Abstract
Regulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Here we show that inhibition of miRNAs -503 and -23a, alone or in combination, enhances tumor proliferation in hepatocyte and non-hepatocyte derived cancers in vitro, driving more aggressive tumor behavior in vivo. Inhibition of miRNA-152 caused induction of DNMT1, site-specific methylation with associated changes in gene expression and in vitro and in vivo growth inhibition. Enforced changes in expression of two miRNA recapitulating changes observed in failed regeneration led to complete growth inhibition of multi-lineage cancers in vivo. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNA-based inhibitors of regeneration may constitute a novel treatment strategy for human cancers.
Highlights
Regulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer
We investigated the influence of the miRNAs -503 and -23a, which we had observed to be downregulated during human liver regeneration, on tumor behavior in vitro
Our findings indicate that key miRNA regulators of human liver regeneration can alter tumor behavior in liver and non-liver derived cancer cell lines
Summary
Regulated cell proliferation is an effector mechanism of regeneration, whilst dysregulated cell proliferation is a feature of cancer. We have previously identified microRNA (miRNA) that regulate successful and failed human liver regeneration. We hypothesized that these regulators may directly modify tumor behavior. Our results indicate that regulation of regeneration and tumor aggressiveness are concordant and that miRNAbased inhibitors of regeneration may constitute a novel treatment strategy for human cancers. In agreement with data from animal models, our results indicated that downregulation of a network of key miRNAs is important in determining regenerative outcome[7,8,9] We hypothesised that this network of regeneration-linked miRNA may influence tumor biology and behaviour. Our data underscore the link between regulation of regeneration and tumorigenesis They indicate a potential novel cancer treatment paradigm using inhibitors of regeneration
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
