Abstract
Micro RNAs (miRNA) are small non-coding RNAs that post-transcriptionally regulate gene expression. Dysregulation of miRNA cluster 143/145 has been reported in several malignancies, but their role in non-small cell lung cancer (NSCLC) remains elusive. This study investigates the prognostic impact of miR-143 and miR-145 in primary tumors and metastatic lymph nodes in NSCLC tissue. Tissue from 553 primary tumors and 143 matched metastatic lymph nodes were collected and tissue microarrays were constructed. In situ hybridization was used to evaluate miR-143 and miR-145 expression in tumor epithelial cells and stromal cells in the primary tumors and lymph nodes. In vivo data was supplemented with functional studies of cell lines in vitro to evaluate the role of miR-143 and miR-145 in NSCLC tumorigenesis. In our cohort, stromal miR-143 (S-miR-143) and miR-145 (S-miR-145) expression in primary tumor tissue were independent prognosticators of improved disease-specific survival (DSS) in female (S-miR-143, HR: 0.53, p = 0.019) and male patients (S-miR-145, HR: 0.58, p = 0.021), respectively. Interesting correlations between the miR cluster 143/145 and previously investigated steroid hormone receptors from the same cohort were identified, substantiating their gender dependent significance.
Highlights
MicroRNAs are small non-coding RNA elements important in various biological processes, including tumorigenesis[4]
We found that miR-143 was primarily observed in the cell cytoplasm, while miR-145 was mainly observed in the nuclei of epithelial and stromal cells
We found correlations between miR-143/miR-145 and aromatase enzyme (AR), the rate limiting enzyme in estradiol production, suggesting the miRs may interact with regional estradiol production and ER signaling in the lung, as observed in breast tissue
Summary
MicroRNAs (miRNAs) are small non-coding RNA elements important in various biological processes, including tumorigenesis[4]. They negatively regulate protein translation by binding to the 3′UTR of target messenger RNAs (mRNAs) leading to mRNA degradation or suppression of translation. MiRNA expression correlates with biological and clinical characteristics of tumors; differentiation, aggression, tissue type and therapy response[6]. MiR cluster 143/145 consists of two miRNAs, miR-143 and miR-145, transcribed from a gene cluster on chromosome 5 It regulates multiple genes involved in cancer cell growth, including well-established cancer related hormone receptors such as ERα, and is generally regarded as a tumor suppressor[9,10,11]. The clinicopathological findings were supplied with data from functional in vitro studies
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