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PPAR?/? promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.

ABSTRACT: Peroxisome proliferator-activated receptor-?/? (PPAR?/?) inhibits skin tumorigenesis through mechanisms that may be dependent on HRAS signaling. The present study examined the hypothesis that PPAR?/? promotes HRAS-induced senescence resulting in suppression of tumorigenesis. PPAR?/? expression increased p-ERK and decreased p-AKT activity. Increased p-ERK activity results from the dampened HRAS-induced negative feedback response mediated in part through transcriptional upregulation of RAS guanyl-releasing protein 1 (RASGRP1) by PPAR?/?. Decreased p-AKT activity results from repression of integrin-linked kinase (ILK) and phosphoinositide-dependent protein kinase-1 (PDPK1) expression. Decreased p-AKT activity in turn promotes cellular senescence through upregulation of p53 and p27 expression. Both over-expression of RASGRP1 and shRNA-mediated knockdown of ILK partially restore cellular senescence in Ppar?/?-null cells. Higher PPAR?/? expression is also correlated with increased senescence observed in human benign neurofibromas and colon adenoma lesions in vivo. These results demonstrate that PPAR?/? promotes senescence to inhibit tumorigenesis and provide new mechanistic insights into HRAS-induced cellular senescence.

SUBMITTER: Zhu B

PROVIDER: S-EPMC4017002 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.

Zhu B B Ferry C H CH Blazanin N N Bility M T MT Khozoie C C Kang B-H BH Glick A B AB Gonzalez F J FJ Peters J M JM

Oncogene 20131111 46

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits skin tumorigenesis through mechanisms that may be dependent on HRAS signaling. The present study examined the hypothesis that PPARβ/δ promotes HRAS-induced senescence resulting in suppression of tumorigenesis. PPARβ/δ expression increased p-ERK and decreased p-AKT activity. Increased p-ERK activity results from the dampened HRAS-induced negative feedback response mediated in part through transcriptional upregulation of RAS guanyl- ...[more]

PMID: 24213576

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Project description:BackgroundAccumulating evidence confirm that aberrant microRNAs (miRNAs) expression contributes to hepatocellular carcinoma (HCC) development and progression. Previous study reported that miR-1468 showed an up-regulated tendency and might be a potential prognostic biomarker in HCC samples derived from TCGA database. However, the role of miR-1468 and its underlying mechanisms involved in the growth and metastasis of HCC remain poorly investigated.MethodsCCK-8, EdU, colony formation and flow cytometry were used to determine proliferation, cell cycle progression and apoptosis of HCC cells in vitro. The subcutaneous tumor model in nude mice was established to detect tumor growth of HCC in vivo. The direct binding of miR-1468 to 3'UTR of Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (CITED2) and Up-frameshift protein 1 (UPF1) was confirmed by luciferase reporter assay.ResultsHere, we demonstrated that miR-1468 expression was up-regulated in HCC tissues and cell lines. Clinical analysis revealed that increased miR-1468 level was significantly correlated with malignant prognostic features and shorter survival. Gain- and loss-of-function experiments indicated that miR-1468 promoted cell proliferation, colony formation, cell cycle progression and induced apoptosis of HCC cells in vitro and in vivo. Moreover, CITED2 and UPF1 were identified as direct downstream targets of miR-1468 in HCC cells, and mediated the functional effects of miR-1468 in HCC, resulting in peroxisome proliferator-activated receptor-γ (PPAR-γ)/AKT signaling activation. In clinical samples of HCC, miR-1468 inversely correlated with the levels of CITED2 and UPF1, which were confirmed to be down-regulated in HCC. Restoration of CITED2 or UPF1 expression at least partially abolished the biological effects of miR-1468 on HCC cells. Moreover, alteration of PPAR-γ or AKT phosphorylation could reverse the function of miR-1468 in HCC.ConclusionsTaken together, this research supports the first evidence that miR-1468 plays an oncogenic role in HCC via activating PPAR-γ/AKT pathway by targeting CITED2 and UPF1, and represents a promising therapeutic strategy for HCC patients.

Dataset Information

PPAR?/? promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.

Publications

PPARβ/δ promotes HRAS-induced senescence and tumor suppression by potentiating p-ERK and repressing p-AKT signaling.

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