title: GPR30 Promotes Prostate Stromal Cell Activation via Suppression of ERα Expression and Its Downstream Signaling Pathway.
abstract: Cancer-associated fibroblasts (CAFs) play a vital role in malignant transformation and progression of prostate cancer (PCa), and accumulating evidence suggests an enhancing effect of estrogens on PCa. The present study aimed to investigate the possible origin of prostate CAFs and the effects of estrogen receptors, G protein-coupled receptor 30 (GPR30) and estrogen receptor (ER)-α, on stromal cell activation. High expression of fibroblast activation protein (FAP), CD44, and nonmuscle myosin heavy chain B (SMemb) accompanied by low expression of smooth muscle differentiation markers was found in the stromal cells of PCa tissues and in cultured human prostate CAFs. Additionally, SMemb expression, which is coupled to cell phenotype switching and proliferation, was coexpressed with FAP, a marker of activated stromal cells, and with the stem cell marker CD44 in the stromal cells of PCa tissue. Prostate CAFs showed high GPR30 and low ERα expression. Moreover, GPR30 was coexpressed with FAP, CD44, and SMemb. Furthermore, the study demonstrated that the overexpression of GPR30 or the knockdown of ERα in prostate stromal cells induced the up-regulation of FAP, CD44, Smemb, and the down-regulation of smooth muscle markers. The conditioned medium from these cells promoted the proliferation and migration of LNCaP and PC3 PCa cells. GPR30 knockdown or ERα overexpression showed opposite effects. Finally, we present a novel mechanism whereby GPR30 limits ERα expression via inhibition of the cAMP/protein kinase A signaling pathway. These results suggest that stem-like cells within the stroma are a possible source of prostate CAFs and that the negative regulation of ERα expression by GPR30 is centrally involved in prostate stromal cell activation.
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Bona
authors.initials: B
authors.lastname: Jia
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Mingming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Jiandang
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Helmut
authors.initials: H
authors.lastname: Klocker
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Natalie
authors.initials: N
authors.lastname: Sampson
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Mengyang
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology (B.J., Y.G., M.L., J.S., X.D., Y.S., J.Z.), College of Life Sciences, Bioactive Materials Key Lab of the Ministry of Education, Nankai University, Tianjin 300071, China; School of Integrative Medicine (Y.P.), Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Department of Urology (H.K., N.S.), Division of Experimental Urology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and Department of Nutrition and Food Science (M.L.), Texas A&M University, College Station, Texas 77843.
authors.forename: Ju
authors.initials: J
authors.lastname: Zhang
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D008297:Male; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D011467:Prostate / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D017154:Stromal Cells / Q000502:physiology*
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled