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RARRES2 functions as a tumor suppressor by promoting ?-catenin phosphorylation/degradation and inhibiting p38 phosphorylation in adrenocortical carcinoma.

ABSTRACT: Tumor suppressor genes and the immune system are critical players in inhibiting cancer initiation and/or progression. However, little is known about whether a tumor suppressor gene can function through both immune-dependent and -independent mechanisms. Retinoic acid receptor responder 2 (RARRES2) is transcriptionally downregulated in multiple cancer types. Previous studies suggested that it can serve as an immune-dependent tumor suppressor by acting as a chemoattractant to recruit anticancer immune cells expressing its receptor, the chemerin chemokine receptor 1 (CMKLR1), to sites of tumor. In this study, we investigated the role of RARRES2 in adrenocortical carcinoma (ACC), a rare lethal malignancy in which aberrant Wnt/?-catenin signaling is frequently detected. We show that RARRES2 expression is downregulated in ACC as compared with normal and benign adrenocortical tissues, which is a result of CpG hypermethylation. Despite minimal CMKLR1 expression and lack of phenotypic tumor-suppressive effect with exogenous RARRES2 treatment, RARRES2 overexpression in ACC cell lines not only reduced cell proliferation, cell invasion and tumorigenicity in vitro, but also inhibited tumor growth in vivo in two immunodeficient mouse xenograft models. Mechanistically, RARRES2 overexpression in ACC cells inhibited Wnt/?-catenin pathway activity by promoting ?-catenin phosphorylation and degradation, it also inhibited the phosphorylation of p38 mitogen-activated protein kinase. Thus our study identifies RARRES2 as a novel tumor suppressor for ACC, which can function through an immune-independent mechanism.

SUBMITTER: Liu-Chittenden Y

PROVIDER: S-EPMC5481486 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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RARRES2 functions as a tumor suppressor by promoting β-catenin phosphorylation/degradation and inhibiting p38 phosphorylation in adrenocortical carcinoma.

Liu-Chittenden Y Y Jain M M Gaskins K K Wang S S Merino M J MJ Kotian S S Kumar Gara S S Davis S S Zhang L L Kebebew E E

Oncogene 20170123 25

Tumor suppressor genes and the immune system are critical players in inhibiting cancer initiation and/or progression. However, little is known about whether a tumor suppressor gene can function through both immune-dependent and -independent mechanisms. Retinoic acid receptor responder 2 (RARRES2) is transcriptionally downregulated in multiple cancer types. Previous studies suggested that it can serve as an immune-dependent tumor suppressor by acting as a chemoattractant to recruit anticancer imm ...[more]

PMID: 28114280

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Project description:BACKGROUND & AIMS:Expression of the SAM pointed domain containing ETS transcription factor (SPDEF or prostate-derived ETS factor) is regulated by Atoh1 and is required for the differentiation of goblet and Paneth cells. SPDEF has been reported to suppress the development of breast, prostate, and colon tumors. We analyzed levels of SPDEF in colorectal tumor samples from patients and its tumor-suppressive functions in mouse models of colorectal cancer (CRC). METHODS:We analyzed levels of SPDEF messenger RNA and protein in more than 500 human CRC samples and more than 80 nontumor controls. Spdef(-/-)and wild-type mice (controls) were either bred with Apc(Min/+) mice, or given azoxymethane (AOM) and dextran sodium sulfate (DSS), or 1,2-dimethylhydrazine and DSS, to induce colorectal tumors. Expression of Spdef also was induced transiently by administration of tetracycline to Spdef(dox-intestine) mice with established tumors, induced by the combination of AOM and DSS or by breeding with Apc(Min/+) mice. Colon tissues were collected and analyzed for tumor number, size, grade, and for cell proliferation and apoptosis. We also analyzed the effects of SPDEF expression in HCT116 and SW480 human CRC cells. RESULTS:In colorectal tumors from patients, loss of SPDEF was observed in approximately 85% of tumors and correlated with progression from normal tissue, to adenoma, to adenocarcinoma. Spdef(-/-); Apc(Min/+) mice developed approximately 3-fold more colon tumors than Spdef(+/+); Apc(Min/+) mice. Likewise, Spdef(-/-) mice developed approximately 3-fold more colon tumors than Spdef(+/+) mice after administration of AOM and DSS. After administration of 1,2-dimethylhydrazine and DSS, invasive carcinomas were observed exclusively in Spdef(-/-) mice. Conversely, expression of SPDEF was sufficient to promote cell-cycle exit in cells of established adenomas from Spdef(dox-intestine); Apc(Min/+) mice and in Spdef(dox-intestine) mice after administration of AOM + DSS. SPDEF inhibited the expression of ?-catenin-target genes in mouse colon tumors, and interacted with ?-catenin to block its transcriptional activity in CRC cell lines, resulting in lower levels of cyclin D1 and c-MYC. CONCLUSIONS:SPDEF is a colon tumor suppressor and a candidate therapeutic target for colon adenomas and adenocarcinoma.

Dataset Information

RARRES2 functions as a tumor suppressor by promoting ?-catenin phosphorylation/degradation and inhibiting p38 phosphorylation in adrenocortical carcinoma.

Publications

RARRES2 functions as a tumor suppressor by promoting β-catenin phosphorylation/degradation and inhibiting p38 phosphorylation in adrenocortical carcinoma.

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