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Open Access Research article

Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation

Sérgia Velho1, Ana Pinto12, Danilo Licastro3, Maria José Oliveira2, Filipa Sousa1, Elia Stupka4 and Raquel Seruca15*

Author Affiliations

1 Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Rua Dr. Roberto Frias, 4200-465 Porto,Portugal

2 New Therapies Group, INEB-Institute for Biomedical Engineering, Porto, Portugal

3 CBM S.c.r.l. AREA SCIENCE PARK, Trieste, Italy

4 Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy

5 Medical Faculty of the University of Porto, Porto, Portugal

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BMC Cancer 2014, 14:182  doi:10.1186/1471-2407-14-182

Published: 14 March 2014

Abstract

Background

MLK3 gene mutations were described to occur in about 20% of microsatellite unstable gastrointestinal cancers and to harbor oncogenic activity. In particular, mutation P252H, located in the kinase domain, was found to have a strong transforming potential, and to promote the growth of highly invasive tumors when subcutaneously injected in nude mice. Nevertheless, the molecular mechanism underlying the oncogenic activity of P252H mutant remained elusive.

Methods

In this work, we performed Illumina Whole Genome arrays on three biological replicas of human HEK293 cells stably transfected with the wild-type MLK3, the P252H mutation and with the empty vector (Mock) in order to identify the putative signaling pathways associated with P252H mutation.

Results

Our microarray results showed that mutant MLK3 deregulates several important colorectal cancer- associated signaling pathways such as WNT, MAPK, NOTCH, TGF-beta and p53, helping to narrow down the number of potential MLK3 targets responsible for its oncogenic effects. A more detailed analysis of the alterations affecting the WNT signaling pathway revealed a down-regulation of molecules involved in the canonical pathway, such as DVL2, LEF1, CCND1 and c-Myc, and an up-regulation of DKK, a well-known negative regulator of canonical WNT signaling, in MLK3 mutant cells. Additionally, FZD6 and FZD10 genes, known to act as negative regulators of the canonical WNT signaling cascade and as positive regulators of the planar cell polarity (PCP) pathway, a non-canonic WNT pathway, were found to be up-regulated in P252H cells.

Conclusion

The results provide an overall view of the expression profile associated with mutant MLK3, and they support the functional role of mutant MLK3 by showing a deregulation of several signaling pathways known to play important roles in the development and progression of colorectal cancer. The results also suggest that mutant MLK3 may be a novel modulator of WNT signaling, and pinpoint the activation of PCP pathway as a possible mechanism underlying the invasive potential of MLK3 mutant cells.

Keywords:
Colorectal cancer; MLK3; WNT pathway; MSI; Planar cell polarity