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 Citations (Scopus)

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

Fingerprint

Tissue Inhibitor of Metalloproteinase-1
Down-Regulation
MicroRNAs
Matrix Metalloproteinases
Non-Small Cell Lung Carcinoma
Stomach
Carcinogenesis
Breast
Theoretical Models
Up-Regulation
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Ghoshal-Gupta, S., Kutiyanawalla, A., Lee, B. R., Ojha, J., Nurani, A., Mondal, A. K., ... Rojiani, M. V. (2018). TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway. Oncotarget, 9(10), 8941-8956. https://doi.org/10.18632/oncotarget.23832

TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway. / Ghoshal-Gupta, Sampa; Kutiyanawalla, Ammar; Lee, Byung Rho; Ojha, Juhi; Nurani, Aliya; Mondal, Ashis K.; Kolhe, Ravindra; Rojiani, Amyn M.; Rojiani, Mumtaz V.

In: Oncotarget, Vol. 9, No. 10, 01.01.2018, p. 8941-8956.

Research output: Contribution to journalArticle

Ghoshal-Gupta, S, Kutiyanawalla, A, Lee, BR, Ojha, J, Nurani, A, Mondal, AK, Kolhe, R, Rojiani, AM & Rojiani, MV 2018, 'TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway', Oncotarget, vol. 9, no. 10, pp. 8941-8956. https://doi.org/10.18632/oncotarget.23832
Ghoshal-Gupta S, Kutiyanawalla A, Lee BR, Ojha J, Nurani A, Mondal AK et al. TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway. Oncotarget. 2018 Jan 1;9(10):8941-8956. https://doi.org/10.18632/oncotarget.23832
Ghoshal-Gupta, Sampa ; Kutiyanawalla, Ammar ; Lee, Byung Rho ; Ojha, Juhi ; Nurani, Aliya ; Mondal, Ashis K. ; Kolhe, Ravindra ; Rojiani, Amyn M. ; Rojiani, Mumtaz V. / TIMP-1 downregulation modulates miR-125a-5p expression and triggers the apoptotic pathway. In: Oncotarget. 2018 ; Vol. 9, No. 10. pp. 8941-8956.
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