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Src controls tumorigenesis via JNK-dependent regulation of the Hippo pathway in Drosophila.

ABSTRACT: Cell-cell interactions within the tumour microenvironment have crucial roles in epithelial tumorigenesis. Using Drosophila genetics, we show that the oncoprotein Src controls tumour microenvironment by Jun N-terminal kinase (JNK)-dependent regulation of the Hippo pathway. Clones of cells with elevated Src expression activate the Rac-Diaphanous and Ras-mitogen-activated protein kinase (MAPK) pathways, which cooperatively induce F-actin accumulation, thereby leading to activation of the Hippo pathway effector Yorkie (Yki). Simultaneously, Src activates the JNK pathway, which antagonizes the autonomous Yki activity and causes propagation of Yki activity to neighbouring cells, resulting in the overgrowth of surrounding tissue. Our data provide a mechanism to explain how oncogenic mutations regulate tumour microenvironment through cell-cell communication.

SUBMITTER: Enomoto M

PROVIDER: S-EPMC3537139 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Src controls tumorigenesis via JNK-dependent regulation of the Hippo pathway in Drosophila.

Enomoto Masato M Igaki Tatsushi T

EMBO reports 20121130 1

Cell-cell interactions within the tumour microenvironment have crucial roles in epithelial tumorigenesis. Using Drosophila genetics, we show that the oncoprotein Src controls tumour microenvironment by Jun N-terminal kinase (JNK)-dependent regulation of the Hippo pathway. Clones of cells with elevated Src expression activate the Rac-Diaphanous and Ras-mitogen-activated protein kinase (MAPK) pathways, which cooperatively induce F-actin accumulation, thereby leading to activation of the Hippo path ...[more]

PMID: 23196366

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Project description:BackgroundBMP3 gene is often found hypermethylated and hence inactivated in several types of cancers including colorectal cancer (CRC), indicating that it has a suppressor role in carcinogenesis. Though BMP3 is a reliable biomarker for screening CRC, the molecular mechanism of BMP3 in carcinogenesis remains largely unknown.MethodsThe expression level of BMP3 was examined by immunohistochemistry staining and western blot. Methylation-specific PCR (MSP) and real-time quantitative MSP were used to test the hypermethylation status of BMP3 gene. Analyses of BMP3 function in colon cancer cell proliferation, migration, invasion, and apoptosis were performed using HCT116 and KM12 cells. BMP3 was further knocked down or overexpressed in CRC cells, and the effects on cell growth of xenograft tumors in nude mice were assessed. Co-immunoprecipitation and immunofluorescence staining were used to analyze the association between BMP3 and BMPR2 or BMP3 and ActRIIB. Microarray analysis was performed to identify most differentially expressed genes and pathways regulated by BMP3. The BMP3-regulated SMAD2-dependent signaling pathway and TAK1/JNK signal axes were further investigated by quantitative PCR and western blot.ResultsBMP3 gene was hypermethylated and its expression was downregulated in both CRC tissues and cell lines. Expressing exogenous BMP3 in HCT116 inhibited cell growth, migration, and invasion and increased rate of apoptosis both in vitro and in vivo. However, shRNA-mediated attenuation of endogenous BMP3 in KM12 reversed such inhibitory and apoptotic effects. Furthermore, BMP3 could bind to ActRIIB, an activin type II receptor at the cellular membrane, thereby activating SMAD2-dependent pathway and TAK1/JNK signal axes to regulate downstream targets including caspase-7, p21, and SMAD4 that play crucial roles in cell cycle control and apoptosis.ConclusionsOur study reveals a previously unknown mechanism of BMP3 tumor suppression in CRC and provides a rationale for future investigation of BMP3 as a potential target for the development of novel therapeutic agents to fight CRC.

Dataset Information

Src controls tumorigenesis via JNK-dependent regulation of the Hippo pathway in Drosophila.

Publications

Src controls tumorigenesis via JNK-dependent regulation of the Hippo pathway in Drosophila.

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