RAB17 promotes endometrial cancer progression by inhibiting TFRC-dependent ferroptosis.

Studies have indicated that RAB17 expression levels are associated with tumor malignancy, and RAB17 is more highly expressed in endometrial cancer (EC) tissues than in peritumoral tissues. However, the roles and potential mechanisms of RAB17 in EC remain undefined. The present study confirmed that the expression of RAB17 facilitates EC progression by suppressing cellular ferroptosis-like alterations. Mechanistically, RAB17 attenuated ferroptosis in EC cells by inhibiting transferrin receptor (TFRC) protein expression in a ubiquitin proteasome-dependent manner. Because EC is a blood-deprived tumor with a poor energy supply, the relationship between RAB17 and hypoglycemia was investigated. RAB17 expression was increased in EC cells incubated in low-glucose medium. Moreover, low-glucose medium limited EC cell ferroptosis and promoted EC progression through the RAB17-TFRC axis. The in vitro results were corroborated by in vivo studies and clinical data. Overall, the present study revealed that increased RAB17 promotes the survival of EC cells during glucose deprivation by inhibiting the onset of TFRC-dependent ferroptosis.

Advanced glycation end products promote the progression of endometrial cancer via activating the RAGE/CHKA/PI3K/AKT signaling pathway.

Endometrial cancer (EC) is a common malignant tumor that is closely associated with metabolic disorders such as diabetes and obesity. Advanced glycation end products (AGEs) are complex polymers formed by the reaction of reducing sugars with the amino groups of biomacromolecules, mediating the occurrence and development of many chronic metabolic diseases. Recent research has demonstrated that the accumulation of AGEs can affect the tumor microenvironment, metabolism, and signaling pathways, thereby affecting the malignant progression of tumors. However, the mechanism by which AGEs affect EC is unclear. Our research aimed to investigate how AGEs promote the development of EC through metabolic pathways and to explore their potential underlying mechanisms. Our experimental results demonstrated that AGEs upregulated the choline metabolism mediated by choline kinase alpha (CHKA) through the receptor for advanced glycation end products (RAGE), activating the PI3K/AKT pathway and enhancing the malignant biological behavior of EC cells. Virtual screening and molecular dynamics simulation revealed that timosaponin A3 (timo A3) could target CHKA to inhibit AGE-induced progression of EC and that a newly discovered CHKA inhibitor could be a novel targeted inhibitor for the treatment of EC. This study provides new therapeutic strategies and contributes to the treatment of EC.

Characterization and validation of fatty acid metabolism-related genes predicting prognosis, immune infiltration, and drug sensitivity in endometrial cancer.

Endometrial cancer is considered to be the second most common tumor of the female reproductive system, and patients diagnosed with advanced endometrial cancer have a poor prognosis. The influence of fatty acid metabolism in the prognosis of patients with endometrial cancer remains unclear. We constructed a prognostic risk model using transcriptome sequencing data of endometrial cancer and clinical information of patients from The Cancer Genome Atlas (TCGA) database via least absolute shrinkage and selection operator regression analysis. The tumor immune microenvironment was analyzed using the CIBERSORT algorithm, followed by functional analysis and immunotherapy efficacy prediction by gene set variation analysis. The role of model genes in regulating endometrial cancer in vitro was verified by CCK-8, colony formation, wound healing, and transabdominal invasion assays, and verified in vivo by subcutaneous tumor transplantation in nude mice. A prognostic model containing 14 genes was constructed and validated in 3 cohorts and clinical samples. The results showed differences in the infiltration of immune cells between the high-risk and low-risk groups, and that the high-risk group may respond better to immunotherapy. Experiments in vitro confirmed that knockdown of epoxide hydrolase 2 (EPHX2) and acyl-CoA oxidase like (ACOXL) had an inhibitory effect on EC cells, as did overexpression of hematopoietic prostaglandin D synthase (HPGDS). The same results were obtained in experiments in vivo. Prognostic models related to fatty acid metabolism can be used for the risk assessment of endometrial cancer patients. Experiments in vitro and in vivo confirmed that the key genes HPGDS, EPHX2, and ACOXL in the prognostic model may affect the development of endometrial cancer.

Estrogen receptor-related receptor γ uppresses hypoxia-induced angiogenesis by regulating VEGFA in endometrial cancer.

OBJECTIVE: Estrogen receptor-related receptor γ (ERRγ), is implicated in cancer cell proliferation and metastasis. The function of ERRγ in tumor angiogenesis, however, is to be revealed. This study was designed to elaborate the regulatory effect of ERRγ on angiogenesis in endometrial cancer (EC). METHODS: Immunohistochemistry (IHC) was adopted to determine the protein expression of ERRγ, VEGFA, CD31 and hypoxia-inducible factor-1 (HIF-1) in tumor tissues. HEC-1A cells stably expressing ERRγ were established bytransfection, and then an endothelial cell tube formation assay was performed. CCK-8 assay was employed for cell viability, and wound healing assay for cell migration ability. Besides, western blot, ELISA and qRT-PCR were used to examine the VEGFA expression. After hypoxia treatment of ERRγ overexpressing HEC-1A cells, the ERRγ expression and VEGFA expression were determined by western blot. Finally, EC xenografts in nude mice were constructed by subcutaneous injection of ERRγ stably expressing HEC-1A cells and control HEC-1A cells. RESULTS: IHC results revealed a negative correlation between the expression of ERRγ and VEGFA in EC tissues. ERRγ overexpression significantly decreased the level of HIF-1 in tumor tissue of nude mice. ERRγ overexpression down-regulated inhibited angiogenesis capability and inhibited the proliferation and migration of HEC-1A cells. Furthermore, ERRγ expression was suppressed under the condition of hypoxia while restoration of ERRγ partially inhibited hypoxia-induced VEGFA expression in HEC-1A cells. CONCLUSIONS: ERRγ is an angiogenesis suppressor and involved in hypoxia-induced VEGFA expression in EC. Hence, ERRγ might be a promising antiangiogenic target for human EC.

Ultra-sensitive biosensor based on CRISPR-Cas12a and Endo IV coupled DNA hybridization reaction for uracil DNA glycosylase detection and intracellular imaging.

As an essential biomarker associated with various diseases, Uracil-DNA Glycosylase (UDG) detection is vital for disease diagnosis, treatment selection, and prognosis assessment. In recent years, the signal amplification effect of the CRISPR-Cas12a trans-cleaved single-stranded DNA probe has provided an available strategy for constructing highly sensitive biosensors. However, its superior trans-cleavage activity has become a "double-edged sword" for building biosensors that can amplify the target signal while also amplifying the leakage signal, causing out of control. Therefore, the construction of structurally simple, extremely low-background, highly sensitive CRISPR-Cas12a-based biosensors is an urgent bottleneck problem in the field. Here, we applied CRISPR-Cas12a with a DNA hybridization reaction to develop a simple, rapid, low background, and highly sensitive method for UDG activity detection. It has no PAM restriction and the detection limit is as low as 2.5 × 10-6 U/mL. As far as we know, this method is one of the most sensitive methods for UDG detection. We also used this system to analyze UDG activity in tumor cells (LOD: 1 cell/uL) and to evaluate the ability to screen for UDG inhibitors. Furthermore, we verified the possibility of intracellular UDG activity imaging by transfecting the biosensors to the cells. We believe this novel sensor has good clinical application prospects and will effectively broaden the application space of CRISPR-Cas12a.

CircRAPGEF5 interacts with RBFOX2 to confer ferroptosis resistance by modulating alternative splicing of TFRC in endometrial cancer.

Endometrial cancer (EC) is one of the most common gynecological cancers. Ferroptosis is a newly identified form of cell death characterized by iron-dependent lipid peroxide accumulation. Circular RNAs (circRNAs) have emerged as critical regulators for cancer development. However, circRNA-mediated modulation of ferroptosis in EC is yet to be clarified. In this study, we found that circRAPGEF5 expression was elevated in EC tissues compared to the normal endometrial tissues. In vitro and in vivo functional analysis demonstrated that circRAPGEF5 facilitates rapid proliferation of EC cells. RNA binding protein fox-1 homolog 2 (RBFOX2), a splicing regulator, was identified as the protein interacts with circRAPGEF5. Further studies revealed that circRAPGEF5 can bind to the Fox-1 C-terminal domain of RBFOX2 and induces specific exon exclusion of TFRC through obstructing the binding of RBFOX2 to pre-mRNA. As a result, elevated levels of circRAPGEF5 lead to ferroptosis resistance via the decreased labile iron pool and attenuated lipid peroxide production in EC cells. Additionally, a series of gain- and loss-of-function experiments demonstrated that knocking down or overexpressing RBFOX2 reversed the effects of knocking down or overexpressing circRAPGEF5 in EC cells. Finally, it is revealed that circRAPGEF5 promote the formation of TFRC with exon-4 skipping and confer ferroptosis resistance in EC cells through the interaction with RBFOX2. Collectively, these findings provide new insight into the molecular mechanism in which circRNAs mediate mediates ferroptosis via modulating alternative splicing, and circRAPGEF5/RBFOX2 splicing axis could be a promising therapeutic target for treating EC.

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.

The Effects of miR-195-5p/MMP14 on Proliferation and Invasion of Cervical Carcinoma Cells Through TNF Signaling Pathway Based on Bioinformatics Analysis of Microarray Profiling.

BACKGROUND/AIMS: This study is aimed at identification of miR-195-5p/MMP14 expression in cervical cancer (CC) and their roles on cell proliferation and invasion profile of CC cells through TNF signaling pathway in CC. METHODS: Microarray analysis, gene set enrichment analysis (GSEA) and DAVID were used to analyze differentially expressed miRNAs, mRNAs and signaling pathways. MiR-195-5p and MMP14 expression levels in CC cell were determined by qRT-PCR. Western blot was employed to measure MMP14 and TNF signaling pathway-relating protein level. Luciferase reporter system was used to confirm the targeting relationship between MMP14 and miR-195-5p. Cell proliferation and invasion was respectively deeded by CCK8, transwell. In vivo experiment was carried out to study the impact of MMP14 and miR-195-5p on CC development in mice. RESULTS: The microarray analysis and the results of qRT-PCR determined that miR-195-5p was under-expressed and MMP14 was over-expressed in CC cells. GSEA and DAVID analysis showed that TNF signaling pathway was regulated by miR-195-5p/MMP14 and activated in cervical carcinoma cells. The miR-195-5p and MMP14 have a negative regulation relation. In vivo experiment found that down-regulated MMP14 and up-regulated miR-195-5p suppressed the tumor development. CONCLUSION: Our results suggest that MMP14 is a direct target of miR-195-5p, and down-regulated MMP14 and up-regulated miR-195-5p suppressed proliferation and invasion of CC cells by inhibiting TNF signaling pathway.

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.

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.].

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.

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.

CRISPR-Cas9-mediated genome editing in one blastomere of two-cell embryos reveals a novel Tet3 function in regulating neocortical development.

Studying the early function of essential genes is an important and challenging problem in developmental biology. Here, we established a method for rapidly inducing CRISPR-Cas9-mediated mutations in one blastomere of two-cell stage embryos, termed 2-cell embryo-CRISPR-Cas9 injection (2CC), to study the in vivo function of essential (or unknown) genes in founder chimeric mice. By injecting both Cre mRNA and CRISPR-Cas9 targeting the gene of interest into fluorescent reporter mice, the 2CC method can trace both wild-type and mutant cells at different developmental stages, offering internal control for phenotypic analyses of mutant cells. Using this method, we identified novel functions of the essential gene Tet3 in regulating excitatory and inhibitory synaptic transmission in the developing mouse cerebral cortex. By generating chimeric mutant mice, the 2CC method allows for the rapid screening of gene function in multiple tissues and cell types in founder chimeric mice, significantly expanding the current armamentarium of genetic tools.

Transcriptomic analysis of stromal cells from patients with endometrial carcinoma.

Tumor microenvironment plays a critical role in cancer pathogenesis. In this study, we performed transcriptomic analysis of stromal cells from patients diagnosed with endometrial carcinoma. Endometrial stromal cells from patients and healthy donors were cultured and total RNA was extracted for RNA integrity examination and gene profiling analysis. Gene ontology (GO) and KEGG analysis were also performed. In this study, we found that, in endometrial stromal cells from endometrial cancer patients, a total of 605 genes were changed (fold change ≥2, p-value <0.05). From these, 275 were up-regulated and 330 were down-regulated genes. In addition, GO analysis showed that the differentially expressed genes (DEGs) were involved in various biological processes including cell adhesion, biological adhesion, bone development and extracellular matrix organization. Furthermore, KEGG analysis of the DEGs identified four pathways including Wnt signaling pathway, cadherin signaling pathway, ECM-receptor interaction, and focal adhesion. Our study identified 605 DEGs in stromal cells from endometrial carcinoma which mapped to a variety of biological processes. These results may contribute to understanding the molecular mechanisms o of endometrial carcinoma pathogenesis.

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.

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.

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.

CD147/EMMPRIN overexpression and prognosis in cancer: A systematic review and meta-analysis.

CD147/EMMPRIN (extracellular matrix metalloproteinase inducer) plays an important role in tumor progression and a number of studies have suggested that it is an indicator of tumor prognosis. This current meta-analysis systematically reevaluated the predictive potential of CD147/EMMPRIN in various cancers. We searched PubMed and Embase databases to screen the literature. Fixed-effect and random-effect meta-analytical techniques were used to correlate CD147 expression with outcome measures. A total of 53 studies that included 68 datasets were eligible for inclusion in the final analysis. We found a significant association between CD147/EMMPRIN overexpression and adverse tumor outcomes, such as overall survival, disease-specific survival, progression-free survival, metastasis-free survival or recurrence-free survival, irrespective of the model analysis. In addition, CD147/EMMPRIN overexpression predicted a high risk for chemotherapy drugs resistance. CD147/EMMPRIN is a central player in tumor progression and predicts a poor prognosis, including in patients who have received chemo-radiotherapy. Our results provide the evidence that CD147/EMMPRIN could be a potential therapeutic target for cancers.