Hsa-miRNA-765 as a key mediator for inhibiting growth, migration and invasion in fulvestrant-treated prostate cancer
Authors: Kin-Mang Lau
Shuk-Mei Ho
Ho-Man Tse
Ka-Fai To
Jodi Maranchie
Yuet-Kin Leung
Queeny Kwan-Yi Chan
Fanny Man-Ting Ma
Chi-Fai Ng
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: Fulvestrant; Prostate cancer; MicroRNAs; ERβ; Tumor suppressor
Affiliations: Department of Environmental Health, Center for Environmental Genetics, and Cancer Institute, University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America., Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China., Department of Surgery, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China., 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., Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America., 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.

Abstract:  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. 

Retracted: No

PubPeer comments:
 May 2019 correction found here: https: journals.plos.org plosone article?id=10.1371 journal.pone.0214184 It reads:  Following the publication of [1] concerns were noted in the following figures: * Fig 1D, the ETOH-treated panel at 0h appear similar to Fulvestrant-treated panel at 0h * Fig 1C u03b2-actin panel appears similar to Fig 5D u03b2-actin panel * Fig 3D u03b2-actin panel appears similar to Fig 5C u03b2-actin panel The authors have explained that an error was made during figure preparation. The authors accidentally used the duplicated micrograph image for the Fulvestrant-treated DU145 cells at 0h to represent the ETOH-treated cells at 0h. The authors have provided a replacement image for Fig 1D ETOH-treated panel at 0h, represented by the one of the micrograph images of these cells captured during the wound healing experiment. All underlying data and images for Fig 1 have been provided in the Supporting Information file S1 Dataset. The lysate samples of the control and Fulvestrant-treated cells used in Western blot analysis were the same for generation of data presented in both Figs 1C, 5D and Figs 3D, 5C, therefore the same image was used for u03b2-actin expression for the purposes of presentation. * Here is the original Figure 1D as reported to the journal in May 2014, marked with red boxes. The actin panels were not reported by me as they represented the same experiments. I thank the authors for correcting the error. ![file] ,