TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway

Sampa Ghoshal-Gupta, Ammar Kutiyanawalla, Byung Rho Lee, Juhi Ojha, Aliya Nurani, Ashis K. Mondal, Ravindra Kolhe, Amyn M. Rojiani, Mumtaz V. Rojiani

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)8941-8956
Number of pages16
JournalOncotarget
Volume9
Issue number10
DOIs
StatePublished - Jan 1 2018

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Keywords

  • Apoptosis
  • NSCLC
  • TIMP-1
  • miR-125a-5p

ASJC Scopus subject areas

  • Oncology

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