miR-211 regulates the expression of RRM2 in tumoral metastasis and recurrence in colorectal cancer patients with a k-ras gene mutation.

Colorectal cancer (CRC) ranks as the third-leading cause of cancer-associated mortalities in Taiwan. The expression of ribonucleotide reductase M2 (RRM2) and p53R2 is associated with tumoral malignancy and progression in several types of cancer. The aim of the present study was to determine the association of p53R2/RRM2 with the upstream expression of microRNA (miR)-211 and the association of expression levels of p53, APC and k-ras with clinical outcomes in patients with CRC. The study consisted of 192 tumor tissue samples obtained from patients with CRC. Immunohistochemistry and direct sequencing of DNA were performed to analyze p53R2/RRM2 protein expression and p53/APC/k-ras gene mutations in these samples. The expression level of miR-211 was detected by reverse transcription-quantitative polymerase chain reaction. The results showed that the expression of p53R2 was lower and that of RRM2 was higher in patients with lymph node metastasis, distant metastasis, and late-stage CRC compared with patients without lymph node metastasis, distant metastasis and early-stage CRC. A high expression of RRM2 in patients had a negative effect on overall survival (OS) and disease-free survival (DFS) in CRC. Positive expression of RRM2 was detected in tumor tissues, and expression associated with the presence of k-ras gene mutation. Furthermore, it was detected that the upstream miR-211 expression was negatively associated with RRM2 expression in tumor tissues of patients with CRC. miR-211 expression was associated with survival and tumoral recurrence in patients with k-ras mutations. The present authors suggest that the downregulation of miR-211 and overexpression of RRM2 in tumor tissues of patients with CRC could be used to predict metastases and disease prognosis, particularly in patients with k-ras gene mutations.

Down-regulation of let-7a-5p predicts lymph node metastasis and prognosis in colorectal cancer: Implications for chemotherapy.

Colorectal cancer (CRC) guidelines recommend adjuvant chemotherapy according to the level of lymph node metastasis. Let-7a-5p is a microRNA, which inhibits migration, invasion, as well as the epithelial-mesenchymal transition by targeting HMGA2. The aim of this study was to investigate the role of let-7a-5p in the clinical impact of CRC. In this study, one hundred and ninety-two CRC patients were enrolled. The expression of let-7a-5p and HMGA2 in serum and tumour tissues were analysed by real-time PCR and immunohistochemistry. Kaplan-Meier analysis was used to analyse primary outcomes, including the survival and tumour recurrence. The expression of let-7a-5p in tumour tissues was significantly negative correlated with the tumour size, stage and lymph node metastasis in CRC patients (p = 0.024 for tumour size, p < 0.0001 for stage and p < 0.0001 for lymph node metastasis). There was a negative correlation between the levels of let-7a-5p and the HMGA2 protein (p < 0.0001). The overall survival (OS) and disease-free survival (DFS) rates of patients with let-7a-5p low/HMGA2 high were poorer than those with let-7a-5p high/HMGA2 high, let-7a-5p high/HMGA2 low and let-7a-5p low/HMGA2 low. In addition, the expression levels of let-7a-5p in serums were positively correlated with let-7a-5p in the tumour tissues of the CRC patients. The expression levels of let-7a-5p in serums also could be used as a biomarker to predict clinical outcome. We suggest that down-regulation of let-7a-5p in serums and tumour tissues of CRC patients could be used to predict lymph node metastasis and the disease prognosis. These results could be implicated for chemotherapy suggestion.

Inactivation of p53 in pterygium influence miR-200a expression resulting in ZEB1/ZEB2 up-regulation and EMT processing.

Loss of p53 function has been linked to progression of pterygium. MiR-200a is known to be controlled by p53. Here, we hypothesize that expression of miR-200a and downstream ZEB1/ZEB2 genes are regulated epithelial-mesenchymal transition (EMT) involved in the pathogenesis and recurrence of pterygium. For this study, 120 primary pterygial samples were collected. Immunohistochemistry and real-time RT-PCR were performed to determine the expression of p53, p53 down-stream EMT associated protein and miR-200a. The molecular correlation of p53, miR-200a and downstream genes were confirmed using primary pterygium cells (PECs). Expression of miR-200a in pterygium tissues was significantly lower than in conjunctiva controls (p = 0.015). Up-regulated miR-200a levels were positively correlated with and p53 protein expression (p < 0.001). The miR-200a downstream ZEB1/ZEB1 protein expression were negative correlated with miR-200a expression. Cell model studies demonstrated that miR-200a controlled the EMT of PECs through up-regulated ZEB1, ZEB2 and Snail gene expression. Our study demonstrated that inactivation of p53 in pterygium may influence miR-200a, resulting in ZEB1/ZEB2 up-regulation and EMT processing of pterygium. Therefore, we suggest that expression of miR-200a play an important role in EMT processing and recurrence of pterygium.

MiR-92a Promotes Cell Metastasis of Colorectal Cancer Through PTEN-Mediated PI3K/AKT Pathway.

BACKGROUND: MicroRNAs regulate gene expression at the posttranscriptional level and play important roles in tumor development, progression, and metastasis. The aim of this study was to investigate the role of microRNA-92a (miR-92a) in metastasis of colorectal cancer (CRC). METHODS: One hundred fifty-eight CRC patients were enrolled. The expression of miR-92a, PTEN, and E-cadherin was analyzed by real-time PCR. Univariate (Kaplan-Meier) analysis was used to analyze primary outcomes included 5-year overall survival and tumor recurrence. CRC cell model studies were used to analyze the miR-92a-involved CRC metastasis. RESULTS: The expression of miR-92a in tumor tissues was significantly positively correlated with lymph node metastasis in CRC patients (p = 0.012). After adjusting for age, sex, and disease differentiation, this correlation remained significant (p = 0.01). In addition, there was a negative correlation between levels of miR-92a and the PTEN gene (p < 0.0001). No any association of miR-92a and E-cadherin was found (p = 0.128). Patients with high miR-92a/low PTEN had poorer overall survival and disease-free survival rates than those with high miR-92a/high PTEN, low miR-92a/high PTEN, and low miR-92a/low PTEN. The association of levels of miR-92a and PTEN with tumor cell migration in CRC was also confirmed in CRC cell models. CONCLUSIONS: We suggest that miR-92a is involved in lymph node metastasis of CRC patients through PTEN-regulated PI3K/AKT signaling pathway.

MiRNA-221 negatively regulated downstream p27Kip1 gene expression involvement in pterygium pathogenesis.

PURPOSE: MiRNAs are small noncoding RNAs that have been implicated in tumor development. They regulate target gene expression either by mRNA degradation or by translation repression. Activation of ß-catenin has been linked to pterygium progression. Here, we hypothesize that ß-catenin-associated miRNA, miRNA-221, and downstream p27Kip1 gene expression are correlated with the pathogenesis of pterygium. METHODS: We collected 120 pterygial and 120 normal conjunctival samples for this study. Immunohistochemistry and real-time reverse transcription (RT)-PCR were performed to determine ß-catenin protein localization, miR-221, and p27Kip1 gene expression. Pterygium cell line (PECs) cell models were used to confirm the effect of ß-catenin, miR-221, and p27Kip1 gene in the proliferation of pterygium cells. RESULTS: Seventy-two (60.0%) pterygial specimens showed high miR-221 expression levels, which was significantly higher than the control groups (13 of 120, 10.8%, p<0.0001). MiR-221 expression was significantly higher in ß-catenin-nuclear/cytoplasmic-positive groups than in ß-catenin membrane-positive and negative groups (p=0.001). We also found that p27Kip1 gene expression in pterygium was negatively correlated with miR-221 expression (p=0.002). In the clinical association, miR-221 expression was significantly higher in the fleshy and intermediate groups than in the atrophic group (p=0.007). The association of miR-221, p27Kip1 and proliferation of pterygium were also confirmed in the PECs model. CONCLUSIONS: Our study demonstrated that activation of ß-catenin in pterygium may interact with miR-221, resulting in p27Kip1 gene downregulation that influences pterygium pathogenesis.

Positive nuclear expression of KLF8 might be correlated with shorter survival in gastric adenocarcinoma.

Kruppel-like factor 8 (KLF8) is important in cell proliferation, epithelial-to-mesenchymal transition, cell migration, and invasion. Gastric adenocarcinoma is among the leading causes of cancer-related death in the world. In this study, the clinicopathologic correlation of KLF8 expression with gastric adenocarcinoma in Taiwan was investigated. The nuclear localization of KLF8 was correlated with advanced stage (P = .008) and 3-year survival rate (P = .043). The nuclear expression of KLF8 was significantly higher in the diffused type of gastric adenocarcinoma compared with the intestinal type (P = .036). Kaplan-Meier analysis results showed that patients with positive nuclear KLF8 had significantly lower overall survival rate compared with those with negative nuclear KLF8 (P = .011). Univariate analysis results indicated that positive nuclear KLF8 expression, advanced stage, and lymph node metastasis are correlated with lower overall survival. Positive nuclear KLF8 might be correlated with lower survival in gastric adenocarcinoma patients and might be an oncogene property in gastric adenocarcinoma carcinogenesis.