Specific alterations of the microRNA transcriptome and global network structure in colorectal cancer after treatment with MAPK/ERK inhibitors

Marco Ragusa, Luisa Statello, Marco Maugeri, Alessandra Majorana, Davide Barbagallo, Loredana Salito, Mariangela Sammito, Manuela Santonocito, Rosario Angelica, Andrea Cavallaro, Marina Scalia, Rosario Caltabiano, Giuseppe Privitera, Antonio Biondi, Maria Di Vita, Alessandro Cappellani, Enrico Vasquez, Salvatore Lanzafame, Elisabetta Tendi, Salvatore CelesteCinzia Di Pietro, Francesco Basile, Michele Purrello

Research output: Contribution to journalArticle

Abstract

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway has a master control role in various cancer-related biological processes as cell growth, proliferation, differentiation, migration, and apoptosis. It also regulates many transcription factors that control microRNAs (miRNAs) and their biosynthetic machinery. To investigate on the still poorly characterised global involvement of miRNAs within the pathway, we profiled the expression of 745 miRNAs in three colorectal cancer (CRC) cell lines after blocking the pathway with three different inhibitors. This allowed the identification of two classes of post-treatment differentially expressed (DE) miRNAs: (1) common DE miRNAs in all CRC lines after treatment with a specific inhibitor (class A); (2) DE miRNAs in a single CRC line after treatment with all three inhibitors (class B). By determining the molecular targets, biological roles, network position of chosen miRNAs from class A (miR-372, miR-663b, miR-1226*) and class B (miR-92a-1*, miR-135b*, miR-720), we experimentally demonstrated that they are involved in cell proliferation, migration, apoptosis, and globally affect the regulation circuits centred on MAPK/ERK signaling. Interestingly, the levels of miR-92a-1*, miR-135b*, miR-372, miR-720 are significantly higher in biopsies from CRC patients than in normal controls; they also are significantly higher in CRC patients with mutated KRAS than in those with wild-type genotypes (Wilcoxon test, p <0.05): the latter could be a downstream effect of ERK pathway overactivation, triggered by KRAS mutations. Finally, our functional data strongly suggest the following miRNA/target pairs: miR-92a-1*/PTEN-SOCS5; miR-135b*/LATS2; miR-372/TXNIP; miR-663b/CCND2. Altogether, these results contribute to deepen current knowledge on still uncharacterized features of MAPK/ERK pathway, pinpointing new oncomiRs in CRC and allowing their translation into clinical practice and CRC therapy.

Original languageEnglish
Pages (from-to)1421-1438
Number of pages18
JournalJournal of Molecular Medicine
Volume90
Issue number12
DOIs
Publication statusPublished - Dec 2012

Keywords

  • Cellular networks
  • Colorectal cancer
  • ERK/MAPK pathway
  • miRNA profile
  • miRNA protein targets

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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  • Cite this

    Ragusa, M., Statello, L., Maugeri, M., Majorana, A., Barbagallo, D., Salito, L., Sammito, M., Santonocito, M., Angelica, R., Cavallaro, A., Scalia, M., Caltabiano, R., Privitera, G., Biondi, A., Di Vita, M., Cappellani, A., Vasquez, E., Lanzafame, S., Tendi, E., ... Purrello, M. (2012). Specific alterations of the microRNA transcriptome and global network structure in colorectal cancer after treatment with MAPK/ERK inhibitors. Journal of Molecular Medicine, 90(12), 1421-1438. https://doi.org/10.1007/s00109-012-0918-8