BRAF and RAS oncogenes regulate Rho GTPase pathways to mediate migration and invasion properties in human colon cancer cells: a comparative study

Makrodouli, Eleni; Oikonomou, Eftychia; Koc, Michal; Anděra, Ladislav; Sasazuki, Takehiko; Shirasawa, Senji; Pintzas, Alexander

doi:10.1186/1476-4598-10-118

Cited by 130 publications

(117 citation statements)

References 62 publications

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“…Loss of E-cadherin is promoted by many tumor-promoting factors, including EMT inducers, cytokines, and several tumor-promoting mutant genes, such as p53 (23) or KRAS (24). In this study, we clarified the notable mechanisms of E-cadherin suppression and CRC progression mediated by PLCδ1 down-regulation.…”

Section: Discussionmentioning

confidence: 89%

Phospholipase Cδ1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells

Satow

Hirano

Batori

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in CRC predict the ineffectiveness of EGF receptor-targeted therapy. Previous transcriptional microarray analysis suggests the association between phospholipase Cδ1 (PLCδ1) expression and KRAS mutation status in CRC. However, both the roles and the regulatory mechanisms of PLCδ1 in CRC are not known. Here, we found that the expression of PLCδ1, one of the most basal PLCs, is down-regulated in CRC specimens compared with normal colon epithelium by immunohistochemistry. Furthermore, we examined the roles of PLCδ1 in CRC cell lines that harbor an activating KRAS mutation. Ectopic expression of PLCδ1 in CRC cells induced the expression of E-cadherin, whereas knockdown of PLCδ1 repressed the expression of E-cadherin. Moreover, the overexpression of PLCδ1 suppressed the expression of several mesenchymal genes and reduced cell motility, invasiveness, and in vivo tumorigenicity of SW620 CRC cells. We also showed that PLCδ1 expression is repressed by the KRAS/mitogen-activated protein kinase kinase (MEK) pathway. Furthermore, PLCδ1 suppressed the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 through E-cadherin induction in CRC cells, suggesting the presence of a negative regulatory loop between KRAS/MEK/ERK signaling and PLCδ1. These data indicate that PLCδ1 has tumor-suppressive functions in CRC through E-cadherin induction and KRAS/MEK/ERK signal attenuation.phospholipase C delta 1 | epithelial-to-mesenchymal transition | tumor suppressor C olorectal cancer (CRC) is one of the most common cancers and causes of cancer-related deaths worldwide. Although CRC patients with unresectable tumors and metastasis have been treated with chemotherapy, recent advances in molecular research about CRC have resulted in the development of molecular targeted therapies, such as cetuximab and panitumumab. Chemotherapy combined with these targeted therapies improves the prognosis of CRC patients with unresectable tumors to some extent (1, 2). However, some CRC patients with activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are unable to benefit from such drugs, because both cetuximab and panitumumab are epidermal growth factor (EGF) receptor-targeting agents and mutant KRAS constitutively activates the downstream signaling of EGF receptor (3). A more vigorous study using KRAS-mutant CRC is needed to identify novel molecular targets for drugs that will improve the prognosis of CRC patients with unresectable tumors, especially those with KRAS mutations.Mutations in KRAS are found in about 40% of CRC patients. Constitutively active KRAS mutations lead to the hyperactivation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) [mitogen-activated protein kinase (MAPK)] signaling and/or phosphatidylinositol-3 kinase (PI3K) pathways (4). Activation of MEK/ERK (MAPK) signaling results in increased phosphorylation...

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Section: Discussionmentioning

confidence: 89%

Phospholipase Cδ1 induces E-cadherin expression and suppresses malignancy in colorectal cancer cells

Satow

Hirano

Batori

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Additionally, NFkB, which can also be regulated by PI3K (Romashkova and Makarov 1999), has been shown to be a direct target of miR-139-5p, which is capable of conferring anti-apoptotic properties on metastatic cancer cells (Buchholz et al 2005). Ras activates the canonical MAPK pathway (RAF → MEK → ERK), through which they regulate Rho GTPases, which are key players in cell migration and invasion (Vega and Ridley 2008;Makrodouli et al 2011). Interaction of PI3K with Rho GTPase members Rac1 and Cdc42 has also been shown to regulate downstream actin reorganization (Tolias et al 1995) miR-139-5p and breast cancer www.rnajournal.org 1775…”

Section: Discussionmentioning

confidence: 99%

miR-139-5p is a regulator of metastatic pathways in breast cancer

Krishnan

Steptoe

Martin

et al. 2013

RNA

138

115

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Metastasis is a complex, multistep process involved in the progression of cancer from a localized primary tissue to distant sites, often characteristic of the more aggressive forms of this disease. Despite being studied in great detail in recent years, the mechanisms that govern this process remain poorly understood. In this study, we identify a novel role for miR-139-5p in the inhibition of breast cancer progression. We highlight its clinical relevance by reviewing miR-139-5p expression across a wide variety of breast cancer subtypes using in-house generated and online data sets to show that it is most frequently lost in invasive tumors. A biotin pull-down approach was then used to identify the mRNA targets of miR-139-5p in the breast cancer cell line MCF7. Functional enrichment analysis of the pulled-down targets showed significant enrichment of genes in pathways previously implicated in breast cancer metastasis (P < 0.05). Further bioinformatic analysis revealed a predicted disruption to the TGFβ, Wnt, Rho, and MAPK/PI3K signaling cascades, implying a potential role for miR-139-5p in regulating the ability of cells to invade and migrate. To corroborate this finding, using the MDA-MB-231 breast cancer cell line, we show that overexpression of miR-139-5p results in suppression of these cellular phenotypes. Furthermore, we validate the interaction between miR-139-5p and predicted targets involved in these pathways. Collectively, these results suggest a significant functional role for miR-139-5p in breast cancer cell motility and invasion and its potential to be used as a prognostic marker for the aggressive forms of breast cancer.

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“…El oncogén KRAS se localiza en el cromosoma 12 y participa en señalización de las vías PI3K/ PTEN/AKT y RAF/MEK/ERK 7,29 . Las proteínas codificadas por estos genes constituyen una estruc-tura proteica de 21Kd (p21), la que posee actividad GTP-asa, actuando en la vía de transducción de señales de crecimiento y diferenciación celular 30 . La mutación de este gen es el evento genético más comúnmente observado en el desarrollo de tumores en el ser humano (pulmón 30%, colon 40%, páncreas 80%, tiroides 55%, etc.)…”

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