Abstract
Matrix metalloproteinases and their natural inhibitors (TIMPs) are important elements in a wide range of oncology settings. Elevated levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) have often been associated with increased tumorigenesis. This has been demonstrated in a number of clinical and experimental models which include breast, gastric, colorectal and non-small cell lung carcinoma (NSCLC). Our earlier studies have identified increased angiogenic activity and aggressive tumor kinetics in TIMP-1 overexpressing H2009 lung adenocarcinoma cells. TIMP-1 overexpression has also been implicated in antiapoptotic responses, inducing a significant upregulation of Bcl-2. These TIMP-1 functions have been shown to be MMP-independent and provide insight into its pleiotropic activities. The current study examines microRNA (miRNA) interactions with this molecule. We have sought to define the relationship between TIMP-1 and miRNA by knocking down TIMP-1 in high TIMP-1 expressing lung adenocarcinoma cell lines. TIMP-1 knockdown resulted in increased expression of miR-125a-5p with a concomitant increase in apoptosis and attenuation of the tumorigenic features of these cells. We have identified TIMP-1 as a bona fide target of miR-125a-5p, and their interaction resulted in an increase in p53 expression. We further corroborated our in vitro data with patient samples, which exhibited an inverse correlation between TIMP-1 and miR-125a-5p expression. Our study lends support to the notion that elevated TIMP-1 levels, which are frequently associated with poor prognosis, cause aberrant modulation of miRNAs.
Highlights
Lung cancer is clinically classified into two main histologic subtypes i.e. small cell lung cancer (SCLC) and non-small cell lung carcinoma (NSCLC)
In order to define the modulation of microRNA profiles upon altering tissue inhibitor of metalloproteinase-1 (TIMP-1) levels, we knocked down TIMP-1 expression by Short hairpin RNA (shRNA) in A549 and H460, two high TIMP-1 expressing NSCLC cell lines
It has been shown that high TIMP-1 levels in blood are associated with unfavorable prognosis and a decrease in progressionfree survival [5, 24] yet it has not been established as a viable biomarker for cancer
Summary
Lung cancer is clinically classified into two main histologic subtypes i.e. small cell lung cancer (SCLC) and non-small cell lung carcinoma (NSCLC). NSCLC accounts for 85% of lung carcinomas and has a 5-year survival rate of only 17%. This subtype includes large cell, squamous cell and adenocarcinomas which is the major subtype [1, 2]. In several cancers including non-small cell lung cancer, high serum levels of TIMP-1 have been associated with poor prognosis [5]. We have shown that overexpressing TIMP-1 in H2009, a lung adenocarcinoma cell line resulted in aggressive tumors when implanted in the mouse brain [6]. We have reported on the antiapoptotic activity of TIMP-1 in a lung adenocarcinoma, with www.impactjournals.com/oncotarget delineation of the signaling pathway downstream of TIMP1 leading to its antiapoptotic function [7]
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