MicroRNA‐203 regulates cell junction and adhesion proteins by modulating Zeb1/Vimentin axis in breast cancer cells after PARP1 inhibition.

Abstract

PARP inhibitors are currently in trend to treat various type of cancers and they have shown promising results in homologous recombination deficient breast and ovarian cancers like those bearing BRCA1/2 mutations. There are many reports describing about the failure of PARP inhibitors due to resistance or unknown factors in clinical trials. It is crucial to look into in‐depth molecular mechanisms behind the role of PARP in cancer pathogenesis and long term effect of PARP inhibition. MicroRNAs (miRNAs) are small non‐coding RNAs, acting as post‐transcriptional regulators of gene expression and known to regulate variety of cellular processes, including the DNA damage response and regulation of cell junction and adhesion proteins. However, little is known about miRNAs mediated regulation of sensitivity to PARP inhibitors and its pathological significance in context to regulation of cell junction and adhesion proteins. Aberrant miRNA regulation of junction proteins is one of the leading causes of cancer pathogenesis. Keeping these views in consideration, we aimed to identify novel miRNAs involved in the regulation of cell junction and adhesion proteins in breast cancer malignancy after PARP inhibition. To investigate this, we performed miRNA microarray analysis of PARP inhibitor treated MDA‐MB‐231 cells and found upregulation of tumor suppressor miR‐203 after PARP inhibition. PARP1 inhibition led to reduced expression of vimentin and Zeb1 while ZO‐1, E‐cadherin and RhoGDI were upregulated in breast cancer cells. To confirm the whether PARP inhibitory effects were mediated by miR‐203, cells were transfected with miR‐203 mimic and anti‐miR. We observed that miR‐203 mimic resulted in inhibition of junction proteins Zeb1 and vimentin, coinciding with PARP inhibition. We also found that PARP inhibition caused reduced cell growth and proliferation of breast cancer cells which correlated with the overexpression of miR‐203. Our findings indicates that upregulation of miR‐203 due to PARP inhibition is involved in regulating cell junction proteins vimentin and zeb1 as well as cytosketelal RhoGTPase and thus regulating cell migration, invasion and proliferation. Taken together, these observations raise the possibility that these miRNAs could be used as biomarkers to identify patients that may benefit from treatment with PARP inhibitors.Support or Funding InformationJR acknowledge the support from Department of Biotechnology (DBT) for DBT Bio‐CARe fellowship. NS acknowledges the support by the senior research fellowship from the Indian Council of Medical Research (ICMR). This work was supported by the grants from Department of Biotechnology (GAP0187) to DP Mishra.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.