Journal Article Epublish 6 citations
PubMed: 33803354 DOI: 10.3390/cancers13051183
Combined De-Repression of Chemoresistance Associated Mitogen-Activated Protein Kinase 14 and Activating Transcription Factor 2 by Loss of microRNA-622 in Hepatocellular Carcinoma.
Cancers (Basel) 13(5)
Authors: Valerie Fritz, Lara Malek, Anne Gaza, Laura Wormser, Majken Appel, Andreas E Kremer, Wolfgang E Thasler, Jürgen Siebler, Markus F Neurath, Claus Hellerbrand, Anja K Bosserhoff, Peter Dietrich
Affiliations
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany.
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany.
- Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany. Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany. Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, 91054 Erlangen, Germany.
- Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, 91054 Erlangen, Germany.
- Department of General and Visceral Surgery, Red Cross Hospital of Munich, 80634 Munich, Germany.
- Comprehensive Cancer Center (CCC) Erlangen-EMN, 91054 Erlangen, Germany.
Abstract
Chemoresistance is a major hallmark driving the progression and poor prognosis of hepatocellular carcinoma (HCC). Limited chemoresponse of HCC was demonstrated to be mediated by mitogen-activated protein kinase 14 (MAPK14) and activating transcription factor 2 (ATF2). Recently, we have demonstrated loss of control of RAS-RAF-ERK-signaling as a consequence of miR-622 downregulation in HCC. However, the majority of target genes of this potent tumorsuppressive microRNA had remained elusive. The MAPK14-ATF2-axis represents a collateral pathway ensuring persisting ERK-activation in the presence of sorafenib-mediated RAF-inhibition. In contrast to the function of the MAPK14-ATF2-axis, both the expression and regulation of MAPK14 and ATF2 in human HCC remained to be clarified. We found combined overexpression of MAPK14 and ATF2 in human HCC cells, tissues and in sorafenib resistant cell lines. High expression of MAPK14 and ATF2 was associated with reduced overall survival in HCC patients. Deciphering the molecular mechanism promoting combined upregulation of MAPK14 and ATF2 in HCC, we revealed that miR-622 directly targets both genes, resulting in combined de-repression of the MAPK14-ATF2-axis. Together, miR-622 represents a superior regulator of both RAS-RAF-ERK as well as MAPK14-ATF2-signaling pathways in liver cancer.
MeSH
Cells, Genes, Mitogens, Carcinoma, Hepatocellular, Protein Kinases, Activating Transcription Factor 2, Micrornas, Transcription Factors, Mitogen-Activated Protein Kinases, Sorafenib, Repression, Psychology, Liver Neoplasms, Mitogen-Activated Protein Kinase 14
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