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DOI: 10.1055/s-0030-1269523
MicroRNAs are key players of the p53 pathway in hepatocellular carcinoma
Introduction: MicroRNAs (miR) are noncoding regulatory RNA molecules which play a role as tumor suppressors or oncogenes in nearly all types of cancer. It has been shown that microRNAs, most notably members of the miR-34 family underlie transcriptional regulation by p53. Of clinical importance a loss of miR-34a has been linked to resistance against apoptosis induced by p53-activating chemotherapeutic agents.We have previously shown a role of p53 and its family members p63 and p73 in the induction of apoptosis, chemosensitivity and treatment response of hepatocellular carcinoma (HCC). Here we investigated the regulation of microRNAs by wild-type (wt) p53 to identify microRNA clusters essential for therapeutic response of HCC. Methods: Hep3B cells (p53-/-) were analyzed following adenoviral transfer of wt p53 or GFP as a control. Total RNA was isolated and expression levels of different microRNAs were detected using microRNA microarrays, qRT-PCR and northern blot analysis. Functional relevance of the p53-regulated microRNAs was investigated using anti-miR-oligonucleotides. Results: Adenoviral transfer of wt p53 in Hep3B cells resulted in the induction of apoptosis. Consequently, wt p53 can itself directly induce expression of a variety of microRNAs. Two of these microRNAs are members of the miR-34 family, miR-34a and –b. By contrast, wt p53 did not regulate miR-34c in Hep3B cells. Furthermore, we detected a wt p53-mediated increase in the expression of the microRNA cluster 192/194 as well as an upregulation of the expression of miR-215 and miR-145. Conclusion: Our results demonstrate that wt p53 induces the expression of miR-34a, miR-34b, miR-192, miR-194, miR-215 and miR-145 in Hep3B cells. This is the first identification of p53-regulated microRNAs in Hep3B cells. These data indicate that wt p53-mediated upregulation of these microRNAs may have an important function in the induction of apoptosis and treatment sensitivity of HCC.
hepatocellular carcinoma - microRNA - p53