for further dilatation during the procedure. In particular, treatment with mifepristone or misoprostol prior to IUD removal was found to increase the width of the cervical canal and reduce the procedure time. Mifepristone was more effective than vaginal misoprostol for cervical dilatation, but it showed similar effectiveness to misoprostol and nilestriol in terms of the ease of IUD removal. Sublingual misoprostol was superior to oral misoprostol for facilitating IUD removal. A dose of misoprostol as low as 200μg was effective for cervical priming. For vaginal and oral misoprostol, the optimum times of application were 2-3h and 1 day prior to the procedure, respectively. All the prophylactic medical methods were able to alleviate pain during IUD removal, and vaginal misoprostol was more effective than nilestriol. Uterine injury was more common with no treatment and with nilestriol. Gastrointestinal side-effects such as nausea and diarrhoea were common with oral misoprostol and vaginal misoprostol, respectively. Therefore, mifepristone or sublingual misoprostol should be the medical treatments of choice. Oestrogen regimens might be alternatives when mifepristone or misoprostol are contraindicated, and there is a need for further study on combined regimens for cervical priming.

Cholesterol Synthetase DHCR24 Induced by Insulin Aggravates Cancer Invasion and Progesterone Resistance in Endometrial Carcinoma

3β-Hydroxysteroid-Δ24 reductase (DHCR24), the final enzyme of the cholesterol biosynthetic pathway, has been associated with urogenital neoplasms. However, the function of DHCR24 in endometrial cancer (EC) remains largely elusive. Here, we analyzed the expression profile of DHCR24 and the progesterone receptor (PGR) in our tissue microarray of EC (n = 258), the existing EC database in GEO (Gene Expression Omnibus), and TCGA (The Cancer Genome Atlas). We found that DHCR24 was significantly elevated in patients with EC, and that the up-regulation of DHCR24 was associated with advanced clinical stage, histological grading, vascular invasion, lymphatic metastasis, and reduced overall survival. In addition, DHCR24 expression could be induced by insulin though STAT3, which directly binds to the promoter elements of DHCR24, as demonstrated by ChIP-PCR and luciferase assays. Furthermore, genetically silencing DHCR24 inhibited the metastatic ability of endometrial cancer cells and up-regulated PGR expression, which made cells more sensitive to progestin. Taken together, we have demonstrated for the first time the crucial role of the insulin/STAT3/DHCR24/PGR axis in the progression of EC by modulating the metastasis and progesterone response, which could serve as potential therapeutic targets for the treatment of EC with progesterone receptor loss.

Bioinformatics analysis reveals potential candidate drugs for cervical cancer

We sought to explore the mechanisms of cervical carcinoma response to epidermal growth factor (EGF), and then identify biologically active small molecules capable of targeting the sub‐pathways that were dysregulated in cervical cancer cells in the response to EGF.