title: GPR116, an adhesion G-protein-coupled receptor, promotes breast cancer metastasis via the Gαq-p63RhoGEF-Rho GTPase pathway.
abstract: Adhesion G-protein-coupled receptors (GPCR), which contain adhesion domains in their extracellular region, have been found to play important roles in cell adhesion, motility, embryonic development, and immune response. Because most adhesion molecules with adhesion domains have vital roles in cancer metastasis, we speculated that adhesion GPCRs are potentially involved in cancer metastasis. In this study, we identified GPR116 as a novel regulator of breast cancer metastasis through expression and functional screening of the adhesion GPCR family. We found that knockdown of GPR116 in highly metastatic (MDA-MB-231) breast cancer cells suppressed cell migration and invasion. Conversely, ectopic GPR116 expression in poorly metastatic (MCF-7 and Hs578T) cells promoted cell invasion. We further showed that knockdown of GPR116 inhibited breast cancer cell metastasis in two mammary tumor metastasis mouse models. Moreover, GPR116 modulated the formation of lamellipodia and actin stress fibers in cells in a RhoA- and Rac1-dependent manner. At a molecular level, GPR116 regulated cell motility and morphology through the Gαq-p63RhoGEF-RhoA/Rac1 pathway. The biologic significance of GPR116 in breast cancer is substantiated in human patient samples, where GPR116 expression is significantly correlated with breast tumor progression, recurrence, and poor prognosis. These findings show that GPR116 is crucial for the metastasis of breast cancer and support GPR116 as a potential prognostic marker and drug target against metastatic human breast cancer.
authors.affiliation: Authors' Affiliations: East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; and Center for Cancer and Stem Cell Biology, Alkek Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Tang
authors.forename: Rongrong
authors.initials: R
authors.lastname: Jin
authors.forename: Guojun
authors.initials: G
authors.lastname: Qu
authors.forename: Xiu
authors.initials: X
authors.lastname: Wang
authors.forename: Zhenxi
authors.initials: Z
authors.lastname: Li
authors.forename: Zengjin
authors.initials: Z
authors.lastname: Yuan
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Stefan
authors.initials: S
authors.lastname: Siwko
authors.forename: Tieliu
authors.initials: T
authors.lastname: Shi
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Luo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D046888:Tissue Array Analysis
chemical_list: C516038:ADGRF5 protein, human; D043562:Receptors, G-Protein-Coupled; D064067:Rho Guanine Nucleotide Exchange Factors; D020558:GTP Phosphohydrolases