lncRNA UCA1 promotes tumor progression by targeting SMARCD3 in cervical cancer.

Long noncoding RNA urothelial carcinoma associated 1 (UCA1) has been identified as a key molecule in human cancers. However, its functional implications remain unspecified in the context of cervical cancer (CC). This research aims to identify the regulatory mechanism of UCA1 in CC. UCA1 was identified through microarray and confirmed through a quantitative real-time polymerase chain reaction. Proteins that bind with UCA1 were recognized using RNA pull-down assays along with RNA immunoprecipitation. Ubiquitination assays and coimmunoprecipitation were performed to explore the molecular mechanisms of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily d, member 3 (SMARCD3) downregulated in CC. The effects of UCA1 and SMARCD3 on the progression of CC were investigated through gain- and loss-of-function assays and xenograft tumor formation in vivo. In this study, UCA1 was found to be upregulated in CC cells as well as in human plasma exosomes for the first time. Functional studies indicated that UCA1 promotes CC progression. Mechanically, UCA1 downregulated the SMARCD3 protein stabilization by promoting SMARCD3 ubiquitination. Taken together, we revealed that the UCA1/SMARCD3 axis promoted CC progression, which could provide a new therapeutic target for CC.

Expression of angiogenic factor with G patch and FHA domains 1 (AGGF1) in placenta from patients with preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a major contributor to maternal and foetal morbidity and mortality worldwide. It manifests as high blood pressure and proteinuria in women at more than 20 weeks of gestation. Abnormal levels of anti- and pro-angiogenesis factors are known to be associated with PE. In the present study, we aimed to determine the localisation of angiogenic factor with G patch and FHA domains 1 (AGGF1) in the placenta and to compare the expression levels of AGGF1 in the third-trimester placentas of preeclamptic and normotensive pregnancies. MATERIALS AND METHODS: Placental tissue samples were collected from women with PE (n = 28) and without PE (n = 28). The normotensive controls without PE were matched for gestational age at delivery with the patients with PE. The expression levels of AGGF1 in the placental tissues were evaluated using immunohistochemistry, quantitative reverse transcription polymerase chain reaction and Western blot. RESULTS: The immunoexpression of AGGF1 was localised in the syncytiotrophoblast tissue. Notable, the mRNA and protein expression levels of AGGF1 were decreased in preeclamptic placentas as compared with the normotensive control group (P < 0.05). DISCUSSION: Our results suggest that the decreased AGGF1 in preeclamptic placentas may be related to the pathogenesis of preeclampsia.

Protein kinase CK2 participates in estrogen-mediated endothelial progenitor cell homing to endometriotic lesions through stromal cells in a stromal cell-derived factor-1- CXCR4-dependent manner.

OBJECTIVE: To explore the possible mechanism of protein kinase CK2, which participates in estrogen recruitment of endothelial progenitor cells (EPCs), and its role in the angiogenesis of endometriosis lesions. DESIGN: Laboratory study. SETTING: University. ANIMAL(S): BALB/c mice. INTERVENTION(S): Exposure of human endometrial stromal cells (HESCs) to estrogen and CK2 inhibitor CX-4945 and endometrial stromal cells transfected with the protein kinase CK2 vector (HESC-CK2). Endometriosis models were induced by allogeneic mice transplantation of the endometrium into dorsal skinfold chambers. The mice received an IP injection of 50 mg/kg emodin per day or were treated with 100 µg/kg estrogen by SC injection once a week. MAIN OUTCOME MEASURE(S): The concentration of cytokines in cells was measured with ELISA. The migration of EPCs was examined using the scratch assay method and Transwell, a capillary tube-formation assay to determine EPC tube-forming capacity, and protein and mRNA expression with Western blot and polymerase chain reaction analyses, respectively. RESULT(S): Protein kinase CK2 participates in estrogen-mediated EPC homing to endometriotic lesions through stromal cells in a stromal cell-derived factor-1 (SDF-1)-CXCR4-dependent manner. Conditioned medium from endometrial stromal cells that were stably transfected with the protein kinase CK2 vector (HESC-CK2) or pretreated with estrogen significantly enhanced the migration and recruitment of EPCs. In contrast, conditioned medium from HESCs that were treated with CX-4945, a selective inhibitor of CK2, inhibited the mobility and viability of EPCs. Furthermore, CK2 overexpression significantly upregulated SDF-1 expression and secretion in endometrial stromal cells by activating the AKT/mTOR pathway. Moreover, treatment with the SDF-1 receptor CXCR4-specific inhibitor AMD3100 completely reversed the CK2-enhanced migration of EPCs. CONCLUSION(S): This study demonstrates that CK2 participates in estrogen-mediated EPC homing to endometriotic lesions through stromal cells in an SDF-1-CXCR4-dependent manner and may be a therapeutic target.

Prognostic value of distant metastatic sites in stage IV endometrial cancer: A SEER database study of 2948 women.

OBJECTIVE: To evaluate the prognosis of women with distant metastasis at the time of endometrial cancer (EC) diagnosis and identify prognostic factors according to metastatic site. METHODS: A retrospective cohort study of women diagnosed with EC according to the SEER database between 2010 and 2014. Univariate and multivariate Cox regression was used to identify variables associated with overall survival. Kaplan-Meier curves were used to compare survival among different groups. RESULTS: Overall, 2948 women with stage IV EC were identified. The most common distant metastatic site was the lung. Having a distant metastatic site independently predicted overall survival. Using brain metastasis as a reference, overall survival was longer for liver (P=0.049), lung (P=0.005), and bone (P=0.019) metastasis. Relative to no distant metastasis, overall survival was shorter for women with one (P<0.001) or two or more (P<0.001) sites of distant metastasis. Overall survival was independently influenced by tumor grade, insurance status, and surgery among women with only lung metastasis. CONCLUSION: The findings showed that the prognosis of women with stage IV EC differs by distant metastatic site, and identified several predictors of poor survival. They may help clinicians to better predict prognosis for newly diagnosed cases of EC with distant metastasis.

UBE2C Is Upregulated by Estrogen and Promotes Epithelial-Mesenchymal Transition via p53 in Endometrial Cancer.

Ubiquitin-conjugating enzyme E2C (UBE2C) plays important roles in tumor progression; nevertheless, its function in endometrial cancer remains unclear. This study elucidated the impact of UBE2C on endometrial cancer and its underlying mechanism. Human endometrial cancer and normal endometrial tissues were acquired from patients at Wuhan Union Hospital and UBE2C expression was detected by Western blotting and qRT-PCR. Endometrial cancer cells were transfected with a UBE2C overexpression plasmid or UBE2C-specific short hairpin RNA (shRNA) to up- or downregulate UBE2C expression, respectively. CCK8 and transwell assays were applied to assess the effects of UBE2C on cell proliferation, migration, and invasion. We found a significant elevation of UBE2C expression in patients with endometrial cancer, and that UBE2C upregulation was associated with advanced histologic grade, FIGO stage, recurrence, and shorter overall survival. UBE2C knockdown inhibited endometrial cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), whereas UBE2C overexpression exerted the opposite effects. UBE2C downregulation increased p53 and its downstream p21 expression, with p53 overexpression reversing the EMT-promoting effects of UBE2C. UBE2C enhanced p53 ubiquitination to facilitate its degradation in endometrial cancer cells. Estradiol (E2) induced UBE2C expression via estrogen receptor α, which binds directly to the UBE2C promoter element. Silencing of UBE2C inhibited E2-promoted migration, invasion, and EMT in vitro and in vivo. IMPLICATIONS: UBE2C-mediated tumor EMT promotion by estrogen is a novel mechanism for the progression of estrogen-induced endometrial cancer, which could offer new biomarkers for diagnosis and therapy of endometrial cancer in the future.

NLRP3 inflammasome activation by estrogen promotes the progression of human endometrial cancer.

BACKGROUND: Activation of NLPR3 inflammasome is associated with the development and progression of some types of malignant tumors, but its role in endometrial cancer is unclear. This study aimed to investigate the expression and function of NLRP3 inflammasome in endometrial cancer. MATERIALS AND METHODS:  The expression levels of NLRP3, its inflammasome components and estrogen receptor ß in endometrial cancer and paired non-tumor tissues were detected. The effects of NLPR3 silencing or overexpression on the proliferation, migration, and invasion of Ishikawa and HEC-1A cells were determined. The impact of NLPR3 silencing on the growth of implanted tumors was determined in vivo. The effects of estrogen on NLPR3 inflammasome activation and Ishikawa cell proliferation were determined. RESULTS: The upregulation of NLRP3, ASC, caspase-1, and IL-1ß was associated with the progression of endometrial cancer and poor survival. NLPR3 silencing inhibited the proliferation, migration, and invasion of endometrial cancer cells while NLPR3 overexpression had opposite effects. NLPR3 silencing reduced IL-1ß and caspase-1 expression and the growth of implanted endometrial tumors, accompanied by decreased pro-IL-1ß maturation. Estrogen enhanced NLPR3, ERß, pro-IL-1ß, IL-1ß expression, and endometrial cancer cell proliferation, which were mitigated by treatment with ERß inhibitor but not ERα inhibitor. CONCLUSION: Our results suggest that estrogen acts through ERß to enhance the activation of NLPR3 inflammasome and promote the progression of endometrial cancer. NLPR3 inflammasome may be a new therapeutic target for endometrial cancer.

Identification of key pathways and genes in endometrial cancer using bioinformatics analyses.

Endometrial cancer (EC) is one of the most common gynecological cancer types worldwide. However, to the best of our knowledge, its underlying mechanisms remain unknown. The current study downloaded three mRNA and microRNA (miRNA) datasets of EC and normal tissue samples, GSE17025, GSE63678 and GSE35794, from the Gene Expression Omnibus to identify differentially expressed genes (DEGs) and miRNAs (DEMs) in EC tumor tissues. The DEGs and DEMs were then validated using data from The Cancer Genome Atlas and subjected to gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. STRING and Cytoscape were used to construct a protein-protein interaction network and the prognostic effects of the hub genes were analyzed. Finally, miRecords was used to predict DEM targets and an miRNA-gene network was constructed. A total of 160 DEGs were identified, of which 51 genes were highly expressed and 100 DEGs were discovered from the PPI network. Three overlapping genes between the DEGs and the DEM targets, BIRC5, CENPF and HJURP, were associated with significantly worse overall survival of patients with EC. A number of DEGs were enriched in cell cycle, human T-lymphotropic virus infection and cancer-associated pathways. A total of 20 DEMs and 29 miRNA gene pairs were identified. In conclusion, the identified DEGs, DEMs and pathways in EC may provide new insights into understanding the underlying molecular mechanisms that facilitate EC tumorigenesis and progression.

Knockdown of long non-coding HOTAIR enhances the sensitivity to progesterone in endometrial cancer by epigenetic regulation of progesterone receptor isoform B.

PURPOSE: Progesterone, particularly medroxyprogesterone acetate (MPA) has been mainly used for young endometrial carcinoma (EC) patients with conservative treatment. However, its treatment benefits are limited by insensitivity or acquired resistance. In this study, we aim to investigate the effect of long non-coding RNA HOTAIR on progesterone sensitivity in endometrial cancer, as well as the underlying mechanisms. METHODS: The expression of HOTAIR was detected by quantitative real-time PCR. The impact of MPA on the endometrial cancer cells was examined by MTT, colony formation, apoptosis-related protein detection and flow cytometry. Chromatin immunoprecipitation (ChIP) assay was performed to detect the regulatory mechanism between HOTAIR and progesterone receptor B (PRB). We further confirm the function of HOTAIR in vivo though xenograft tumor assay. RESULTS: We found that HOTAIR inversely correlated with PRB expression in endometrial carcinoma. Knockdown of HOTAIR promoted the MPA sensitivity by upregulating PRB, which can be largely reversed by PRB downregulation. Moreover, inhibiting LSD1, a HOTAIR-associated protein that removed activating H3K4me2 chromatin marks, induced PRB expression and promoted apoptosis induced by MPA. We further showed that silencing HOTAIR strengthened the H3K4me2 occupation on the promotor of PRB. CONCLUSIONS: Our findings provide compelling evidence that HOTAIR and LSD1 collaboratively repress PRB expression and thus mediate progesterone sensitivity in endometrial carcinoma cells. HOTAIR is a potential predictor for progesterone response in EC and down-regulated expression of HOTAIR might be an effective strategy for overcoming progesterone resistance.

Estrogen­related receptor γ promotes the migration and metastasis of endometrial cancer cells by targeting S100A4.

S100 calcium binding protein A4 (S100A4) is a well­established tumor metastasis mediator in various malignancies, including endometrial cancer (EC). However, the regulatory mechanism underlying S100A4 expression remains elusive. In the present study, by analyzing public datasets and clinical samples, we found that estrogen­related receptor Î³ (ERRγ) was upregulated and positively correlated with S100A4 transcription in EC. ERRγ knockdown inhibited S100A4 expression and promoted the expression of its downstream target E­cadherin, and vice versa. Mechanistic studies indicated that ERRγ enhanced the promoter activity of S100A4 to facilitate its transcription. In addition, knockdown of ERRγ suppressed migration and invasion of EC cells in vitro, while ectopic ERRγ expression promoted migration and invasion of EC cells in vitro and tumor growth in vivo. Importantly, restoration of S100A4 expression prevented EC cells from undergoing ERRγ­mediated changes in these biological features. In addition, synchronous changes in S100A4 and ERRγ expression were observed after incubation with estrogen. Overall, ERRγ may exert oncogenic activity mainly associated with aggressiveness of EC by activating S100A4 transcription and thus may be a novel therapeutic target in EC.

The suppressive role of calcium sensing receptor in endometrial cancer.

Studies have shown that calcium sensing receptor (CaSR) is involved in the progressions of several human cancers. However, the role of CaSR in endometrial cancer remains unknown. This study provides a preliminary analysis of the CaSR effect on endometrial cancer development. Ectopic CaSR expression by lentiviral transfection (CaSR-OV) in Ishikawa cells significantly increased intracellular calcium ([Ca2+]i) levels and cell apoptosis. E-cadherin and ß-catenin expression and complex formation at the membrane were increased in CaSR-OV Ishikawa cells relative to control Ishikawa cells (vector). Furthermore, CaSR-OV Ishikawa cells showed a reduced invasive potential, which was attributed to E-cadherin/ß-catenin complex formation. Moreover, a reduction in CaSR expression in endometrial cancer relative to normal specimens was evident by immunohistochemistry and was positively associated with E-cadherin, but not ß-catenin, expression. Furthermore, VEGFR3 was significantly down-regulated in CaSR-OV Ishikawa cells. Additionally, an immunohistochemical analysis showed that VEGFR3 was significantly increased in endometrial cancer compared with the normal endometrium and was inversely correlated with CaSR expression. However, the CaSR knockdown produced the opposite effects. These findings suggest an inhibitory role for CaSR in endometrial cancer. Therefore, reduced CaSR expression may be a suitable explanation and valuable predictor for endometrial cancer progression.

Propensity score matching analysis of the prognosis for the rare insular subtype of thyroid cancer based on SEER database.

Insular thyroid carcinoma (ITC) is an uncommon thyroid malignancy with an unclear prognosis. The aim of this study was to determine the prognoses of patients with ITC. We investigated a large cohort of patients with differentiated thyroid cancer from the Surveillance, Epidemiology, and End Results (SEER) database who were registered between 2004 and 2013, and compared the prognosis of patients with ITC to those with classic papillary thyroid cancer (CPTC) and follicular thyroid cancer (FTC). Patient mortality was determined using Kaplan-Meier analyses with log-rank tests, as well as Cox proportional hazards regression analyses. The study cohort comprised of 165 patients with ITC, 5419 patients with FTC, and 60739 patients with CPTC. The rate of cancer-specific mortality per 1000 person-years for ITC was higher than that for CPTC or FTC. According to multivariate Cox regression analysis, however, the cancer-specific and all-cause mortality rates of ITC were similar to those of CPTC and FTC. The cancer-specific survival rate in patients with ITC was higher than that in patients with CPTC, but similar to that in patients with FTC, after adjusting for potentially influencing factors using propensity score matching analysis. These findings, which contrast with previously published data, provide new implications for the treatment of patients with ITC.

Correction: Prognostic and diagnostic significance of lncRNAs expression in cervical cancer: a systematic review and meta-analysis.

[This corrects the article DOI: 10.18632/oncotarget.18323.].

Prognostic and diagnostic significance of lncRNAs expression in cervical cancer: a systematic review and meta-analysis.

Long noncoding RNAs (lncRNAs) have been reported to be abnormally expressed in cervical cancer (CC) and presumably serve as diagnostic or prognostic markers. We thus performed a systematic review and meta-analysis to evaluate the clinical values of dysregulated lncRNAs in CC. A literature search was performed using the electronic databases PubMed, Embase, and Web of Science. A total of 22 relevant studies were eligible, including 21 on clinicopathological features, 18 on prognosis, and 4 on diagnosis. For clinicopathological features, HOTAIR expression was positively associated with tumor size (odds ratio [OR]=2.19, 95% confidence interval [CI] 1.42-3.38, P=0.000) and lymph node metastasis (OR=6.04, 95% CI 3.51-10.42, P=0.000). For the prognostic values, up-regulated HOTAIR had an unfavorable impact on overall survival ([OS]; hazard ratio [HR]=1.94, 95%CI 1.17-3.22, P=0.011) and disease-free survival (HR=2.61, 95%CI 1.35-5.05, P=0.004), and high PVT1 expression was correlated with shorter OS (HR=1.66, 95%CI 1.21-2.29, P=0.002). For the diagnostic values, the pooled result showed an area under the curve (AUC) of 0.85, with 85% sensitivity and 81% specificity in discriminating patients with CC from healthy controls. Overall, we conclude that lncRNAs might serve as promising indicators for prognostic and diagnostic evaluation of patients with CC.

Altered expression of hormone receptor, integrin ß3 and pinopode in the endometrium of luteal phase defect women.

OBJECTIVE: To invistigate estrogen receptor (ER), progesterone receptor (PR), integrin ß3, and pinopode expression in luteal phase deficiency (LPD) women. METHODS: There were 52 nulligravidas consecutive infertile patients undergoing a routine assistant reproduction consultation included in this study. An endometrial biopsy sample was randomly obtained between days 4 and 10 of the luteal phase. Endometrial morphology was examined with scanning electron microscopy. Expressions of ER, PR, integrin ß3 were determined in the endometrium of LPD patients with immunohistochemistry. RESULTS: The incidence of LPD was 15.3% (8/52) in this study. On day luteinizing hormone (LH) surge + 9∼LH + 10, noted regressing pinopodes resembling a day LH + 7∼LH + 8 in the endometrium of the control group. The expressions of ER and PR in glandular epithelium were significantly increased in endometrium of LPD than that in the control group (p < 0.05). In contrast, there was a statistically significant decrease expression of the integrin ß3 in women from the group of LPD (p < 0.05). CONCLUSION: The altered expression of ER and PR may be associated with the expression variation of integrin and pinopode formation in endometrium of LPD women. This alteration may imply the association of low rates of cycle fecundity and high rates of embryonic loss in LPD women.

Prognostic significance of L1 cell adhesion molecule in cancer patients: A systematic review and meta-analysis.

The L1 cell adhesion molecule (L1CAM) extensively participates in nervous system development and the malignant progression of human tumours. The prognostic value of L1CAM for the survival of patients with solid tumours remains controversial. The present meta-analysis was thus performed to highlight the relationship between L1CAM expression and prognosis in cancer patients. Relevant publications were identified after searching several widely used databases, including PubMed, EMBASE and the ISI Web of Science. A fixed-effect or random-effect meta-analytical model was employed to correlate L1CAM expression with different outcome measures in both entire tumours and stratified subgroups. 37 studies in total with 8552 patients were eligible for the final analysis. Combined hazard ratios (HRs) and 95% confidence intervals (CIs) suggested that high L1CAM expression had an unfavourable impact on overall survival (HR=2.06, 95%CI 1.65-2.57, P<0.001), disease-specific survival (HR=2.45, 95%CI 1.48-4.05, P<0.001), disease-free survival (HR=2.42, 95%CI 1.4-4.19, P=0.002) and progression-free survival/recurrence-free survival (HR=2.07, 95%CI 1.41-3.05, P<0.001). Subgroup analysis revealed a similar correlation in most tumour types. Overall, L1CAM might be an effective poor prognostic factor for patients with various tumour types.

Efficacy of Anti-VEGF/VEGFR Agents on Animal Models of Endometriosis: A Systematic Review and Meta-Analysis.

BACKGROUND/OBJECTIVE: Vascular endothelial growth factor (VEGF) is the most important promotor of angiogenesis. Some studies indicate that anti-angiogenic agents that interfere with VEGF and its receptor (VEGFR), i.e., anti-VEGF/VEGFR agents, may be applied to treat endometriosis. This meta-analysis investigated the efficacy of anti-VEGF/VEGFR agents in animal models of endometriosis. METHODS: A systematic literature search was performed for animal studies published in English or Chinese from January 1995 to June 2016, which evaluated the effect of anti-VEGF/VEGFR agents on endometriosis. The databases were: PubMed, Web of Science, BIOSIS, Embase, and CNKI. The quality of included studies was assessed using the SYRCLE tool. The random-effect models were used to combine the results of selected studies. Heterogeneity was assessed using H2statistic and I2 statistic. Subgroup analyses were performed to determine the source of heterogeneity in endometriosis scores and follicle numbers. RESULTS: We identified 13 studies that used anti-VEGF/VEGFR agents in various animal models. The meta-analysis showed that anti-VEGF/VEGFR agents were associated with smaller size (standardized mean difference (SMD) -0.96, 95% CI -1.31 to -0.62; P < 0.0001) and weight (SMD -1.70, 95% CI -2.75 to -0.65; P = 0.002) of endometriosis lesions, relative to the untreated controls, as well as a lower incidence rate of endometriosis (risk ratio 0.26, 95% CI 0.07 to 0.93; P = 0.038) and endometriosis score (SMD -1.17, 95% CI -1.65 to -0.69; P < 0.0001); the number of follicles were similar (SMD -0.78, 95% CI -1.65 to 0.09; P = 0.08). CONCLUSIONS: Anti-VEGF/VEGFR agents appeared to inhibit the growth of endometriosis, with no effect on ovarian function. Anti-angiogenic therapy may be a novel strategy in treating endometriosis.

S100A4 promotes endometrial cancer progress through epithelial-mesenchymal transition regulation.

Epithelial-mesenchymal transition (EMT) is a major cause of endometrial cancer (EC) to initiate invasion and metastasis. S100A4, a calcium-binding protein, is implicated in multistage of tumorigenesis and tumor progression. The correlation between S100A4 and EMT in EC is still unclear. This study was aimed to clarify the role of S100A4 in EC and the relationship between S100A4 expression and EMT markers. S100A4, E-cadherin, and vimentin were detected in tissues of EC patients (n=50) by immunohistochemistry. The impact of S100A4 on EC cell proliferation, migration and invasion was investigated via RNA interference, and the correlation between S100A4 and EMT markers were also explored. The results showed that S100A4 was significantly increased in epithelial cells of EC compared with the normal endometrium (P<0.05), also S100A4 level was positively related to age (P=0.021), histological grade (P<0.001), and lymph node metastasis (P<0.001). Additionally, silencing of S100A4 remarkably attenuated EC cell migration and invasion. Significant morphological change accompanied with the downregulation of EMT markers, E-cadherin and vimentin were also observed. Aberrant S100A4 expression may predict EC progression and play an important role in regulating EC cell invasion through EMT regulation. Hence, S100A4 is a promising therapeutic target.