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Wild type N-ras displays anti-malignant properties, in part by downregulating decorin

ABSTRACT: Previously, we have demonstrated that wild type N-ras (wt N-ras) harbors an anti-malignant effect against mutated Ras and in tumors without Ras mutations. To investigate the molecular bases of this anti-malignant activity, we have studied the potency of this anti-malignant effect in a model system against SV40 T. We show that wild-type N-ras (wt N-ras) counteracts the effects of SV40T in NIH3T3 cells as seen by a decrease in proliferation, anchorage independence and changes in migration). We also show that wt N-ras also elicits the same anti-malignant effects in some human tumor cell lines (HT1080 and MDA-MB-231). Through mRNA and microRNA (miRNAs) expression profiling we have identified genes and miRNAs modulated by wt N-ras potentially responsible for the anti-malignant effect. wt N-ras appears to mediate its anti-malignant effect by downregulating some of the targets of the TGFb pathway and decorin, which are able to reverse the inhibition of migration induced by wt N-ras. Our experiments show that the molecules that mediate the anti-malignant effect appear to be different than those modulated by transforming N-ras. The components of the pathways modulated by wt N-ras mediating its anti-malignant effects are potential targets for therapeutic intervention in cancer. We report that the N-ras proto-oncogene has anti-malignant effects and that it does so by modulating different genes than its oncogenic counterpart, which indicates that it should be activating different pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE28678 | GEO | 2011/04/19

SECONDARY ACCESSION(S): PRJNA138933

REPOSITORIES: GEO

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Project description:The association of doublet chemotherapy (FOLFOX and FOLFIRI) and anti-EGFR-moAbs (panitumumab or cetuximab) is a standard option for the first-line treatment of unresectable RAS and BRAF wt mCRC patients, especially with left-sided primary tumour. In RAS wt mCRC patients refractory to chemotherapy and anti-EGFR naive, the standard treatment sequence is an anti-EGFR-based therapy (panitumumab or cetuximab +/- irinotecan) followed by regorafenib. In a phase II randomized Japanese study named REVERCE, a higher OS was reported in favour of an experimental strategy of regorafenib followed at progression by cetuximab +/- irinotecan compared with the reverse standard sequence in chemorefractory and anti-EGFR-naïve, RAS wt mCRC patients. However, the limitations of the REVERCE study (phase II trial with a premature conclusion for poor accrual) do not allow us to draw definitive conclusions. In addition, nowadays, patients candidates to an anti-EGFR-based treatment, receive anti-EGFRMoAbs in earlier lines of therapy thus affecting the translation of these results in the current clinical practice. Retrospective analyses and a phase II single-arm trial showed promising activity of anti-EGFR rechallenge in patients who previously achieved benefit from a first-line anti- EGFR-based treatment and not bearing RAS mutation on ct-DNA at the rechallenge baseline. Based on these considerations, the Investigators designed the present phase II randomized study of panitumumab followed at progression by regorafenib versus the reverse sequence in RAS and BRAF wt mCRC patients with the following characteristics: 1. previous treatment with, or not considered candidates for, fluoropyrimidine, oxaliplatin, irinotecan and an anti-angiogenic agent (bevacizumab or aflibercept); 2. RECIST response or stable disease lasting at least 6 months to a previous first-line anti-EGFR-based treatment; 3. RAS and BRAF wt ct-DNA at the time of screening. The aim of this study is to compare the two sequences in a Caucasian population of patients candidates to anti-EGFR rechallenge.

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Wild type N-ras displays anti-malignant properties, in part by downregulating decorin

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