Expressions Of EGFR Signaling Pathway-related MiRNAs And Their Implications In Non-small Cell Lung Cancer

Background:Lung cancer is becoming the leading cause of cancer-related deaths with high mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common type accounting for approximately 85% of all cases. Over 70% of cases are at advanced stages by the time of presentation with subsequently poor prognosis. Low-dose helical CT plays an important role in the screening of high risk group. Mutation of epidermal growth factor receptor (EGFR) and rearrangement of anaplastic lymphoma kinase (ALK) have more frequently been found in NSCLC, thus its target therapy and individualized treatment strategy request more accurate classification on histological subtypes of NSCLC and need immunohistochemistry (IHC) to make a definite diagnosis. With the development of genomics, it is becoming a hot spot of molecular genetics of NSCLC to explore the regulatory mechanism from microRNAs (miRNAs), which are small non-protein-coding RNA molecules of 19-24 nucleotides. Many miRNAs are involved in carcinogenesis, inflammation and other pathological processes. EGFR signaling pathway is an important link and plays an important role in cell migration and invasion. Some investigations have validated that miR-125a-5p, miR-145 and miR-146a play biological roles through targeting the EGFR signaling pathway and its downstream genes in human cancers.Purpose:1. To analyze the CT features of NSCLC of different pathological types and evaluate the role of IHC in pathological diagnosis of NSCLC.2. To establish the method of extracting miRNAs from tissue to detect the expression of miRNAs (miR-125a-5p, miR-145 and miR-146a) in the tumors and their adjacent tissue in NSCLC patients and to analyze the relationship between the expression of these miRNAs in tumor tissue of NSCLC and clinical pathological factors, and prognosis as well.Methods:1. The CT features were retrospectively analyzed and the expression of CK.5/6, P63, TTF-1 and Napsin-A was detected in 62 cases of NSCLC by IHC (MaxVision method).2. Expression levels of miRNAs were detected in paired tumor tissue and its adjacent tissue using quantitative real-time PCR analysis and their differences were compared using t-test. Correlations between miRNAs expression and clinicopathological factors, prognosis were analyzed by chi-squared test and Kaplan-Meier method respectively.Results:1. Lobulation and speculation were the common features of lung cancer in CT images. The expression of CK5/6 and P63 in squamous cell carcinoma was significantly higher than that in adenocarcinoma, and the positive percentage of TTF-1 and Napsin-A in adenocarcinoma was significantly higher than that in squamous cell carcinoma (P<0.01).2. The expression of miR-125a-5p and miR-145 in tumor tissue was significantly lower than that in tumor adjacent tissue (P<0.0001). The area under the ROC curves (AUC) for miR-145 was 0.895. For miR-125a-5p and miR-146a, the area was lower than 0.7.3. The expression of miR-145 was significantly lower in stage Ⅲ-Ⅳ and in moderate-poorly differentiated tumor tissue than that in stage Ⅰ-Ⅱ and in well-differentiated tumor tissue (P<0.05). The overall survival rate in low expression group of miR-145 was significantly lower than that in high expression group (P<0.05).Conclusions:1. There are different CT features in different pathological types of NSCLC, which can be used as one of the evidences in the screening and preliminary diagnosis. The expression of CK5/6, P63, TTF-1 and Napsin-A can be a panel of IHC for subclassification in NSCLC.2. The expression of miR-125a-5p and miR-145 is down regulated and these two miRNAs might function as anti-oncogenes in NSCLC. miR-145 might be one of the potential biomarkers for the diagnosis and prognosis in patients with NSCLC.