title: Cholesterol import and steroidogenesis are biosignatures for gastric cancer patient survival.
abstract: Androgens, estrogens, progesterone and related signals are reported to be involved in the pathology of gastric cancer. However, varied conclusions exist based on serum hormone levels, receptor expressions, and in vitro or in vivo studies. This report used a web-based gene survival analyzer to evaluate biochemical processes, including cholesterol importing via lipoprotein/receptors (L/R route), steroidogenic enzymes, and steroid receptors, in gastric cancer patients prognosis. The sex hormone receptors (androgen receptor, progesterone receptor, and estrogen receptor ESR1 or ESR2), L/R route (low/high-density lipoprotein receptors, LDLR/LRP6/SR-B1 and lipoprotein lipase, LPL) and steroidogenic enzymes (CYP11A1, HSD3B1, CYP17, HSD17B1, HSD3B1, CYP19A1 and SRD5A1) were associated with 5-year survival of gastric cancer patients. The AR, PR, ESR1 and ESR2 are progression promoters, as are the L/R route LDLR, LRP6, SR-B1 and LPL. It was found that CYP11A1, HSD3B1, CYP17, HSD17B1 and CYP19A1 promote progression, but dihydrotestosterone (DHT) converting enzyme SRD5A1 suppresses progression. Analyzing steroidogenic lipidome with a hazard ratio score algorithm found that CYP19A1 is the progression confounder in surgery, HER2 positive or negative patients. Finally, in the other patient cohort from TCGA, CYP19A1 was expressed higher in the tumor compared to that in normal counterparts, and also promoted progression. Lastly, exemestrane (type II aromatase inhibitor) dramatically suppress GCa cell growth in pharmacological tolerable doses in vitro. This work depicts a route-specific outside-in delivery of cholesterol to promote disease progression, implicating a host-to-tumor macroenvironmental regulation. The result indicating lipoprotein-mediated cholesterol entry and steroidogenesis are GCa progression biosignatures. And the exemestrane clinical trial in GCa patients of unmet medical needs is suggested.
authors.affiliation: Sex Hormone Research Center, Department of Obstetrics and Gynecology, Department of Gastroenterology, Research Center for Tumor Medical Science, and Organ Transplantation Center, China Medical University/Hospital, Taichung, Taiwan.|Graduate Institute of Biomedical Sciences/Clinical Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Sex Hormone Research Center, Department of Obstetrics and Gynecology, Department of Gastroenterology, Research Center for Tumor Medical Science, and Organ Transplantation Center, China Medical University/Hospital, Taichung, Taiwan.
authors.forename: Shang-Fen
authors.initials: SF
authors.lastname: Huang
authors.affiliation: Graduate Institute of Biomedical Sciences/Clinical Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.|Department of Endocrinology and Metabolism, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Yang-Ming
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Sex Hormone Research Center, Department of Obstetrics and Gynecology, Department of Gastroenterology, Research Center for Tumor Medical Science, and Organ Transplantation Center, China Medical University/Hospital, Taichung, Taiwan.|Graduate Institute of Biomedical Sciences/Clinical Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Hsueh-Chou
authors.initials: HC
authors.lastname: Lai
authors.affiliation: Department of OBs& GYN, Chia-Yi Chang-Gong Memorial Hospital, Chia-Yi, Taiwan.
authors.forename: Bi-Hua
authors.initials: BH
authors.lastname: Cheng
authors.affiliation: Sex Hormone Research Center, Department of Obstetrics and Gynecology, Department of Gastroenterology, Research Center for Tumor Medical Science, and Organ Transplantation Center, China Medical University/Hospital, Taichung, Taiwan.|Graduate Institute of Biomedical Sciences/Clinical Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Wei-Chung
authors.initials: WC
authors.lastname: Cheng
authors.affiliation: Sex Hormone Research Center, Department of Obstetrics and Gynecology, Department of Gastroenterology, Research Center for Tumor Medical Science, and Organ Transplantation Center, China Medical University/Hospital, Taichung, Taiwan.
authors.forename: Jason Yen-Ping
authors.initials: JY
authors.lastname: Ho
authors.affiliation: Sex Hormone Research Center, Department of Obstetrics and Gynecology, Department of Gastroenterology, Research Center for Tumor Medical Science, and Organ Transplantation Center, China Medical University/Hospital, Taichung, Taiwan.
authors.forename: Long-Bin
authors.initials: LB
authors.lastname: Jeng
authors.affiliation: Sex Hormone Research Center, Department of Obstetrics and Gynecology, Department of Gastroenterology, Research Center for Tumor Medical Science, and Organ Transplantation Center, China Medical University/Hospital, Taichung, Taiwan.|Graduate Institute of Biomedical Sciences/Clinical Medical Science, School of Medicine, China Medical University, Taichung, Taiwan.|Department of Nursing, Asia University, Taichung, Taiwan.
authors.forename: Wen-Lung
authors.initials: WL
authors.lastname: Ma
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D002784:Cholesterol / Q000378:metabolism*; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D058990:Molecular Targeted Therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D018110:Receptors, Lipoprotein / Q000378:metabolism; D013256:Steroids / Q000096:biosynthesis*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D008074:Lipoproteins; D018110:Receptors, Lipoprotein; D013256:Steroids; D002784:Cholesterol; D001141:Aromatase; C561410:CYP19A1 protein, human
keywords: CYP19A1; cholesterol; gastric cancer; steroidogenesis