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

Sérgia Velho, Ana Pinto, Danilo Licastro, Maria J. Oliveira, Filipa Sousa, Elia Stupka, Raquel Seruca

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number182
JournalBMC Cancer
Volume14
Issue number1
DOIs
Publication statusPublished - Mar 14 2014

Fingerprint

Cell Polarity
Mutation
Colorectal Neoplasms
Gastrointestinal Neoplasms
HEK293 Cells
Nude Mice
Transforming Growth Factor beta
Microsatellite Repeats
Genes
Phosphotransferases
Up-Regulation
Down-Regulation
Genome
Growth
Neoplasms

Keywords

  • Colorectal cancer
  • MLK3
  • MSI
  • Planar cell polarity
  • WNT pathway

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Velho, S., Pinto, A., Licastro, D., Oliveira, M. J., Sousa, F., Stupka, E., & Seruca, R. (2014). Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation. BMC Cancer, 14(1), [182]. https://doi.org/10.1186/1471-2407-14-182

Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation. / Velho, Sérgia; Pinto, Ana; Licastro, Danilo; Oliveira, Maria J.; Sousa, Filipa; Stupka, Elia; Seruca, Raquel.

In: BMC Cancer, Vol. 14, No. 1, 182, 14.03.2014.

Research output: Contribution to journalArticle

Velho, S, Pinto, A, Licastro, D, Oliveira, MJ, Sousa, F, Stupka, E & Seruca, R 2014, 'Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation', BMC Cancer, vol. 14, no. 1, 182. https://doi.org/10.1186/1471-2407-14-182
Velho, Sérgia ; Pinto, Ana ; Licastro, Danilo ; Oliveira, Maria J. ; Sousa, Filipa ; Stupka, Elia ; Seruca, Raquel. / Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation. In: BMC Cancer. 2014 ; Vol. 14, No. 1.
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