CircHIF1A induces cetuximab resistance in colorectal cancer by promoting HIF1α-mediated glycometabolism alteration.

Epidermal growth factor receptor (EGFR)-targeted therapy is an important treatment for RAS wild-type metastatic colorectal cancer (mCRC), but the resistance mechanism remains unclear. Here, the differential expression of circRNAs between Cetuximab sensitive and resistant cell lines was analyzed using whole-transcriptome sequencing. We identified that the expression of circHIF1A was significantly higher in LIM1215-R than in LIM1215. When treated with Cetuximab, downregulation of circHIF1A level weakened the proliferation and clonal formation ability of LIM1215-R, caused more cells to enter G0-G1 phase, and significantly reduced the basal respiration, ATP production, and maximal respiration, as well as the glycolytic capacity and glycolytic reserve. The response rate and prognosis of circHIF1A-positive patients were inferior to those of negative patients. Mechanistically, circHIF1A can upregulate the level of hypoxia-inducible factor 1 A (HIF1A) by competitively binding to miR-361-5p, inducing the overexpression of enzymes such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). In a xenograft model, inhibition of circHIF1A expression increased the sensitivity to Cetuximab treatment. In conclusion, circHIF1A can promote HIF1α-mediated glycometabolism alteration to induce Cetuximab resistance in CRC. It has the potential to become a screening indicator for the Cetuximab beneficial population in mCRC and a new therapeutic target for enhancing treatment efficacy.

Peritoneal Metastasis: A Dilemma and Challenge in the Treatment of Metastatic Colorectal Cancer.

Peritoneal metastasis (PM) is a common mode of distant metastasis in colorectal cancer (CRC) and has a poorer prognosis compared to other metastatic sites. The formation of PM foci depends on the synergistic effect of multiple molecules and the modulation of various components of the tumor microenvironment. The current treatment of CRC-PM is based on systemic chemotherapy. However, recent developments in local therapeutic modalities, such as cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC), have improved the survival of these patients. This article reviews the research progress on the mechanism, characteristics, diagnosis, and treatment strategies of CRC-PM, and discusses the current challenges, so as to deepen the understanding of CRC-PM among clinicians.

Single-cell transcriptome analysis of tumor immune microenvironment characteristics in colorectal cancer liver metastasis.

Background: Liver metastasis is the leading cause of death in colorectal cancer (CRC) patients, and the precise mechanisms remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) was used to analyze the cellular and molecular heterogeneity between CRC primary lesion and corresponding liver metastasis, and to clarify the characteristics of the tumor microenvironment (TME) in synchronous liver metastasis of CRC. Methods: A case of microsatellite stable (MSS) sigmoid carcinoma with synchronous liver metastasis was selected, and tissues from the primary tumor and the liver metastasis were collected for scRNA-seq. The EdgeR package software was used to identify the differentially expressed genes between cells. Gene Set Enrichment Analysis (GSEA) was performed and the clusterProfiler R package was used for Gene Ontology (GO) enrichment analysis. The SCENIC and CellphoneDB packages were used to reconstruct the transcriptional regulatory networks and to analyze the intercellular interaction network, respectively. Results: Compared to the primary tumor, the proportion of myeloid cells in the metastatic tumor was significantly increased, while B cells and plasma cells were decreased. In the metastatic tumor, the myeloid-derived suppressor cell (MDSC) characteristic gene, mannose receptor C-type 1 (MRC1) and tumor associated macrophage 2 (TAM2)-related gene, were highly expressed. Furthermore, angiogenesis, oxidative phosphorylation, and endothelial mesenchymal transition (EMT) of myeloid cells were also significantly enhanced. There were less myeloid cells in primary tumors, and these were mainly monocytes and TAM1; while the number of TAM2 was significantly upregulated in the metastatic samples. In liver metastasis, the T cell population was exhausted, and this was accompanied by a significant increase in the number of CD4+ T cells and a decrease in the number of CD8+ T cells. Furthermore, some immune checkpoint molecules were highly expressed. Interactions between myeloid cells and other cell populations appeared to be strong. Conclusions: The TME of CRC liver metastasis is significantly immunosuppressed. Interactions between myeloid cells and other cell populations in the TME contribute to the establishment of a pro-metastatic niche that promotes colonization and growth of CRC cells in the liver. TAMs may be a potential immunotherapeutic target for MSS CRC.

N-acetyltransferase 10 promotes colon cancer progression by inhibiting ferroptosis through N4-acetylation and stabilization of ferroptosis suppressor protein 1 (FSP1) mRNA.

BACKGROUND: N-acetyltransferase 10 (NAT10) is the only enzyme known to mediate the N4-acetylcytidine (ac4C) modification of mRNA and is crucial for mRNA stability and translation efficiency. However, its role in cancer development and prognosis has not yet been explored. This study aimed to examine the possible role of NAT10 in colon cancer. METHODS: The expression levels of NAT10 were evaluated by immunohistochemical analyses with a colon cancer tissue microarray, and its prognostic value in patients was further analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines. Stable NAT10-knockdown and NAT10-overexpressing colon cancer cell lines were constructed using lentivirus. The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit-8 (CCK-8), wound healing, Transwell, cell cycle, and ferroptosis assays. Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo. Dot blotting, acetylated RNA immunoprecipitation-qPCR, and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression. RESULTS: NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines. This increased NAT10 expression was associated with shorter patient survival. Knockdown of NAT10 in two colon cancer cell lines (HT-29 and LoVo) impaired the proliferation, migration, invasion, tumor formation and metastasis of these cells, whereas overexpression of NAT10 promoted these abilities. Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1 (FSP1) in HT-29 and LoVo cells. In these cells, FSP1 mRNA was found to be modified by ac4C acetylation, and this epigenetic modification was associated with the inhibition of ferroptosis. CONCLUSIONS: Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis, suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.

Promotion or remission: a role of noncoding RNAs in colorectal cancer resistance to anti-EGFR therapy.

Anti-epidermal-growth-factor-receptor (EGFR) monoclonal antibodies (mAbs) are of great significance for RAS and BRAF wild-type metastatic colorectal cancer (mCRC) patients. However, the generation of primary and secondary resistance to anti-EGFR mAbs has become an important factor restricting its efficacy. Recent studies have revealed that non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are implicated in anti-EGFR antibodies resistance, affecting the sensitivity of CRC cells to Cetuximab and Panitumumab. This paper briefly reviewed the research advance of the expression, signaling network and functional mechanism of ncRNAs related to anti-EGFR mAbs resistance in CRC, as well as their relationship with clinical prognosis and the possibility of therapeutic targets. In addition, some ncRNAs that are involved in the regulation of signaling pathways or genes related to anti-EGFR resistance, but need to be further verified by resistance experiments were also included in this review, thereby providing more ideas and basis for ncRNAs as CRC prognostic markers and anti-EGFR therapy sensitizers. Video Abstract.

Survival and prognostic factors for postoperative primary appendiceal cancer: a retrospective cohort study based on the Surveillance, Epidemiology, and End Results database.

Background: The factors affecting the postoperative survival of patients with primary appendiceal cancer (PAC) have yet to be fully explored. And there are no clear guidelines for adjuvant treatment after appendectomy. Whether chemotherapy can prolong patient survival after appendectomy, is critical in guiding postoperative medications. The majority of studies on appendiceal cancer are single case reports, and they focused on the incidence of appendiceal cancer. The present study aimed to investigate the survival characteristics of patients with primary appendiceal cancer after surgery using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: The data of 2,891 cases of primary appendiceal cancer between 2004 to 2015 were obtained from the SEER database and subjected to survival analysis using the Kaplan-Meier method and Cox proportional-hazards model. The annual percentage change (APC) was calculated using the weighted least squares method. Results: The overall age-adjusted incidence rate per 100,000 population steadily increased from 0.58 in 2004 to 1.63 in 2015. For patients who received chemotherapy, the median overall survival (OS) was 65 months and the 5-year OS rate was 51.9%, and for patients who did not receive chemotherapy or whose chemotherapy status was unknown, the median OS was not reached and the 5-year OS rate was 78.9%. Age [35< age <69: hazard radio (HR) =2.147; 95% confidence interval (CI): 1.442-3.197, P<0.001; age >69: HR =5.259; 95% CI: 3.485-7.937, P<0.001], race (White race: HR =0.728; 95% CI: 0.590-0.899, P=0.003), histologic type (mucinous neoplasm: HR =0.690; 95% CI: 0.580-0.821, P<0.001; malignant carcinoid: HR =0.657; 95% CI: 0.536-0.806, P<0.001), grade (II: HR =1.794; 95% CI: 1.471-2.187, P<0.001; III: HR =2.905; 95% CI: 2.318-3.640, P<0.001; IV: HR =3.128; 95% CI: 2.159-4.533, P<0.001), and stage (localized: HR =0.236; 95% CI: 0.194-0.287, P<0.001; regional: HR =0.425; 95% CI: 0.362-0.499, P<0.001) were identified as independent predictors of survival. And after adjusting for known factors (age, sex, race, tumor size, marital status, histologic type, grade, stage), chemotherapy (HR =1.220; 95% CI: 1.050-1.417, P=0.009) was revealed to be an independent indicator of poor prognosis. Conclusions: There was an increasing trend in the incidence of appendiceal cancer in the United States between 2004 and 2015. Chemotherapy was revealed to be an independent indicator of poor prognosis, which provide valuable insight into the therapy of primary appendiceal cancer. Large clinical trials of chemotherapy and targeted therapy for appendiceal cancer are urgently needed.

CircNEIL3 promotes cervical cancer cell proliferation by adsorbing miR-137 and upregulating KLF12.

BACKGROUND: CircRNAs play crucial roles in multiple tumours. However, the functions of most circRNAs in cervical cancer remain unclear. METHODS: This study collected GSE113696 data from the GEO database to search for differentially expressed circRNAs in cervical cancer. Quantitative reverse transcription PCR was used to detect the expression level of circNEIL3 in cervical cancer cells and tissues. Then, functional experiments in vitro and in vivo were performed to evaluate the effects of circNEIL3 in cervical cancer. RESULTS: CircNEIL3 was highly expressed in cervical cancer. In vivo and in vitro experiments verified that circNEIL3 enhanced the proliferation capacity of cervical cancer cells. RNA immunoprecipitation, luciferase reporter assay, pull-down assay, and fluorescent in situ hybridization confirmed the interaction between circNEIL3 and miR-137 in cervical cancer. A luciferase reporter assay showed that circNEIL3 adsorbed miR-137 and upregulated KLF12 to regulate the proliferation of cervical cancer cells. CONCLUSIONS: CircNEIL3 is an oncogene in cervical cancer and might serve as a ceRNA that competitively binds to miR-137, thereby indirectly upregulating the expression of KLF12 and promoting the proliferation of cervical cancer cells.

Knockdown of Long Non-coding RNA LINC00200 Inhibits Gastric Cancer Progression by Regulating miR-143-3p/SERPINE1 Axis.

BACKGROUND: An increasing number of studies have found that long non-coding RNAs (lncRNAs) play an important role in carcinogenesis and tumor progression, whereas their molecular mechanisms of function remain largely unknown. AIMS: This study was aimed to explore the biological function and underlying mechanism of a new lncRNA LINC00200 in gastric cancer (GC). METHODS: qRT-PCR analysis was conducted to examine the LINC00200 expression level in both GC tissues and cell lines. Functional assays were carried out to detect the effect of LINC00200 on GC cell proliferation, invasion and migration. The interaction between LINC00200 and miR-143-3p was confirmed by luciferase reporter assays. Rescue assays were performed to confirm the influence of LINC00200-miR-143-3p-SERPINE1 axis on GC development. RESULTS: LINC00200 was found to be upregulated in GC tissues and cell lines. Moreover, knockdown of LINC00200 suppressed GC cell proliferation, invasion and migration in vitro and inhibited tumorigenesis in mouse xenografts. Finally, mechanism research indicated that LINC00200 functioned as a ceRNA to sponge for miR-143-3p, thus leading to the disinhibition of its target gene SERPINE1. CONCLUSIONS: LINC00200 is significantly overexpressed in GC and accelerates GC progression through regulating miR-143-3p/SERPINE1 axis. Our results may provide a potential diagnostic biomarker and therapeutic target for the management of GC patients.

Hsa_circ_0009361 acts as the sponge of miR-582 to suppress colorectal cancer progression by regulating APC2 expression.

Circular RNA (circRNA) plays an important role in the development of human malignant tumors. Recently, an increasing number of circRNAs have been identified and investigated in various tumors. However, the expression pattern and biological function of circRNAs in colorectal cancer (CRC) still remain largely unexplored. In the present study, hsa_circ_0009361 was significantly down-regulated in CRC tissues and cells. Low expression level of hsa_circ_0009361 promoted the proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion of CRC cells. Hsa_circ_0009361 was identified as the sponge of miR-582 by fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP), and luciferase reporter assays. Overexpression of hsa_circ_0009361 up-regulated the expression of adenomatous polyposis coli 2 (APC2) and inhibited the activity of the Wnt/ß-catenin pathway by competitively combining with miR-582. Exogenous miR-582 and APC2 interventions could reverse the multiple biological functions mediated by hsa_circ_0009361 in CRC cells. In vivo experiments also confirmed that hsa_circ_0009361 inhibited the growth and metastasis of CRC. Hsa_circ_0009361 acted as a tumor suppressive sponge of miR-582, which could up-regulate the expression of APC2, inhibit the Wnt/ß-catenin signaling, and suppress the growth and metastasis of CRC. Collectively, the hsa_circ_0009361/miR-582/APC2 network could be employed as a potential therapeutic target for CRC patients.

A novel systemic inflammation response index (SIRI) for predicting postoperative survival of patients with esophageal squamous cell carcinoma.

BACKGROUND: Inflammation is closely associated with the initiation and development of tumors. Based on the counts of peripheral neutrophils, monocytes and lymphocytes, we established a new systemic inflammation response index (SIRI) to predict postoperative survival of patients with esophageal squamous cell carcinoma (ESCC). METHODS: A total of 916 ESCC patients treated with radical esophagectomy were enrolled in the present study. RESULTS: Survival analysis indicated that the median overall survival (OS) in patients with SIRI≤1.2 was significantly higher than that in patients with SIRI>1.2. The nomogram including SIRI could more accurately predict OS compared with the TNM staging system. In addition, the changes of SIRI from baseline to 8 weeks after the operation were correlated with patient survival. The patients with an increase in SIRI >75% had worse OS compared with those with no change, while the patients with a decrease in SIRI >75% or in the scope of 25% ~75% exhibited better OS. CONCLUSIONS: SIRI was an independent prognostic index of ESCC patients after the radical resection. The nomogram integrating the SIRI could help clinicians to screen the high-risk patients and formulate the individualized treatment schemes.

Function and clinical significance of circRNAs in solid tumors.

Circular RNA (circRNA) is a new type of endogenous non-coding RNAs (ncRNAs). circRNA regulates gene expression in many biological processes, and it also participates in the initiation and development of various diseases, including tumors, which are the focus of present research. With the development of high-throughput sequencing technique, an increasing number of circRNAs closely related to tumors have been discovered. According to numerous studies, there is a significant difference in the expressions of circRNAs among a variety of tumor tissues and para-carcinoma normal tissues. Some specifically expressed circRNAs may potentially serve as new biomarkers for tumor diagnosis and prognosis. This systemic review briefly introduces the characteristics, biogenesis, and functions of circRNAs, as well as discusses their relationship with cancer in detail. In addition, this article also describes several research strategies for circRNAs.

Predictive analysis of long non-coding RNA expression profiles in diffuse large B-cell lymphoma.

Long non-coding RNAs (lncRNAs) are implicated in many tumors. To find novel targets for study of diffuse large B-cell lymphoma (DLBCL), our team performed genome-wide analyses of lncRNA expression in 5 DLBCL cell lines using the 4*180K Agilent lncRNA Chip system, and in normal B cells. Five lncRNAs were validated by quantitative reverse transcription polymerase chain reaction. The differentially expressed lncRNAs and mRNAs were identified via false discovery rate and fold-change filtering. Potential targets correlated with DLBCL were recognized via gene ontology and pathway analysis. Establishment of the co-expression network was done using Cytoscape. In total, 1053 lncRNAs and 4391 mRNAs were dysregulated in DLBCL cells, being comparing with normal B cells. The results suggested that the expressions of the 5 lncRNAs were consistent with the chip results. Several terms including the cell cycle, apoptosis, B cell receptor and NF-κB signaling pathways were important in the progression of DLBCL. The chromosome locations of a few lncRNAs and the associated coexpressed genes were demonstrated by cis-regulatory gene analyses. The results of trans-analyses showed that multiple transcription factors regulated lncRNA and gene expression. Those outstanding lncRNAs in each group were implicated in the regulation of the TF-lncRNA-target gene network. Our study identified a set of lncRNAs differentially expressed in DLBCL cells.

Systemic Immune-Inflammation Index Predicts Prognosis of Patients with Esophageal Squamous Cell Carcinoma: A Propensity Score-matched Analysis.

Systemic immune-inflammation index (SII), based on peripheral lymphocyte, neutrophil, and platelet counts, was recently investigated as a prognostic marker in several tumors. However, SII has not been reported in esophageal squamous cell carcinoma (ESCC). We evaluated the prognostic value of the SII in 916 patients with ESCC who underwent radical surgery. Univariate and multivariate analyses were calculated by the Cox proportional hazards regression model. The time-dependent receiver operating characteristics (ROC) curve was used to compare the discrimination ability for OS. PSM (propensity score matching) was carried out to imbalance the baseline characteristics. Our results showed that SII, PLR, NLR and MLR were all associated with OS in ESCC patients in the Kaplan-Meier survival analysis. However, only SII was an independent risk factor for OS (HR = 1.24, 95% CI 1.01-1.53, P = 0.042) among these systemic inflammation scores. The AUC for SII was bigger than PLR, NLR and MLR. In the PSM analysis, SII still remained an independent predictor for OS (HR = 1.30, CI 1.05-1.60, P = 0.018). SII is a novel, simple and inexpensive prognostic predictor for patients with ESCC undergoing radical esophagectomy. The prognostic value of SII is superior to PLR, NLR and MLR.

Assessment of Lymph Node Ratio to Replace the pN Categories System of Classification of the TNM System in Esophageal Squamous Cell Carcinoma.

INTRODUCTION: The seventh edition of the TNM staging system for esophageal cancer outlined by the American Joint Committee on Cancer (AJCC) defines the N classification on the basis of the number of metastatic lymph nodes. However, this classification is dependent on the actual number of examined lymph nodes. Here in this study, we have focused on revising this N classification system with the metastatic lymph nodes ratio (LNR) and also assessing whether this modification to the current AJCC staging system can better define the prognostic characteristics of esophageal squamous cell carcinoma (ESCC). METHODS: We retrospectively reviewed 916 patients with ESCC who underwent curative resection. Prognostic performance of two staging systems was compared using the Akaike information criterion value and receiver operating characteristics curve. In addition, decision curve analysis evaluated the clinical practical usefulness of the prediction models by quantifying their net benefits. RESULTS: The univariate and multivariate Cox regression analyses indicated that LNR was an independent risk factor for overall survival. The modified staging system based on LNR had better discriminatory ability, monotonicity, homogeneity, and stratification than the TNM staging system in determining the prognosis of patients with ESCC. However, the decision curves analysis suggested that the modified staging based on LNR has poor clinical practical value over the AJCC TNM staging system. CONCLUSIONS: LNR can supplement the pN categorization system for more effective evaluation of prognosis. But the modified staging system based on LNR has a poor clinical practical value for patients with ESCC compared with the current TNM system and is not superior to AJCC pN staging for ESCC.

Prognostic nomogram integrated systemic inflammation score for patients with esophageal squamous cell carcinoma undergoing radical esophagectomy.

Growing evidence indicates that nomogram combined with the biomarkers of systemic inflammation response could provide more accurate prediction than conventional staging systems in tumors. This study aimed to establish an effective prognostic nomogram for resectable thoracic esophageal squamous cell carcinoma (ESCC) based on the clinicopathological parameters and inflammation-based prognostic scores. We retrospectively investigated 916 ESCC patients who underwent radical esophagectomy. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve, and compared with the 6(th) and 7(th) AJCC TNM classifications. The neutrophil lymphocyte ratio (NLR), C-reactive protein albumin (CRP/Alb) ratio, histological grade, T stage and modified N stage were integrated in the nomogram. The C-index of the nomogram for predicting the survival was 0.72, which showed better predictive ability of OS than the 6(th) or 7(th) TNM stages in the primary cohort (P < 0.001). The calibration curve showed high consistency between the nomogram and actual observation. The decision curve analysis showed more potential of clinical application of the prediction models compared with TNM staging system. Moreover, our findings were supported by the validation cohort. The proposed nomogram showed more accurate prognostic prediction for patients with ESCC after radical esophagectomy.

Prognostic Role of Tumor-Infiltrating Lymphocytes in Lung Cancer: a Meta-Analysis.

BACKGROUND/AIMS: The role of Tumor-infiltrating lymphocytes (TILs) in the prognosis of patients with lung cancer is still controversial. We performed a meta-analysis to evaluate the prognostic role of TILs in lung cancer. METHODS: Studies were recruited by searching PubMed, Embase and the Cochrane Library and assessed by further quality evaluation. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to investigate the association between TIL subsets and lung cancer patients' outcome. RESULTS: A total of 29 articles including 8,600 patients were enrolled into the meta-analysis. Our results indicated that high level of CD8+ cells infiltration in tumor stroma (TS) or tumor nest (TN) was associated with better OS in lung cancer patients (HR = 0.76, 95% CI 0.62-0.93, P = 0.006; HR = 0.80, 95% CI 0.67-0.96; P = 0.018, respectively). Similar results could be also observed in CD3+ T cells infiltration. High CD4+ T lymphocytes infiltration in TS was explicitly accompanied by better OS (HR = 0.65, 95% CI 0.46-0.91; P = 0.013), rather than in TN. In contrast, high density of FOXP3+ T cells infiltration in TS showed a poor PFS (HR = 2.67, 95% CI, 1.74-4.08, P < 0.001). CONCLUSION: This meta-analysis clarified that high level of CD8+ and CD3+ T cells infiltration in TS or TN, and high CD4+ T lymphocytes infiltration in TS showed better OS in lung cancer patients, whereas high density of FOXP3+ T cells infiltration in TS could be recognized as a negative prognostic factor.

Prognostic role of tissue and circulating microRNA-200c in malignant tumors: a systematic review and meta-analysis.

BACKGROUND: Recently, many studies have shown that microRNAs (miRNA) exhibit altered expression in various cancers and may serve as prognostic biomarkers. We performed a systematic review and meta-analysis to evaluate the prognostic role of miR-200c expression in different cancers. METHODS: Studies were recruited by searching PubMed, Embase and the Cochrane Library (last search update was May 2014) and assessed by further quality evaluation. RESULTS: A total of 25 studies dealing with various carcinomas were identified for systematic review. Among them, 18 studies were ultimately included in the meta-analysis. Our results indicated that the expression of tissue miR-200c was not associated with OS and PFS in various carcinomas; however, downregulation of tissue miR-200c did predict poor OS of patients with stage I disease (HR=0.41, 95% CI 0.25-0.68, P=0.001). Furthermore, overexpression of blood miR-200c was significantly related to poor OS and PFS (HR=3.07 95% CI 1.58-5.96 P=0.001, HR=2.26 95% CI 1.66-3.08 P<0.001, respectively), especially in patients with advanced disease. CONCLUSION: This systematic review and meta-analysis clarified that low expression of miR-200c in primary tissue was significantly associated with poor survival in cancer patients at early stage, whereas a high level of blood miR-200c predicted poor prognosis in patients with advanced tumors.

Expression of costimulatory molecules B7-H1, B7-H4 and Foxp3+ Tregs in gastric cancer and its clinical significance.

OBJECTIVE: Immune escape plays an important role in tumor progression. In the present study, the expression of B7-H1, B7-H4 and Foxp3 involved in immune escape in gastric carcinoma was investigated and the corresponding clinical significance was evaluated. METHODS: Immunohistochemistry was used to detect the expression of B7-H1, B7-H4 and Foxp3 in 100 gastric cancer specimens, and 30 paracarcinoma tissues were used as the control. RESULTS: Both B7-H1 and B7-H4 showed high expression levels in gastric cancer tissues (65.0 and 71.0 %, respectively), and the expressions of B7-H1 and B7-H4 were positively correlated with the depth of tumor invasion, lymph node metastasis and American Joint Committee on Cancer (AJCC) stage (P < 0.05). The number of Foxp3(+) Tregs was much higher in gastric cancer tissues than control tissues, which was positively correlated with lymph node metastasis (P < 0.05). Similarly, a positive correlation between B7-H1 or B7-H4 expression and the number of Foxp3(+) Tregs was observed. The median overall survival rate of patients with high expression of B7-H1, B7-H4 and Foxp3 was significantly poorer than that of patients with low expression of these proteins (P < 0.05). Cox regression multivariate analysis confirmed that lymph node metastasis, AJCC stage, and B7-H1 and Foxp3 overexpression were independent prognostic factors. CONCLUSION: B7-H1, B7-H4 and Foxp3 were overexpressed in gastric cancer tissues. B7-H1 and Foxp3 are negative prognostic factors for patients with gastric cancer.

Prognostic role of high Bmi-1 expression in Asian and Caucasian patients with solid tumors: a meta-analysis.

Recently, many studies have shown that the B-cell-specific moloney leukemia virus insertion site 1 (Bmi-1) exhibits altered expression in various cancers and may serve as prognostic biomarkers. We performed a meta-analysis to evaluate the prognostic role of Bmi-1 expression in solid cancers. Studies were recruited by searching PubMed, Embase and the Cochrane Library. Thirty-nine articles including 40 studies were involved in this meta-analysis. Our results indicated that the Bmi-1 showed the opposite prognostic effect in Asian and Caucasian populations. High Bmi-1 expression as a negative predictor for overall survival (OS) in Asian patients (HR=1.96, 95% CI 1.62-2.36), but a positive predictor in Caucasian populations (HR=0.77, 95% CI 0.63-0.93). Furthermore, we took a further subgroup analysis based on tumor type in these two populations, respectively. In Asian cases, high expression of Bmi-1 was associated with poor OS in oesophageal carcinoma (HR=1.93, 95% CI 1.52-2.46), gastric cancer (HR=1.50, 95% CI 1.22-1.85), lung cancer (HR=1.73, 95% CI 1.05-2.85), cervical cancer (HR=2.80, 95% CI 2.26-3.47) and colorectal cancer (HR=3.36, 95% CI 2.19-5.15), rather than in breast cancer and HCC. In Caucasian populations, high expression of Bmi-1 was associated with better OS in breast cancer (HR=0.70, 95% CI 0.51-0.97), but it showed no significance in oesophageal carcinoma. In conclusion, high Bmi-1 expression was significantly associated with poor survival in Asian patients with oesophageal carcinoma, gastric cancer, lung cancer, colorectal cancer and cervical carcinoma, whereas high level of Bmi-1 can predict better prognosis in Caucasian patients with breast cancer.

Prognostic significance of microRNA-375 downregulation in solid tumors: a meta-analysis.

OBJECTIVE: Recently, many studies have shown that microRNAs (miRNA) exhibit altered expression in various cancers and may play an important role as prognostic biomarker of cancers. We performed a meta-analysis to evaluate the impact of miR-375 expression in solid tumors on patients' overall survival (OS). METHODS: Studies were identified by searching PubMed, Embace, and Cochrane Library (last search update was in May 2014) and were assessed by further quality evaluation. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for total and stratified analyses were calculated to investigate the association between miR-375 expression and cancer patients OS. RESULTS: Our analysis results indicated that downregulation of miR-375 predicted poor OS (HR = 1.91, 95% CI 1.48-2.45, P < 0.001). Subgroup analyses showed that lower expression of miR-375 was significantly related with poor OS in patients with esophageal carcinoma (HR = 2.24, 95% CI 1.69-2.96, P < 0.001) and non-small-cell lung cancer (NSCLC) (HR = 1.71, 95% CI 1.31-2.24, P < 0.001). CONCLUSIONS: The findings from this meta-analysis suggest that miR-375 expression is associated with OS of patients with malignant tumors and could be a useful clinical prognostic biomarker.