Down-regulation of microRNA-126 and microRNA-133b acts as novel predictor biomarkers in progression and metastasis of non small cell lung cancer

Objective: MiRNAs play crucial roles in progression of cancer. However, the underlying mechanisms of miRNAs in non small cell lung cancer are still poorly understood. The aim of this study was to investigate the expression level of microRNA-126 (miR-126) and microRNA-133b (miR-133b) and also their association with clinicopathological features in patients with non small cell lung cancer (NSCLC). Methods: Total RNA was purified from NSCLC tissues and adjacent non-tumor tissues and then quantitative real-time PCR (qRT-PCR) was used to evaluate the expression rate of microRNAs. Furthermore, the association of miR-126 and miR-133b level with clinicopathological features and prognosis were evaluated. Results: Our findings showed that expression of miR-126 was decreased in NSCLC tissues compared with adjacent non-tumor tissues. On the other hand, a lower expression of miR-133b was seen in NSCLC tissues when compared with adjacent non-tumor tissues. In term of miR-126, our results showed that miR-126 was associated with tumor stage and lymph nodes metastasis (P<0.05). In term of miR-133b, our finding indicated that decreased expression of miR-133b was correlated with advanced tumor stage and lymph nodes metastasis (P<0.05). Kaplan-Meier analysis and log-rank test indicated that patients with low expression of miR-126 and miR-133b had a shorter overall survival (log-rank test; P<0.05). Multivariate Cox proportional hazards model revealed that low expression of miR-126 and miR-133b, advanced tumor stage and lymph nodes metastasis were independent prognostic factors for overall survival of NSCLC patients. Conclusions: These findings suggested that miR-126 and miR-133b might play a key role in the progression and metastasis of NSCLC and would be applied as a novel therapeutic agent.     

Down-regulation of microRNA-124 is correlated with tumor metastasis and poor prognosis in patients with lung cancer

Introduction: MicroRNA-124 (miR-124) has been proven dysregulated in several human malignancies and correlated with tumor progression. However, its expression and clinical significance in non-small cell lung cancer (NSCLC) is still unclear. Thus, the aim of this study was to investigate the clinical significance of miR-124 expression in NSCLC. Methods: Expression levels of miR-124 in 92 pairs of NSCLC and adjacent non-tumor tissues were detected by quantitative real-time PCR (qRT-PCR). In order to determine its prognostic value, overall survival (OS) and disease-free survival (DFS) were evaluated using the Kaplan-Meier method, and multivariate analysis was performed using the Cox proportional hazard analysis. Results: miR-124 expression level was significantly lower in NSCLC tissues compared with adjacent non-tumor tissues (P < 0.05). The 5-year OS of low miR-124 expression group was significantly shorter than that of high miR-124 expression group (P < 0.05). Moreover, the 5-year DFS of low miR-124 expression group was also significantly shorter than that of high miR-124 expression group (P < 0.05). In a multivariate Cox model, we found that miR-124 expression was an independent prognostic factor for both 5-year OS and 5-year DFS in NSCLC (P < 0.05). Conclusions: Our results offer the convincing evidence that miR-124 may play key roles in the progression of lung cancer and that the down-regulated expression of miR-124 may be independently associated with shorter OS and DFS of patients, suggesting that miR-124 might be a potential marker for further risk stratification in the treatment of lung cancer.     

MicroRNA-153 expression and prognosis in non-small cell lung cancer

Background: miR-153 has been found to be significantly decreased in non-small cell lung cancer (NSCLC) tissues; however, its clinical significance has not been investigated. Methods: The expression patterns of miR-153 in 137 pairs of human lung cancer tissues and adjacent normal lung tissues were analyzed using qRT-PCR. The relationships between miR-153 expression and clinicopathological parameters were examined by chi-square test. Kaplan-Meier method and the log-rank test were used to determine the difference in overall survival (OS) rates between two groups. Results: The expression of miR-153 was reduced significantly, compared with adjacent normal lung tissues (P<0.05). We observed that the expression level of miR-153 was positively correlated with the clinical stage (P=0.005), lymph node status (P=0.014), distant metastasis (P=0.004), and differentiated degree (P<0.001) in NSCLC patients. According to the Kaplan-Meier survival analysis, the patients with low miR-153 expression exhibited evidently poorer overall survival rates than those with high miR-153 expression (P=0.003). Multivariate analysis showed that the expression of miR-153 was an independent and significant factor associated with poor OS rates (P=0.002). Conclusion: Decreased expression of miR-153 might be a potential unfavorable prognostic factor for patients with NSCLC, and further studies would be needed to prove our findings.     

MicroRNA-148b is down-regulated in non-small cell lung cancer and associated with poor survival

Background: The aim of this study was to clarify the clinicopathological significance of miRNA-148b (miR-148b) expression in NSCLC, and to explore the correlation between miR-148b level and the prognosis of patients with NSCLC. Methods: 151 patients diagnosed with NSCLC between May 2007 and April 2012 were included in the present study. Real-time RT-PCR method was used to assess the expression levels of miR-148b. The differences between two groups were assessed using Student’s t -test, and the Kaplan-Meier method was used to estimate overall survival. Results: The expression of miR-148b was decreased in tumor tissues compared to corresponding adjacent normal lung tissues (0.37 ± 0.12 vs. 1.00 ± 0.53, P < 0.05). Low miR-148b expression was significantly associated with TNM stage (P = 0.014), lymph node metastasis (P = 0.031), and distant metastasis (P = 0.008). Kaplan-Meier survival analysis showed that patients with low expression of miR-148b had significantly worse overall survival rates compared with those who had cancers with high miR-148b expression (log-rank test P = 0.039). Furthermore, multivariate Cox proportional hazards model analysis showed that miR-148b expression was independently associated with overall survival of patients with NSCLC (HR = 2.357, 95% CI: 1.612-9.212, P = 0.011). Conclusion: our data indicate that decreased expression of miR-148b in NSCLC tissues has prognostic value.     

PTEN and Ki67 expression is associated with clinicopathologic features of non-small cell lung cancer

Phosphatase and tensin homolog deleted on chromosome 10（PTEN） and the proliferating antigen Ki67 have been widely studied in several tumors.However,their role as indicator in non-small cell lung cancer（NSCLC）remains unknown.Here,we investigated the expression of PTEN and Ki67 in NSCLC tissues and paired normal lung tissues to identify whether these proteins are associated with lung cancer development and survival.Immunohistochemistry for PTEN and Ki67 was performed on 67 lung cancer tissues and 41 paired adjacent normal lung tissues to detect the expression of these two proteins.The expression of PTEN in NSCLC tissues（32.8%） was significantly lower than that in normal tissues（82.9%,P 〈 0.05）.In contrast,the expression of Ki67 in NSCLC tissues（76.1%） was significantly higher than that in normal tissues（27.3%,P 〈 0.05）.Expression of both PTEN and Ki67 were strongly associated with tumor histology,clinical stage,lymph node metastasis,differentiation and4-year postoperative survival rate（P 〈 0.05）.However,PTEN expression was negatively correlated with Ki67 expression（r =-0.279,P 〈 0.05）.In conclusion,low PTEN expression and Ki67 overexpression are associated with malignant invasion and lymph node metastasis of NSCLC.These proteins may serve as diagnostic and prognostic biomarkers of NSCLC.     

Low expression of long non-coding RNA LET inhibits carcinogenesis of cervical cancer

Introduction: Long non-coding RNAs (lncRNAs) have been demonstrated to play key roles in tumorgenesis, and the lncRNA LET is down-regulated in several cancers. However, little is known about the function of lncRNA LET in human cervical cancer. The aim of this study was to investigate the clinical significance of lncRNA LET expression in cervical cancer. Methods: We examined the expression of lncRNA LET in 94 cervical cancer tissues and matched adjacent non-tumor tissues using quantitative real-time PCR and analyzed its correlation with the clinicopathological features. Results: The results showed that lncRNA LET expression in cervical cancer tissues was significantly down-regulated compared with the adjacent non-tumor tissues (P < 0.05). Decreased lncRNA LET expression was significantly correlated with FIGO stage, lymph node metastasis, and depth of cervical invasion (P < 0.05), but not other clinical characteristics. Moreover, cervical cancer patients with lncRNA LET lower expression have shown significantly poorer overall survival than those with higher lncRNA LET expression (P < 0.05). Univariate and multivariate analyses suggested that lncRNA LET expression served as an independent predictor for overall survival. Conclusions: Our data provided the first evidence that lncRNA LET may represent a prognostic marker and a potential therapeutic target for cervical cancer.     

Expression of IRAK1 in lung cancer tissues and its clinicopathological significance: a microarray study

The interleukin-1 receptor associated kinases 1 (IRAK1) is a down stream effector molecule of the toll like receptor (TLR) signaling pathway, which is involved in inflammation, autoimmunity and cancer. However, the role of IRAK1 in lung cancer remains unclarified. Herein, we investigated the protein expression and the clinicopathological significance of IRAK1 in 3 formalin-fixed paraffin-embedded lung cancer tissue microarrays by using immunohistochemistry, which included 365 tumor and 30 normal lung tissues. We found that the expression of IRAK1 in lung cancer was significantly higher compared with that in normal lung tissues (P=0.002). Receiver operating characteristic (ROC) curves were generated to evaluate the power of IRAK1 to distinguish lung cancer from non-cancerous lung tissue. The area under curve (AUC) of ROC of IRAK1 was 0.643 (95% CI 0.550~0.735, P=0.009). Additionally, IRAK1 expression was related to clinical TNM stage (r=0.241, P < 0.001), lymph node metastasis (r=0.279, P < 0.001) and tumor size (r=0.299, P < 0.001) in lung cancer. In the subgroup of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), the positive rates of IRAK1 were both higher than that in the normal lung tissues (P=0.003, P=0.002, respectively). Further spearman analysis showed that IRAK1 protein in NSCLC was positive correlated with clinical TNM stage (r=0.222, P < 0.001), lymph node metastasis (r=0.277, P < 0.001), tumor size (r=0.292, P < 0.001) and distal metastasis (r=0.110, P=0.043). In conclusion, the expression of IRAK1 protein might be valuable in identifying patients with increased risks of lung cancer and might act as a target for diagnosis and gene therapy for lung cancer.     

High expression of MAGE-A9 in tumor and stromal cells of non-small cell lung cancer was correlated with patient poor survival

Melanoma associated antigen-A (MAGE-A) is an oncogene and correlated with tumor initiation and development. However the roles of MAGE-A9 in non-small cell lung cancer (NSCLC) are still unknown. We investigated MAGE-A9 mRNA expression in 18 tumor tissues of NSCLC by qRT-PCR and MAGE-A9 protein expression in 213 NSCLC samples of tissue arrays by immunohistochemical staining. We assessed the relationship between MAGE-A9 expression and clinical parameters. The results showed that the high expression of MAGE-A9 protein in NSCLC tumor cells were commonly present in squamous cell carcinomas (P = 0.030). It was also related to larger tumor diameter, lymph node metastasis and later stage grouping with TNM classification (all P < 0.05). Whereas the expression of MAGE-A9 in stromal cells was higher in squamous cell carcinomas as well. Cox regression univariate and multivariable analysis revealed that MAGE-A9 expression in tumor cells of NSCLC (P < 0.001) is an independent prognostic factor in five-year overall survival rate. We concluded that the molecular assessment of MAGEA9 could be considered to improve prognostic evaluation and to identify eligible patients for potential target therapy.     

miR-143在胃癌中的表达及其临床病理意义

目的:分析miR-143在胃癌中的表达及其与临床病理特征的关系。方法:分别取胃癌手术标本32例及其癌旁组织,提取总RNA,采用茎环逆转录实时定量PCR方法检测miR-143在胃癌及其癌旁正常组织中的表达量,并分析其与临床病理特征关系。结果:与癌旁组织比较,miR-143在胃癌组织中表达显著下调(P0.05);miR-143的表达与细胞分化程度(P0.05)及淋巴结转移(P0.05)相关,与性别、年龄、血型、肿块位置、肿块大小、肿块侵润深度及肿瘤淋巴结转移分期无关。低分化胃癌组织的miR-143表达明显低于中高分化的标本(P0.05);有淋巴结转移胃癌组织的miR-143表达明显低于无淋巴结转移的胃癌组织(P0.05)。ROC曲线分析显示,miR-143评价胃癌细胞分化程度的特异性和敏感性可达75.0%和79.2%。结论:miR-143表达下调可能与胃癌的发生发展有关,miR-143可作为评价低分化胃癌的辅助指标。     

miRNA-124 down-regulates SOX8 expression and suppresses cell proliferation in non-small cell lung cancer

Non-small lung cell carcinoma (NSCLC) is a leading lethal disease and a global health burden. The function of the Sex determining region Y (SRY)-related high mobility group box (SOX) family gene in cancer has attracted the attention of more and more scientists recently, yet there are few reports regarding the role of SOX in NSCLC. Our study aimed to investigate the expression of SOX8, a protein belonging to the E group of the SOX family, as well as SOX9, in non-small cell lung cancer (NSCLC) and the relationship of gene expression to clinicopathological factors and prognosis in patients. Immunohistochemical analysis was used to measure the expression of SOX8 in 80 NSCLC and 7 adjacent normal tissues. SOX8 expression was detected as elevated in tumor samples and correlated to tumor size (P < 0.001), lymph node metastasis (P = 0.001), differentiation classification (P = 0.015), and clinical stage (P = 0.013) significantly. Moreover, Kaplan-Meier survival analysis demonstrated that shorter survival time for patients who had higher SOX8 expression (P < 0.001). In addition, our experiments indicate that miRNA-124 functions as a tumor suppressor in NSCLC. We also demonstrate miRNA-124 directly targeted and decreased SOX8 in NSCLC cell lines, suggesting smiRNA-124 may regulate NSCLC cell proliferation via decreasing SOX8 (oncogenicity of biomarker in NSCLC).     

Increased expression of microRNA-150 is associated with poor prognosis in non-small cell lung cancer

Objectives: The aim was to evaluate the clinical significance and prognostic value of tissue miR-150 expression in non-small cell lung cancer (NSCLC) patients. Materials and methods: Quantitative real-time PCR was used to analyze the expression of miR-150. Overall survival (OS) was estimated using the Kaplan-Meier method, and the differences in survival were compared using the log-rank test. A Cox proportional hazards model was used for multivariate analysis. Results: Mean miR-150 levels were significantly higher in NSCLC tissues compared with matched non-cancerous tissues (4.07 ± 2.33 vs. 1.00 ± 0.46, P < 0.0001). The level of miR-150 in NSCLC was strongly correlated with lymph node metastasis (P = 0.04), distant metastasis (P = 0.01) and clinical TNM stage (P = 0.02). Kaplan-Meier analysis showed that the cumulative 5-year OS rate was 40.8% in the high expression group, and 69.2% in the low expression group. The log-rank test showed that the OS rate of patients with high miR-150 expression was significantly poorer than that of the remaining cases (P = 0.007). Conclusion: Our data indicated that overexpression of miR-150 in NSCLC tissues has prognostic value.     

Up-regulation of miR-335 predicts a favorable prognosis in esophageal squamous cell carcinoma

Introduction: MicroRNAs (miRNAs) are noncoding RNAs that regulate multiple cellular processes during cancer progression. MiR-335 has recently been identified to be involved in tumorigenesis of several cancers such as ovarian cancer and gastric cancer. However, the regulation of miR-335 in esophageal squamous cell carcinoma (ESCC) has not been reported yet. Methods: Expression of miR-335 in tumor and their normal matched tissues was determined by quantitative real-time PCR in 67 ESCC patients and its association with overall survival of patients was analyzed by statistical analysis. Results: The expression level of miR-335 was reduced in malignant tissue samples in comparison to normal matched tissue (P < 0.05). It was also proved that miR-335 expression was associated with ESCC histological grade, lymph node metastasis, tumor stage and clinical stage (P < 0.05). In addition, the Kaplan-Meier survival curves revealed that low miR-335 expression was associated with poor prognosis in ESCC patients. Multivariate analysis showed that miR-335 expression was an independent prognostic marker of overall survival of ESCC patients. Conclusions: The study proves for the first time that miR-335 is down regulated in a majority of ESCC patients. Our results indicate that miR-335 expression is an independent prognostic factor for patients with esophageal cancer, which might be a potential valuable biomarker for ESCC.     

Increased expression of miRNA-182 in colorectal carcinoma: an independent and tissue-specific prognostic factor

Increasing evidence has revealed that miRNAs play a pivotal role in multiple processes of carcinogenesis, and are being explored as diagnostic, prognostic and predictive biomarker. In this study, we investigated the status of miR-182 expression in colorectal carcinoma (CRC) by in situ hybridization and its underlying clinicopathologic significance for patients with CRC. We found that 79/138 (57.25%) CRCs had high-level expression of miR-182, while 17/67 (25.37%) normal mucosa tissues had high-level expression of miR-182. The expression level of miR-182 was remarkably up-regulated in CRC tissues compared with non-neoplastic normal tissues (P < 0.001). The over-expression of miR-182 in cancer parenchyma cells in CRC were strongly correlated with T-stage (P = 0.020), lymph node metastasis (P = 0.003), distant metastasis (P = 0.002), and Dukes’ stage (P = 0.005) in patients with CRC. Patients with high-level expression of miR-182 had short overall survival time than those with low-level expression of miR-182 (P < 0.001). Univariate and multivariate survival analyses further showed that miR-182 expression was a potential unfavorable prognostic factor for CRC, suggesting a potential application of miR-182 in prognosis prediction and therapeutic application in CRC.     

Overexpression of eIF3e is correlated with colon tumor development and poor prognosis

EIF3e is a component of the eukaryotic translation initiation factor 3 (eIF-3) complexes, which is an essential factor for initiation of protein synthesis in mammalian cells. Translational control plays key roles in the complex mechanism of cancer development and progression. However, the clinical significance of eIF3e in colon cancer remains to be elucidated. We analyzed the eIF3e expression in a tissue microarray (TMA), which contained 173 colon cancer tissues paired with adjacent normal mucosa and lymph node metastasis. The expression of eIF3e was significantly elevated in colon cancer tissues in comparison with those in adjacent normal mucosa (P < 0.001) and lymph node metastasis (P < 0.001). The high expression of eIF3e in colon cancer was significantly correlated with tumor size (P < 0.001), lymph node involvement (P < 0.001), distant metastasis (P < 0.001), clinical stage (P < 0.001), histopathologic classification (P < 0.001), and vessel invasion (P = 0.036). Univariate and multivariate analysis revealed that eIF3e is an independent prognosis factor for overall survival and disease-free survival in colon cancer. Down-regulation of eIF3e in vitro inhibited colon cancer cell proliferation, clonality and promoted cell apoptosis. Taken together, high eIF3e expression may contribute to tumor progression and predict poor prognosis in colon cancer.     

miRNA-124 down-regulates SOX8 expression and suppresses cell proliferation in non-small cell lung cancer

Non-small lung cell carcinoma (NSCLC) is a leading lethal disease and a global health burden. The function of the Sex determining region Y (SRY)-related high mobility group box (SOX) family gene in cancer has attracted the attention of more and more scientists recently, yet there are few reports regarding the role of SOX in NSCLC. Our study aimed to investigate the expression of SOX8, a protein belonging to the E group of the SOX family, as well as SOX9, in non-small cell lung cancer (NSCLC) and the relationship of gene expression to clinicopathological factors and prognosis in patients. Immunohistochemical analysis was used to measure the expression of SOX8 in 80 NSCLC and 7 adjacent normal tissues. SOX8 expression was detected as elevated in tumor samples and correlated to tumor size (P < 0.001), lymph node metastasis (P = 0.001), differentiation classification (P = 0.015), and clinical stage (P = 0.013) significantly. Moreover, Kaplan-Meier survival analysis demonstrated that shorter survival time for patients who had higher SOX8 expression (P < 0.001). In addition, our experiments indicate that miRNA-124 functions as a tumor suppressor in NSCLC. We also demonstrate miRNA-124 directly targeted and decreased SOX8 in NSCLC cell lines, suggesting smiRNA-124 may regulate NSCLC cell proliferation via decreasing SOX8 (oncogenicity of biomarker in NSCLC).     

Correlation and prognostic significance of MMP-2 and TFPI-2 differential expression in pancreatic carcinoma

Aberrant expression of matrix metalloproteinase (MMP)-2 and tissue factor pathway inhibitor (TFPI)-2 not only correlate with tumorigenesis, but also with tumor invasion and metastasis. This study aims to investigate the correlation and prognostic significance of MMP-2 and TFPI-2 differential expression in pancreatic carcinoma. Immunohistochemistry was used to evaluate MMP-2 and TFPI-2 expression in tumor tissues and corresponding non-tumor tissues from 122 patients with pancreatic carcinoma. The results showed that the expression of MMP-2 was significantly (P < 0.05) higher in tumor tissues (78.7%) than in adjacent non-tumor tissues (27.9%), whereas the expression of TFPI-2 was significantly (P < 0.001) lower in tumor tissues (27.9%) than in adjacent non-tumor tissues (79.5%). Spearman’s rank correlation test showed a negative correlation between MMP-2 and TFPI-2 expression (r = -0.346, P < 0.001). Kaplan-Meier survival analysis showed that high MMP-2 expression was significantly correlated with decreased disease-free survival (DFS) (P < 0.001) and overall survival (OS) (P < 0.001), while high TFPI-2 expression was significantly associated with increased DFS (P < 0.001) and OS (P < 0.001) of the patients. Multivariate analysis showed that high MMP-2 expression can act as an independent predictive factor for poor DFS (P = 0.01); and low TFPI-2 expression as an independent prognostic factor for poor DFS (P < 0.001) and OS (P < 0.001). In conclusion, our findings suggested that the differential expression of MMP-2 and TFPI-2 have a negative correlation in pancreatic carcinoma tissues; they may be considered as valuable biomarkers for prognosis of pancreatic carcinoma.     

Down-regulation of miR-503 expression predicate advanced mythological features and poor prognosis in patients with NSCLC

Objective: We aimed to explore what impact miR-503 has on the prognosis of patients with non-small cell lung cancer (NSCLC). Methods: Cancer and matched non-malignant lung tissue specimens were collected from 109 patients who underwent surgery in Tanisha Hospital from Jun 2006 to July 2013. Overall survival (OS) curves were analyzed using the Lapland-Meier method, and the differences were examined using log-rank tests. Cox proportional- hazards regression analysis was applied in order to estimate univariate and multivariate hazard ratios for OS. Results: The relative expression of miR-503 in NSCLC tissues (0.366 ± 0.130) was significantly lower than that in matched noncancerous lung tissues (1.667 ± 1.047, P < 0.01). Statistically significant association was observed between miR-503 expression and lymphatic invasion (P = 0.005), distant metastasis (P = 0.002), TNM stage (P = 0.008), and tumor grade (P = 0.043). Lapland Meier analysis clearly illustrated that the patients with the lower expression of miR-503 had a worse outcome compared to patients with higher miR-503 expression (P = 0.004). Furthermore, multivariate analysis revealed that miR-503 expression level was an independent prognostic factor for overall survival (HR = 3.992, 95% CI: 2.276-9.872; P = 0.018) in NSCLC. Conclusion: In patients with NSCLC, low miR-503 expression is an independent prognostic factor.