Hsa-miRNA-765 as a key mediator for inhibiting growth, migration and invasion in fulvestrant-treated prostate cancer.
Fulvestrant (ICI-182,780) has recently been shown to effectively suppress prostate cancer cell growth in vitro and in vivo. But it is unclear whether microRNAs play a role in regulating oncogene expression in fulvestrant-treated prostate cancer. Here, this study reports hsa-miR-765 as the first fulvestrant-driven, ERβ-regulated miRNA exhibiting significant tumor suppressor activities like fulvestrant, against prostate cancer cell growth via blockage of cell-cycle progression at the G2/M transition, and cell migration and invasion possibly via reduction of filopodia/intense stress-fiber formation. Fulvestrant was shown to upregulate hsa-miR-765 expression through recruitment of ERβ to the 5'-regulatory-region of hsa-miR-765. HMGA1, an oncogenic protein in prostate cancer, was identified as a downstream target of hsa-miR-765 and fulvestrant in cell-based experiments and a clinical study. Both the antiestrogen and the hsa-miR-765 mimic suppressed HMGA1 protein expression. In a neo-adjuvant study, levels of hsa-miR-765 were increased and HMGA1 expression was almost completely lost in prostate cancer specimens from patients treated with a single dose (250 mg) of fulvestrant 28 days before prostatectomy. These findings reveal a novel fulvestrant signaling cascade involving ERβ-mediated transcriptional upregulation of hsa-miR-765 that suppresses HMGA1 protein expression as part of the mechanism underlying the tumor suppressor action of fulvestrant in prostate cancer.
Department of Environmental Health, Center for Environmental Genetics, and Cancer Institute, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America.
Yuet-Kin
YK
Leung
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
Queeny Kwan-Yi
QK
Chan
Department of Surgery, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
Chi-Fai
CF
Ng
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
Fanny Man-Ting
FM
Ma
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
Ho-Man
HM
Tse
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory in Southern China in Oncology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
Ka-Fai
KF
To
Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Jodi
J
Maranchie
Department of Environmental Health, Center for Environmental Genetics, and Cancer Institute, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America; Cincinnati Veteran Affairs Medical Center, Cincinnati, Ohio, United States of America.
Shuk-Mei
SM
Ho
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China; State Key Laboratory in Southern China in Oncology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
Kin-Mang
KM
Lau
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077267:Fulvestrant; D024003:HMGA Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
D018931:Antineoplastic Agents, Hormonal; D065171:Estrogen Receptor Antagonists; D047629:Estrogen Receptor beta; D024003:HMGA Proteins; C000600151:MIRN765 microRNA, human; D035683:MicroRNAs; D000077267:Fulvestrant; D004958:Estradiol