Dataset Information

MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway.

ABSTRACT: Tumor growth cascade is a complicated and multistep process with numerous obstacles. Until recently, evidences have shown the involvement of microRNAs (miRNAs) in tumorigenesis and tumor progression of various cancers, including colorectal cancer (CRC). In this study, we explored the role of miR-194 and its downstream pathway in CRC. We acquired data through miRNA microarray profiles, showing that the expression of miR-194 was significantly suppressed in CRC tissues compared with corresponding noncancerous tissues. Decreased miR-194 expression was obviously associated with tumor size and tumor differentiation, as well as TNM stage. Both Kaplan-Meier and multivariate survival analysis showed that downregulated miR-194 was associated with overall survival. Moreover, functional assays indicated that overexpression of miR-194 in CRC cell lines inhibited cell proliferation both in vitro and in vivo. In addition, using dual-luciferase reporter gene assay, we found MAP4K4 was the direct target of miR-194. Silencing of MAP4K4 resulted in similar biological behavior changes to that of overexpression of miR-194. We also observed through Human Gene Expression Array that MDM2 was one of the downstream targets of MAP4K4. Knockdown of MAP4K4 downregulated MDM2 expression through transcription factor c-Jun binding to the -1063 to -1057 bp of the promoter. These results suggest that miR-194, regulating the MAP4K4/c-Jun/MDM2 signaling pathway, might act as a tumor suppressor and serve as a novel target for CRC prevention and therapy.

SUBMITTER: Wang B

PROVIDER: S-EPMC4615039 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway.

Wang Bo B Shen Zhan-long ZL Gao Zhi-dong ZD Zhao Gang G Wang Chun-you CY Yang Yang Y Zhang Ji-zhun JZ Yan Yi-chao YC Shen Chao C Jiang Ke-wei KW Ye Ying-jiang YJ Wang Shan S

Cell cycle (Georgetown, Tex.) 20150101 7

Tumor growth cascade is a complicated and multistep process with numerous obstacles. Until recently, evidences have shown the involvement of microRNAs (miRNAs) in tumorigenesis and tumor progression of various cancers, including colorectal cancer (CRC). In this study, we explored the role of miR-194 and its downstream pathway in CRC. We acquired data through miRNA microarray profiles, showing that the expression of miR-194 was significantly suppressed in CRC tissues compared with corresponding n ...[more]

PMID: 25602366

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Project description:BackgroundThe aberrant expression of microRNAs (miRNAs) has emerged as important hallmarks of cancer. However, the molecular mechanisms underlying the differences of miRNA expression remain unclear. Many studies have reported that miR-98-5p plays vital functions in the development and progression of multiple cancers. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unknown.MethodsThe expression of miR-98-5p and its specific target gene were determined in human PDAC specimens and cell lines by miRNA qRT-PCR, qRT-PCR and western blot. The effects of miR-98-5p depletion or ectopic expression on PDAC proliferation, migration and invasion were evaluated in vitro using CCK-8 proliferation assays, colony formation assays, wound healing assays and transwell assays. Furthermore, the in vivo effects were investigated using the mouse subcutaneous xenotransplantation and pancreatic tail xenotransplantation models. Luciferase reporter assays were employed to identify interactions between miR-98-5p and its specific target gene.ResultsMiR-98-5p expression was significantly lower in cancerous tissues and associated with tumor size, TNM stage, lymph node metastasis and survival. Notably, a series of gain- and loss-of-function assays elucidated that miR-98-5p suppressed PDAC cell proliferation, migration and invasion both in vitro and in vivo. Luciferase reporter assays, western blot and qRT-PCR revealed MAP4K4 to be a direct target of miR-98-5p. The effects of ectopic miR-98-5p were rescued by MAP4K4 overexpression. In contrast, the effects of miR-98-5p depletion were impaired by MAP4K4 knockdown. Furthermore, miR-98-5p suppressed the MAPK/ERK signaling pathway through downregulation of MAP4K4. In addition, the expression level of miR-98-5p was negatively correlated with MAP4K4 expression in PDAC tissues and cell lines.ConclusionsThese results suggest that downregulation of miR-98-5p promotes tumor development by downregulation of MAP4K4 and inhibition of the downstream MAPK/ERK signaling, thus, highlighting the potential of miR-98-5p as a therapeutic target for PDAC.

Project description:BackgroundRenal cell carcinoma (RCC) is characterized by a high rate of distant metastasis, which leads to poor prognosis in patients with advanced RCC. PUS10 has been recognized as a member of the pseudouridine synthase family, and recently other functions beyond the synthesis of the RNA modification have been uncovered. However, little is known about its role in diseases such as cancer.MethodsRT-qPCR, western blot and immunohistochemistry were used to measure the expression of PUS10 in RCC tissues. Transwell assay, wound healing assay, and in vivo metastasis model were conducted to determine the function of PUS10 in RCC progression. MicroRNA sequencing and GEO database were used to screen for the downstream microRNAs of PUS10. RNA immunoprecipitation, dual luciferase reporter assay, immunostaining, and rescue experiments were employed to establish the PUS10/miR-194-5p/nuclear distribution protein C(NUDC)/Cofilin1 axis in RCC migration. Chromatin immunoprecipitation and dual luciferase reporter assay were used to verify its upstream transcriptional regulator.ResultsThe expression of PUS10 was significantly decreased in RCC tissues, and low expression predicted poor prognosis. In vitro and in vivo experiments showed that PUS10 suppressed RCC migration, which, however, was independent of its classical pseudouridine catalytic function. Mechanically, PUS10 promoted the maturation of miR-194-5p, which sequentially inhibited RCC migration via disrupting NUDC-dependent cytoskeleton. Furthermore, hypoxia and HIF-1 A were found involved in the downregulation of PUS10.ConclusionWe unraveled PUS10 restrained RCC migration via the PUS10/miR-194-5p/NUDC/Cofilin1 pathway, which independent of its classical catalytic function. Furthermore, a linkage between the critical tumor microenvironment hallmark with malfunction of the forementioned metastasis inhibition mechanism was presented, as demonstrated by repressed expression of PUS10 due to hypoxia and HIF-1A.

Dataset Information

MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway.

Publications

MiR-194, commonly repressed in colorectal cancer, suppresses tumor growth by regulating the MAP4K4/c-Jun/MDM2 signaling pathway.

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