Poster Presentation 50 Years Shine-Dalgarno Symposium 2023

MicroRNA-142-3p targets YES1 and TWF1 in human hepatocellular carcinoma to inhibit proliferation, migration and invasion, and to restore lenvatinib sensitivity (#155)

Khadijeh Mahboobnia 1 2 , Dianne J Beveridge 1 2 , Ji Kevin Li 1 , George C.T. Yeoh 1 3 , Tasnuva Kabir 1 2 , Peter J Leedman 1 2
  1. Harry Perkins Institute of Medical Research, QEII Medical Centre, 6 Verdun St, Nedlands 6009, Perth, Western Australia, Australia
  2. Centre for Medical Research, the University of Western Australia, Crawley 6009, Perth, Western Australia, Australia
  3. School of Molecular Sciences, the University of Western Australia, Crawley 6009, Perth, Western Australia, Australia

Background:

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer with poor long-term patient survival. Patients invariably develop resistance to current targeted therapies which include tyrosine kinase inhibitors (TKIs) (e.g., lenvatinib and sorafenib) and relapse. New therapeutics are urgently needed. In this study, we characterized “miR-142-3p”, a tumour suppressor microRNA (miRNA) as a novel anti-cancer agent for drug-resistant HCC.   

 

Methodology and results:

Using bioinformatics we analyzed clinical data, including gene and miRNA expression profiles of sorafenib-treated HCC patients from the BIOSTORM cohort of a phase III trial. “Sorafenib responder” patients expressed higher levels of miR-142-3p and correspondingly lower levels of its mRNA targets e.g., YES1 and TWF1. Lenvatinib-resistant HCC cell lines, including acquired (Huh-7/LR) and de novo (SNU475) lines were used to functionally validate the clinical data. miR-142-3p overexpression reduced the expression of YES1 and TWF1 mRNA in these cells, and lead to a reduction in proliferation, migration, and invasion. miR-142-3p exerted its growth inhibitory effect on these cells, in part, via the induction of apoptosis and ferroptosis; and on invasion via a reduced expression of the epithelial to mesenchymal associated genes N-cadherin, Vimentin, Slug, and Snail. Furthermore, siRNA-mediated knockdown of YES1 and TWF1 in Huh-7/LR and SNU475 cells recapitulated the anti-cancer effects of miR-142-3p. Finally, low doses of miR-142-3p could reverse the sensitivity of these cells to lenvatinib, thereby overcoming drug resistance.

 

Conclusions: We identified a novel miRNA-based anticancer agent “miR‑142‑3p” to treat drug-resistant HCC, and miR-142-3p was able to restore tumour sensitivity to lenvatinib in HCC cells. Therefore, the therapeutic development of miR-142-3p for HCC as a single agent or in combination may benefit HCC patients.