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

Abstract

BackgroundMLK3 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.MethodsIn 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.ResultsOur 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.ConclusionThe 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.

Review of anticancer mechanisms of isoquercitin

“…These pathways have been associated with several diseases including cancer [88,89,92] . Mutations in the MLK3 gene were first described in gastric and colorectal cancer [94] and the oncogenic effect was related to invasive induction of tumor cells. The study evaluated signaling pathways underlying the effect of MLK3 gene.…”

MLK3 silence induces cervical cancer cell apoptosis via the Notch‐1/autophagy network

“…MLK3 can activate multiple signal pathways, including the p38 MAPK, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases 1 and 2 (ERK1/2) MAPK and notch pathway. 8,19 Ample evidence has implicated Notch-1 in autophagy, 20,21 and we speculate that MLK3 may be involved in the regulation of Notch-1 in cervical cancer. In this study, we aim to determine how MLK3 regulates cervical cancer cell apoptosis through the Notch-1/autophagy network.…”

“…The microarray data shows that MLK3 plays oncogenic effects in colorectal cancer through regulating several important signalling pathways such as MAPK, WNT, TGF‐β, Notch, and p53 . It also plays a role in cell apoptosis.…”

“…The current study provides the first evidence for MLK3 dysregula- The microarray data shows that MLK3 plays oncogenic effects in colorectal cancer through regulating several important signalling pathways such as MAPK, WNT, TGF-β, Notch, and p53. 19 It also plays a role in cell apoptosis. Silencing of MLK3 significantly reduces the expression of apoptotic associated proteins such as cleaved caspase-3, cleaved PARP, Bad and Bax, as well as increasing the expression of Bcl-2 and ratio of Bcl-2/Bax in cardiomyocytes.…”

“…Gnanadhas et al found that MLK3 inhibitor could induce autophagy in monocyte‐derived macrophages. MLK3 can activate multiple signal pathways, including the p38 MAPK, c‐Jun N‐terminal kinase (JNK), extracellular signal‐regulated kinases 1 and 2 (ERK1/2) MAPK and notch pathway . Ample evidence has implicated Notch‐1 in autophagy, and we speculate that MLK3 may be involved in the regulation of Notch‐1 in cervical cancer.…”