title: RARRES2 functions as a tumor suppressor by promoting β-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/β-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/β-catenin pathway activity by promoting β-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.
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Y
authors.identifier: 0000-0001-6357-5360
authors.initials: Y
authors.lastname: Liu-Chittenden
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Jain
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Gaskins
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Merino
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kotian
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kumar Gara
authors.affiliation: Cancer Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: S
authors.identifier: 0000-0002-8991-6458
authors.initials: S
authors.lastname: Davis
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: E
authors.initials: E
authors.lastname: Kebebew
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism*; D018268:Adrenocortical Carcinoma / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000235:genetics; D059748:Proteolysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018925:Chemokines; D036341:Intercellular Signaling Peptides and Proteins; C478630:RARRES2 protein, human; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases