SF3B4 downregulation restrains lung adenocarcinoma tumorigenesis via 5' alternative splicing of KAT2A.

Aberrant expression of splicing factors, including SF3B4, plays a vital role in lung adenocarcinoma (LUAD). However, the impact of SF3B4 in the progression of LUAD has not been studied well. Here, we demonstrated the effects of SF3B4 in LUAD via apoptosis, proliferation, migration assays, etc. Gene manipulations confirmed the role of SF3B4 via KAT2A. SF3B4 was found to promote LUAD growth. Further studies found that, upon SF3B4 knockdown in LUAD cells, an alternative splice site occurred at the 5'-UTR of KAT2A, which led to the downregulation of KAT2A at both RNA and protein levels. Furthermore, the decrease in KAT2A expression partially reversed the effect of SF3B4 in promoting tumorigenesis. The axis SF3B4/ KAT2A was identified as a significant player in LUAD progression, shedding light on the therapeutic development in LUAD.

Prognostic and predictive value of a lncRNA signature in patients with stage II colon cancer.

The current staging method is inadequate to identify high-risk recurrence patients with stage II colon cancer (CC). Using a systematic and comprehensive-biomarker discovery and validation method, we aimed to construct a lncRNA-based signature to improve the prognostic prediction of stage II CC. We identified 1,377 differently expressed lncRNAs by analyzing 16 paired stage II CC tumor tissue and adjacent normal mucosal tissue from the TCGA dataset. Subsequently, using a univariable and step multivariable Cox regression model, we trained an 11-lncRNA signature in the training cohort (n = 141), which could divide patients into high-risk and low-risk groups (AUC at 3 years = 0.801, 95% CI: 0.724-0.877; AUC at 5 years = 0.801, 95% CI: 0.718-0.885). Significantly, patients in the high-risk group had poorer recurrence-free survival (RFS) compared with the low-risk group (log-rank test, P < 0.001 in the training cohort). This lncRNA-based signature was further confirmed in the validation cohort (P < 0.001). Multivariate Cox regression and stratified survival analyses showed that the prognostic value of this signature was independent of other clinicopathological risk factors (CEA, T stage, and chemotherapy). Time-dependent receiver operating characteristic (ROC) analysis demonstrated that this signature had better prognostic ability than any other clinical risk factors or single lncRNAs (all P < 0.05). A nomogram was constructed for clinical use, which integrated both the lncRNA-based signature and clinical risk factors (CEA and T stage) and performed well in the calibration plots. Altogether, our lncRNA-based signature was an independent prognostic factor and possessed a stronger predictive power compared with the currently used clinicopathological risk factors when predicting the recurrence of patients with stage II CC. Collectively, this lncRNA-based signature might facilitate individualized treatment decisions and postoperative counseling, ultimately contributing to improved survival.

Genome-wide DNA methylation analysis by MethylRad and the transcriptome profiles reveal the potential cancer-related lncRNAs in colon cancer.

Colon cancer (CC) is characterized by global aberrant DNA methylation that may affect gene expression and genomic stability. A series of studies have demonstrated that DNA methylation could regulate the expressions of not only protein-coding genes but also ncRNAs. However, the regulatory role of lncRNA genes methylaton in CC remains largely unknown. In the present study, we systemically characterize the profile of DNA methylation, especially the aberrant methylation of lncRNAs genes using MethylRAD technology. A total of 132 999 CCGG/8487 CCWGG sites were identified as differentially methylated sites (DMSs), which were mainly located on the introns and intergenic elements. Moreover, 1,359 CCGG/1,052 CCWGG differentially methylated genes (DMGs) were screened. Our results demonstrated that aberrant methylation of lncRNA genes occurred most frequently, accounting for 37.5% and 44.3% in CCGG and CCWGG DMGs respectively. In addition, 963 lncRNA DMGs were co-analyzed with 1328 differentially expressed lncRNAs which were identified from TCGA database. We found that 15 lncRNAs might be CC-related lncRNAs. ZNF667-AS1 and MAFA-AS1 were down-regulated in CC, which might be silenced by hypermethylation. Besides, 13 lncRNAs were hypomethylated and up-regulated in CC. Moreover, our results validated the expression and methylation level of CC-related lncRNAs by RT-qPCR and pyrosequencing assay. In conclusion, we performed a genome-wide DNA methylation analysis by MethylRAD to acquire both CCGG and CCWGG DMSs and DMGs in CC. The results screened lncRNA DMSs as potential biomarkers and identified 15 lncRNAs as CC-related lncRNAs. This study provided novel therapy targets and valuable insights into molecular mechanism in tumorigenesis and development of CC.

HOTTIP Predicts Poor Survival in Gastric Cancer Patients and Contributes to Cisplatin Resistance by Sponging miR-216a-5p.

Gastric cancer (GC) is a significant public health burden worldwide, and cisplatin resistance is the leading cause for the failure of chemotherapy in this disease. Previous studies have revealed that HOXA transcript at the distal tip (HOTTIP) is involved in the pathology of GC and is associated with poor overall survival. However, the functional role of HOTTIP in GC chemoresistance remains unclear. In this study, quantitative real-time PCR was used to analyze HOTTIP expression in GC cell lines and in tissues of GC patients who received cisplatin-based chemotherapy. The mechanism of HOTTIP-mediated chemoresistance was assessed using cell viability, apoptosis, and autophagy assays. The relationships among HOTTIP, miR-216a-5p, and Bcl-2 were determined using luciferase reporter and western blot assays. HOTTIP was markedly upregulated in the tissues of GC patients who were treated with gastrectomy and cisplatin chemotherapy, especially in those with recurrent tumors. Further, HOTTIP was increased in the cisplatin-resistant cell line, SGC7901/DDP, compared to the parental cells, SGC7901. Functional assays demonstrated that HOTTIP expression promoted cisplatin resistance and inhibited apoptosis and autophagy in GC cells. Mechanistic investigations revealed that HOTTIP may regulate the functions of GC cells by sponging miR-216a-5p. MiR-216a-5p overexpression decreased Bcl-2 expression, enhanced Beclin1 expression, and active autophagy. Taken together, our study demonstrated that HOTTIP is closely associated with recurrence in GC patients. HOTTIP expression confers cisplatin resistance by regulating the miR-216a-5p/BCL-2/Beclin1/autophagy pathway, which provides a novel strategy to overcome resistance to chemotherapy in GC.

Prognostic value of a hypoxia-related microRNA signature in patients with colorectal cancer.

Hypoxia has been particularly associated with poor prognosis in cancer patients. Recent studies have suggested that hypoxia-related miRNAs play a critical role in various cancers, including colorectal cancer (CRC). In the present study, we found 52 differentially expressed miRNAs in HT-29 cells under hypoxic conditions versus normoxic conditions by analyzing the profiles of miRNAs. Using Cox model, we developed a hypoxia-related miRNA signature consisting of four miRNAs, which could successfully discriminate high-risk patients in the Cancer Genome Atlas (TCGA) training cohort (n=381). The prognostic value of this signature was further confirmed in the TCGA testing cohort (n=190) and an independent validation cohort composed of formalin-fixed paraffin-embedded clinical CRC samples (n=220), respectively. Multivariable Cox regression and stratified survival analysis revealed this signature was an independent prognostic factor for CRC patients. Time-dependent receiver operating characteristic (ROC) analysis showed that the area under the curve (AUC) of this signature was significantly larger than that of any other clinical risk factors or single miRNA alone. A nomogram was constructed for clinical use, which incorporated both the miRNA signature and clinical risk factors and performed well in the calibration plots. Collectively, this novel hypoxia-related miRNA signature was an independent prognostic factor, and it possessed a stronger predictive power in identifying high-risk CRC patients than currently used clinicopathological features.

A serum piRNA signature as promising non-invasive diagnostic and prognostic biomarkers for colorectal cancer.

Purpose: Piwi-interacting RNAs (piRNAs) are a novel class of small non-coding RNAs, which are not easily degraded but detectable in human body fluids. Recent studies have shown that aberrant piRNA expression is a signature feature across multiple tumor types. However, the expressions of piRNAs in serum of tumor patients and their potential clinical values remain largely unclear. Patients and methods: High-throughput sequencing was performed to investigate the serum piRNA profiles, followed by evaluations in serum samples of 220 colorectal cancer (CRC) patients and 220 healthy controls using reverse transcription quantitative real-time PCR (RT-qPCR). Biomarker panels including piRNA-based Panel I and carcinoembryonic antigen (CEA)-based Panel II, were developed by logistic regression model, and their diagnostic potentials were compared. Fagan's nomogram was plotted to promote clinical application. Results: We identified five differentially expressed serum piRNAs (piR-001311, piR-004153, piR-017723, piR-017724 and piR-020365), which, when combined in the piRNA-based Panel I, outperformed the CEA-based Panel II (P<0.001) and could detect CRC with an area under the receiver operating characteristic curve of 0.867. In addition, Kaplan-Meier analysis showed that patients with low serum piR-017724 level had worse overall survival (OS) and progression-free survival (PFS). In multivariate Cox regression analysis, serum piR-017724 was an independent prognostic factor for OS and PFS (P<0.05). Conclusion: Our findings suggest serum piRNA expression signatures have potential for use as biomarkers for CRC detection and to predict prognosis at the time of diagnosis.

Development of a preoperative prediction nomogram for lymph node metastasis in colorectal cancer based on a novel serum miRNA signature and CT scans.

BACKGROUND: Preoperative prediction of lymph node (LN) status is of crucial importance for appropriate treatment planning in patients with colorectal cancer (CRC). In this study, we sought to develop and validate a non-invasive nomogram model to preoperatively predict LN metastasis in CRC. METHODS: Development of the nomogram entailed three subsequent stages with specific patient sets. In the discovery set (n = 20), LN-status-related miRNAs were screened from high-throughput sequencing data of human CRC serum samples. In the training set (n = 218), a miRNA panel-clinicopathologic nomogram was developed by logistic regression analysis for preoperative prediction of LN metastasis. In the validation set (n = 198), we validated the above nomogram with respect to its discrimination, calibration and clinical application. FINDINGS: Four differently expressed miRNAs (miR-122-5p, miR-146b-5p, miR-186-5p and miR-193a-5p) were identified in the serum samples from CRC patients with and without LN metastasis, which also had regulatory effects on CRC cell migration. The combined miRNA panel could provide higher LN prediction capability compared with computed tomography (CT) scans (P < .0001 in both the training and validation sets). Furthermore, a nomogram integrating the miRNA-based panel and CT-reported LN status was constructed in the training set, which performed well in both the training and validation sets (AUC: 0.913 and 0.883, respectively). Decision curve analysis demonstrated the clinical usefulness of the nomogram. INTERPRETATION: Our nomogram is a reliable prediction model that can be conveniently and efficiently used to improve the accuracy of preoperative prediction of LN metastasis in patients with CRC.

Genome-wide identification of a novel miRNA-based signature to predict recurrence in patients with gastric cancer.

The current tumor node metastasis (TNM) staging system is inadequate for identifying high-risk gastric cancer (GC) patients. Using a systematic and comprehensive-biomarker discovery and validation approach, we attempted to build a microRNA (miRNA)-recurrence classifier (MRC) to improve the prognostic prediction of GC. We identified 312 differentially expressed miRNAs in 446 GC tissues compared to 45 normal controls by analyzing high-throughput data from The Cancer Genome Atlas (TCGA). Using a Cox regression model, we developed an 11-miRNA signature that could successfully discriminate high-risk patients in the training set (n = 372; P < 0.0001). Quantitative real-time polymerase chain reaction-based validation in an independent clinical cohort (n = 88) of formalin-fixed paraffin-embedded clinical GC samples showed that MRC-derived high-risk patients succumb to significantly poor recurrence-free survival in GC patients (P < 0.0001). Cox and stratification analysis indicated that the prognostic value of this signature was independent of clinicopathological risk factors. Time-dependent receiver operating characteristic (ROC) analysis revealed that the area under the curve of this signature was significantly larger than that of TNM stage in the TCGA (0.733 vs. 0.589 at 3 years, P = 0.004; 0.802 vs. 0.635 at 5 years, P = 0.005) and validation cohort (0.835 vs. 0.689 at 3 years, P = 0.003). A nomogram was constructed for clinical use, which integrated both MRC and clinical-related variables (depth of invasion, lymph node status and distance metastasis) and did well in the calibration plots. In conclusion, this novel miRNA-based signature is superior to currently used clinicopathological features for identifying high-risk GC patients. It can be readily translated into clinical practice with formalin-fixed paraffin-embedded specimens for specific decision-making applications.

miR-422a is an independent prognostic factor and functions as a potential tumor suppressor in colorectal cancer.

AIM: To determine the expression of miR-422a in colorectal cancer (CRC) tissues and to further explore the prognostic value and function of miR-422a in CRC carcinogenesis. METHODS: miR-422a expression was analyzed in 102 CRC tissues and paired normal mucosa adjacent to carcinoma by quantitative real-time PCR. The relationship of miR-422a expression with clinicopathological parameters was also analyzed. Kaplan-Meier analysis and Cox multivariate analysis were performed to estimate the potential role of miR-422a. Cell proliferation, migration, and invasion were used for in vitro functional analysis of miR-422a. RESULTS: The levels of miR-422a were dramatically reduced in CRC tissues compared with normal mucosa (P < 0.05), and significantly correlated with local invasion (P = 0.004) and lymph node metastasis (P < 0.001). Kaplan-Meier survival and Cox regression multivariate analyses revealed that miR-422a expression (HR = 0.568, P = 0.015) and clinical TNM stage (HR = 2.942, P = 0.003) were independent prognostic factors for overall survival in CRC patients. Furthermore, in vitro experiments showed that overexpression of miR-422a inhibited the proliferation, migration, and invasion of SW480 and HT-29 cells. CONCLUSION: Down-regulation of miR-422a may serve as an independent prognosis factor in CRC. MiR-422a functions as a tumor suppressor and regulates progression of CRC.

Serum miR-210 Contributes to Tumor Detection, Stage Prediction and Dynamic Surveillance in Patients with Bladder Cancer.

MiR-210 is the master hypoxamir that generally exhibits oncogenic properties in most human solid tumors including bladder cancer (BC). However, it remains unknown about the clinical significance of circulating miR-210 levels in BC. In this study, we found that serum miR-210 was up-regulated in patients with BC, and serum levels of miR-210 increased with advancing stage and grade. Moreover, serum miR-210 expression was found to be significantly reduced in paired post-operative samples and elevated in most patients with relapsed BC. Taken together, our data suggest that serum miR-210 could be a potential noninvasive biomarker for screening, predicting and monitoring BC.

Identification and validation of reference genes for the detection of serum microRNAs by reverse transcription-quantitative polymerase chain reaction in patients with bladder cancer.

Serum microRNAs (miRNAs) have been proposed as novel non-invasive biomarkers for the early detection of cancer. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is the most commonly used method for investigating miRNA expression levels, however, the interpretation of RT-qPCR results depends largely on normalization to an appropriate endogenous control. The present study involved 129 patients with non-muscle-invasive bladder cancer (NMIBC), 121 patients with muscle-invasive bladder cancer (MIBC) and 158 healthy controls. The aim of the present study was to determine the most stable reference genes for the investigations of serum miRNA in bladder cancer (BC). MiSeq sequencing was performed and the expression levels of 10 miRNAs and U6 were then measured using RT-qPCR. Following RT­qPCR, five genes (hsa-miR-193a-5p, hsa-miR-16-5p, U6, hsa-miR-191-5p and hsa-let-7d-3p) were selected for stability analysis using geNorm and NormFinder software. These algorithms identified hsa-miR-193a-5p and hsa-miR-16-5p as the most stably expressed reference genes. The availability of hsa-miR-193a-5p and hsa-miR-16-5p was confirmed in an additional cohort. One-way analysis of variance indicated that no significant differences were present in the expression levels among the three groups. Furthermore, miR-148b-3p was selected as a target miRNA to determine the effect of hsa-miR-193a-5p and hsa-miR-16-5p on miRNA quantification. The combined use of hsa-miR-193a-5p and hsa-miR-16-5p enabled the detection of a significant upregulation of miR-148b-3p in the BC serum. The results of the present study demonstrated that normalization of miRNA data, using a combination of hsa-miR-193a-5p and hsa-miR-16-5p as reference genes, may produce reliable and accurate results for the detection of serum miRNAs in BC.

Aberrant CCR4 expression is involved in tumor invasion of lymph node-negative human gastric cancer.

Cellular chemotaxis is the best-known function of chemokine receptors which are closely linked with tumor metastasis. In fact, positive expression of chemokine receptors could also be identified even in some patients without metastatic tumors, while the clinical relevance of this data has not been fully established. Our studies were designed to clarify the CCR4 expression profiles and to explore its potential role in histologically node-negative (pN0) gastric cancer (GC). Immunohistochemistry (IHC) or immunohistofluorescence (IHF) analysis was performed on specimens obtained from 108 patients with pN0 GC. We found that CCR4 was aberrantly over-expressed inpN0 GC tissues, with different expression patterns on tumor cells and being associated with T-stage (P = 0.002). The matrigel in vitro invasion assay revealed that over-expression of CCR4 in GC cell lines significantly enhanced the invasive capacity of these cells. Results from real-time RT-PCR and gelatinzymography showed a significant increase in matrix metalloproteinase (MMP)-9 production induced by the forced expression of CCR4 in GC cell lines. Our data suggest that the aberrant CCR4 expression is involved in tumor invasion of pN0 GC and, conceivably, antagonists of CCR4 might be useful candidates for controlling early events in tumor progression.

MiR-203 suppresses ZNF217 upregulation in colorectal cancer and its oncogenicity.

Zinc finger protein 217 (ZNF217) is essential for cell proliferation and has been implicated in tumorigenesis. However, its expression and exact roles in colorectal cancer (CRC) remain unclear. In this study, we demonstrated that ZNF217 expression was aberrantly upregulated in CRC tissues and associated with poor overall survival of CRC patients. In addition, we found that ZNF217 was a putative target of microRNA (miR)-203 using bioinformatics analysis and confirmed that using luciferase reporter assay. Moreover, in vitro knockdown of ZNF217 or enforced expression of miR-203 attenuated CRC cell proliferation, invasion and migration. Furthermore, combined treatment of ZNF217 siRNA and miR-203 exhibited synergistic inhibitory effects. Taken together, our results provide new evidences that ZNF217 has an oncogenic role in CRC and is regulated by miR-203, and open up the possibility of ZNF217- and miR-203-targeted therapy for CRC.

Down-regulation of miR-24-3p in colorectal cancer is associated with malignant behavior.

Deregulation of microRNAs is a frequent event in the tumorigenesis and tumor progression. The aim of this study was to investigate the clinical significance and potential role of miR-24-3p expression in colorectal cancer (CRC). The expression level of miR-24-3p was determined in 95 CRC patients who underwent radical resection by quantitative real-time PCR. The associations between miR-24-3p expression and clinicopathological parameters were analyzed. In vitro function assays including cell proliferation, cell migration and invasion were further explored. We found that miR-24-3p was reduced in CRC tissues compared with their corresponding non-cancerous tissues (P < 0.001) and significantly correlated with local invasion (P = 0.002), lymph node metastasis (P = 0.0007) and clinical stage (P < 0.001). Moreover, Kaplan-Meier survival analysis showed that patients with low miR-24-3p level had a significantly poorer prognosis than those with high miR-24-3p level (P < 0.001). Multivariate analysis revealed that miR-24-3p (HR 2.767; 95 % CI 1.203-6.364; P = 0.017) and clinical TNM stage (HR 0.456; 95 % CI 0.212-0.978; P = 0.044) could be independent prognostic indicators for overall survival rates of CRC patients. In addition, functional assays showed that over-expression of miR-24-3p suppressed CRC cell proliferation, cell migration and invasion. miR-24-3p functions as a tumor suppressor in CRC. Down-regulation of miR-24-3p contributes to the development and progression of CRC and may have a potential role in prognosis and therapy.

Serum microRNA expression signatures identified from genome-wide microRNA profiling serve as novel noninvasive biomarkers for diagnosis and recurrence of bladder cancer.

Recent advantages of serum microRNAs (miRNAs) open a new realm of possibilities for noninvasive diagnosis and prognosis of bladder cancer (BC). The aim of our study was to identify serum miRNA expression signatures in patients with BC and establish new models for the diagnosis of BC and recurrence prediction. We performed genome-wide serum miRNA analysis by Miseq sequencing followed by evaluations in the training and validation sets with reverse transcription quantitative real-time PCR assays from serum samples of 250 patients with BC and 240 controls. A six-miRNA panel (miR-152, miR-148b-3p, miR-3187-3p, miR-15b-5p, miR-27a-3p and miR-30a-5p) for the diagnosis of BC was finally developed by multivariate logistic regression model with an area under the receiver operating characteristic curve of 0.899. The corresponding sensitivities of this panel for Ta, T1 and T2-T4 were 90.00, 84.85 and 89.36%, significantly higher than those of urine cytology, which were 13.33, 30.30 and 44.68%, respectively (all at p<0.001). In addition, Kaplan-Meier analysis showed that patients with nonmuscle-invasive BC (NMIBC) with high miR-152 level and low miR-3187-3p level had worse recurrence-free survival (p=0.023 and 0.043, respectively). In multivariate Cox regression analysis, miR-152 was independently associated with tumor recurrence of NMIBC (p=0.028). Our results suggested that a serum miRNA signature may have considerable clinical value in diagnosing BC. Furthermore, expression level of serum miR-152 could provide information on the recurrence risk of NMIBC.

Overexpression of miR-223 correlates with tumor metastasis and poor prognosis in patients with colorectal cancer.

The purpose of the study was to investigate microRNA-223 (miR-223) expression in colorectal cancer (CRC) and its relationship with tumorigenesis and disease prognosis. Quantitative real-time PCR was used to measure levels of miR-223 in tumor samples and adjacent non-cancerous tissues from 62 patients undergoing radical resection for the treatment of CRC. The associations between miR-223 expression and patient age, sex, as well as clinicopathologic parameters, such as tumor size, differentiation, location, invasion depth, metastasis, tumor-node-metastasis (TNM) stage, and overall patient survival, were analyzed by Mann-Whitney U and Kruskal-Wallis tests. Kaplan-Meier method and Cox proportional hazards regression analyses were performed to estimate the prognostic factors for patient survival prediction. The expression of miR-223 was significantly upregulated in CRC tissues compared with adjacent non-cancerous tissues (P < 0.05). This overexpression was associated with TNM stage and lymph node and distant metastases, (P < 0.05). Moreover, Kaplan-Meier analysis demonstrated that patients with high miR-223 expression had a poorer overall survival (OS) than those with low miR-223 expression (P = 0.002). Univariate analysis revealed a statistically significant correlation between OS and miR-223 level, histology grade, metastasis and TNM stage (P < 0.001). Furthermore, miR-223 levels and histology grade were independently associated with OS (HR 0.204, 95 % CI 0.101-0.415, P < 0.05 and HR 2.252, 95 % CI 1.429-3.546, P < 0.05, respectively). The overexpression of miR-223 may play an important role in the progression of CRC and can be used as an independent factor to determine CRC prognosis.

Decreased expression of miR-133a correlates with poor prognosis in colorectal cancer patients.

AIM: To investigate microRNA-133a (miR-133a) expression in colorectal cancer (CRC) and its relationship with tumorigenesis and disease prognosis. METHODS: Quantitative real-time polymerase chain reaction was used to measure levels of miR-133a in tumor samples and adjacent non-cancerous tissues from 169 patients undergoing radical resection for CRC. The associations between miR-133a expression and patient age, sex, as well as clinicopathologic parameters, such as tumor size, differentiation, location, invasion depth, metastasis, tumor-node-metastasis (TNM) stage and overall patient survival, were analyzed by Mann-Whitney U and Kruskal-Wallis tests. The Kaplan-Meier method and Cox proportional hazards regression analyses were performed to estimate the prognostic factors for patient survival prediction. RESULTS: The expression of miR-133a was significantly downregulated in CRC tissues compared with adjacent non-cancerous tissues (P < 0.05). This reduction was associated with the depth of the local invasion, poor differentiation, lymph node metastasis and advanced disease (P < 0.05). Moreover, Kaplan-Meier analysis demonstrated that patients with low miR-133a expression had poorer overall survival (OS) than those with high miR-133a expression (P < 0.001). Univariate analysis revealed statistically significant correlations between OS and miR-133a level, tumor local invasion, lymph node metastasis and TNM stage (P < 0.001). Furthermore, miR-133a levels and TNM stage were independently associated with OS (HR = 0.590, 95%CI: 0.350-0.995, P < 0.05; and HR = 6.111, 95%CI: 1.029-36.278, P < 0.05, respectively). CONCLUSION: The downregulation of miR-133a may play an important role in the progression of CRC and can be used as an independent factor to determine CRC prognosis.

Urinary cell-free microRNA-106b as a novel biomarker for detection of bladder cancer.

Cell-free microRNAs (miRNAs) stably and abundantly exist in body fluids and emerging evidence suggests cell-free miRNAs as a novel class of noninvasive disease biomarkers. In this study, we hypothesized that the quantitative detection of the oncogenic miR-106b-25 cluster in urine could be a useful clinical biomarker for bladder cancer (BCa). Three members of the miR-106b-25 cluster (miR-106b, miR-93 and miR-25) were quantified by real-time RT-PCR in urine supernatant of 112 BCa patients and 78 age-matched controls. In our study, the urinary levels of miR-106b were significantly higher in BCa patients than controls (P<0.001). No significant difference was observed in the urinary levels of miR-93 and miR-25 between two groups. Furthermore, the levels of urinary miR-106b were significantly reduced in postoperative samples compared with the levels in the preoperative samples (P=0.007). With respect of clinicopathological characteristics, the level of urinary miR-106b was associated with advanced tumor stage. Receiver operating characteristic (ROC) analysis revealed that urinary miR-106b had considerable diagnostic accuracy, yielding an AUC (the areas under the ROC curve) of 0.802 with 76.8% sensitivity and 72.4% specificity in differentiating BCa from controls. In conclusion, our data indicate that urinary cell-free miR-106b might provide new complementary tumor biomarkers for BCa.

Hypoxia-inducible MiR-210 is an independent prognostic factor and contributes to metastasis in colorectal cancer.

MicroRNA-210 (miR-210), the master hypoxamir, plays pleiotropic roles in certain cancers; however, its role in the development of human colorectal cancer remains unclear. Herein, we report that miR-210 is frequently up-regulated in colorectal cancer tissues, with high miR-210 expression significantly correlating with large tumor size, lymph node metastasis, advanced clinical stage and poor prognosis. Functionally, miR-210 overexpression promotes the migration and invasion of colorectal cancer cells. Furthermore, miR-210 can be induced by hypoxia and mediates the hypoxia-induced metastasis of colorectal cancer cells. In addition, vacuole membrane protein 1 (VMP1) is identified as the direct and functional target of miR-210. Thus, miR-210 is a useful biomarker for hypoxic tumor cells and a prognostic factor that plays an essential role in colorectal cancer metastasis.

Investigation of cell free BIRC5 mRNA as a serum diagnostic and prognostic biomarker for colorectal cancer.

BACKGROUND: BIRC5 (Survivin), a key member of inhibitor of apoptosis family, has been shown in colorectal cancer (CRC) tumorigenesis and progress. This study investigated the expression levels of cell free BIRC5 mRNA in serum of CRC and assess its diagnostic and prognostic potential. METHODS: Levels of cell free BIRC5 mRNA were detected by reverse transcription quantitative real-time PCR in serum of 92 CRC patients and 60 healthy volunteers. RESULTS: Cell free BIRC5 mRNA levels were significantly increased in serum of CRC (P < 0.001), and significantly correlated with tumor differentiation (P = 0.035), regional lymph node metastasis (P < 0.001) and TNM stage (P < 0.001). ROC curve demonstrated an optimal cut-off value of 0.128, providing a sensitivity of 84.8% and a specificity of 80.0% for discriminating CRC from controls. The area under the ROC curve for BIRC5 mRNA was significantly larger than that for CEA (0.855 vs. 0.691, P < 0.001). Furthermore, a significantly higher diagnosis capability was showed when combined BIRC5 mRNA and CEA. High serum BIRC5 mRNA expression has a lower OS, compared with low group (36.4% vs. 73.3%, P = 0.022), and was an independent prognostic factor for CRC. CONCLUSION: Serum cell free BIRC5 mRNA is a promising non-invasive biomarker for diagnosis and prognosis of CRC.