Z Gastroenterol 2012; 50 - P5_01
DOI: 10.1055/s-0031-1295957

Identification of miRNA–34a, miRNA–145 and miRNA–149 as TAp73 and DNp73 targets in hepatocellular carcinoma

M Balachandran 1, M Bender 1, R Pschowski 1, N Joschko 1, A Lovas 1, W Stremmel 2, M Müller 1
  • 1Department of Internal Medicine IV, Hepatology and Gastroenterology, University Hospital Heidelberg, Germany, Heidelberg
  • 2Innere Medizin IV, Gastroenterologie, Hepatologie, Infektionskrankheiten und Vergiftungen, Universitätsklinikum Heidelberg, Heidelberg

MicroRNAs (miRNAs) are small endogenous noncoding RNAs that were shown to be essential posttranscriptional regulators of gene expression. MiRNAs most notably members of the miR–34 family, have been shown to be subject to transcriptional regulation by wild-type p53. We have established a relevant role for the p53 family in the induction of apoptosis, therapeutic response and prognosis of hepatocellular carcinoma (HCC). TAp73–like wild-type p53- is a mediator of apoptosis. The dominant negative isoform of p73 (DNp73)–on the contrary–is antiapoptotic and enhanced expression of DNp73 correlates with reduced survival of HCC patients.

The aim of this study was to determine whether TAp73 and DNp73–like wild-type p53–can regulate miRNAs and to identify miRNA clusters relevant for treatment response of HCC.

Adenoviral transduction of Hep3B cells (p53-/-) with p53 led to an increase in the expression of miR–34a, miR–192, miR–194, miR–215 and miR–145. Importantly, we identified miR–34a, miR–145 and miR–149 as novel targets of TAp73 and DNp73 in Hep3B cells. Of clinical relevance, chemotherapeutic drugs known to exert their action via a DNA damage response (DDR) mediated by p53 and TAp73 led to increased expression levels of miR–34a, miR–145 and miR–149 in Hep3B as well as in HepG2 cells. Blocking p53 family function using siRNA in HepG2 cells prevented the increase in expression of miR–34, miR–145, and miR–149 and conferred protection against chemotherapy-induced apoptosis.

Our data show that not only wild-type p53 but also TAp73 can increase the expression of miR–34a, miR–145 and miR–149 in HCC.We showed for the first time that DNp73 down-regulates miRNAs which were induced by wild-type p53 and TAp73. Of clinical importance, our data show that upregulation of miRNAs by wild-type p53 and TAp73 and downregulation of miRNAs by DNp73 on the other hand are involved in the DDR following chemotherapeutic treatment and determine treatment sensitivity of HCC.