Hsa-miRNA-765 as a key mediator for inhibiting growth, migration and invasion in fulvestrant-treated prostate cancer

Yuet-Kin Leung, Queeny Kwan-Yi Chan, Chi-Fai Ng, Fanny Man-Ting Ma, Ho-Man Tse, Ka-Fai To, Jodi Maranchie, Shuk-Mei Ho, Kin-Mang Lau, Yuet-Kin Leung, Queeny Kwan-Yi Chan, Chi-Fai Ng, Fanny Man-Ting Ma, Ho-Man Tse, Ka-Fai To, Jodi Maranchie, Shuk-Mei Ho, Kin-Mang Lau

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.

Conflict of interest statement

Competing Interests: Dr. Jodi Maranchie received the Investigator-Sponsored Study Program of AstraZeneca. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Fulvestrant inhibits DU145 cell growth,…
Figure 1. Fulvestrant inhibits DU145 cell growth, migration, and invasion.
(A) Fulvestrant induces growth inhibition of DU145 cells via an ERβ-dependent mechanism. Growth of the fulvestrant-treated DU145 cells with or without ERβ siRNA knockdown for 4 days relative to the ethanol-treated control cells with negative-control siRNA are presented and compared (n = 8). ERβ expression was also knocked down by another siRNA (siRNA#2) and the similar results were obtained (Figure S5). (B) Fulvestrant induces DU145 cell-cycle arrest at G2/M phase. Representative DNA histograms of 48 hrs fulvestrant -or ethanol- (control) treated cells and percentage distributions of the cells at G0/G1 and G2/M phases (n = 3) are presented and compared. (C) Fulvestrant induces expression of G2/M markers. DU145 cells were treated with fulvestrant or ethanol for 2 days (control) and cell cycle markers were determined by Western blot analysis. Two independent experiments were performed and one representative set of data was presented. (D) Fulvestrant suppresses cell migration. A wound-healing assay was performed on the fulvestrant- and ethanol (EtOH)-treated DU145 cells (n = 3). Representative micrographs of the fulvestrant- and ethanol-treated cell cultures with scratches at 0 h and after 16 h are shown. The wound is marked by dotted lines. (E) Fulvestrant inhibits transwell migration (left panel) and invasion (right panel) in DU145 cells (n = 3) after 5 hrs of fulvestrant treatment. (F) Reductions of filopodial cells and cells with intense stress fibers by fulvestrant (treated with 48 hrs) via an ERβ-dependent mechanism. Representative micrographs and the percentages of the cells with intense stress fibers and the filopodial cells (n = 3) are presented. Student t-test was performed to determine significance with a cutoff p value of 0.05. ** p

Figure 2. Fulvestrant upregulates hsa-miR-765 expression in…

Figure 2. Fulvestrant upregulates hsa-miR-765 expression in DU145 cells.

(A) Hsa-miR-765 is highly expressed in…

Figure 2. Fulvestrant upregulates hsa-miR-765 expression in DU145 cells.
(A) Hsa-miR-765 is highly expressed in fulvestrant-treated DU145 cells. Total RNAs of treated cells were labeled directly and arrayed on the NCode Human miRNA Microarray. The median- and linear regression-normalized data are presented in a scatterplot. (B) Hsa-miR-765 is induced by fulvestrant in two prostate cancer cell lines. The hsa-miR-765 in the fulvestrant- and ethanol-treated control DU145 and PC-3 cells was quantified by miRNA qRT-PCR analysis. Relative fold changes between the expression of hsa-miR-765 in the fulvestrant-treated and control cells are presented. Student t-test was performed to determine their significance using a cutoff p value of 0.05 (n = 3). **p<0.01; bars = S.D.

Figure 3. Hsa-miR-765 suppresses DU145 cell growth,…

Figure 3. Hsa-miR-765 suppresses DU145 cell growth, migration, and invasion.

(A) Hsa-miR-765 mimic effectively recognizes…

Figure 3. Hsa-miR-765 suppresses DU145 cell growth, migration, and invasion.
(A) Hsa-miR-765 mimic effectively recognizes reporter with complementary sequence of hsa-miR-765 in DU145 cells. Fold changes of luciferase activities of the hsa-miR-765 mimic treated cells relative to the cells treated with the negative-control mimic are presented (n = 3). Transfection reagents were used as control. (B) Hsa-miR-765 mimic reduces DU145 cell growth. MTS assay was performed on the cells treated with hsa-miR-765 mimic or negative-control mimic or transfection control for 4 days (n = 8). (C) Hsa-miR-765 mimic significant reduces G0/G1 to G2/M ratio in DU145. Representative DNA histograms (n = 3) are presented. (D) Hsa-miR-765 mimic treatment causes up-regulation of cyclin A, cyclin B, and phosphorylated-cdc2 expression in DU145 cells. Protein expression levels of cell cycle regulator proteins were determined by Western blot analyses. Two independent experiments were performed and one representative set of data was presented. (E) Hsa-miR-765 mimic suppresses DU145 cell migration and invasion as shown in transwell migration assay (top left) and invasion assay (top right), respectively. Representative micrographs of the cells after transwell migration (top left) or invasion assay (top right) are presented. Fold changes of migration (bottom left) and invasion (bottom right) of DU145 cells with either hsa-miR-765 mimic or negative-control mimic relative to the control cells with negative-control mimic are presented (n = 3). (F) Hsa-miR-765 mimic significantly reduces stress fibers and filopodia formations in DU145 cells. Representative micrographs and the percentages of the cells with intense stress fibers and the filopodial cells (n = 3) are presented. Student's t-test was used for comparisons with a cutoff p value of 0.05. ** p<0.01; bar = S.D.

Figure 4. ERβ is involved in fulvestrant-induced…

Figure 4. ERβ is involved in fulvestrant-induced upregulation of hsa-miR-765 expression.

(A) ERβ siRNA knockdown…

Figure 4. ERβ is involved in fulvestrant-induced upregulation of hsa-miR-765 expression.
(A) ERβ siRNA knockdown blocks fulvestrant-induced upregulation of hsa-miR-765 expression in DU145 cells. Expression levels of hsa-miR-765 determined by qRT-PCR analysis of the fulvestrant-treated cells with ERβ-siRNA (siERβ) or scramble negative-control (siNeg) were compared (n = 3). (B) SiRNA knockdown of ERβ blocks fulvestrant-induced transactivation of the 5′ upstream regulatory region of hsa-miR-765 in DU145 cells. 5′ upstream regulatory region of hsa-miR-765 was cloned into a luciferase vector. The reporter activities with ERβ-knockdown (siERβ) or scramble negative-control (siNeg) in the presence of fulvestrant were compared (n = 3). (C) Deletion mapping analysis defines a fulvestrant-responsive segment in hsa-miR-765 regulatory region in DU145 cells. The 5′ upstream DNA sequence of hsa-miR-765 from nt. −3208 to +100 was analyzed using luciferase reporter system. Serial deletions from the 5′ end of the cloned sequence in the vector were conducted. Reporter activities were compared between the fulvestrant-treated (Fulvestrant) and control (ETOH) cells for each reporter vector (n = 3). (D) Fulvestrant-induces recruitment of ERβ onto the putative hsa-miR-765 regulatory region. Chromatin-immunoprecipitation revealed the recruitment of ERβ to a sequence in the 5′-regulatory region of hsa-miR765. Mouse IgG and RNA polymerase II serve as negative and positive control, respectively. Fulvestrant induced 17 fold increase in ERβ recruitment when compared with non-ERβ binding region (the 0N promoter of ERβ [33], [41]). Student's t-test was performed to determine significance of between groups using a cutoff p value of 0.05. ** p<0.01; bar = S.D.

Figure 5. HMGA1 is a direct target…

Figure 5. HMGA1 is a direct target of hsa-miR-765 .

(A) The 3′UTR of HMGA1 from…

Figure 5. HMGA1 is a direct target of hsa-miR-765.
(A) The 3′UTR of HMGA1 from +8910 to +8929 is predicted to be hsa-miR-765 binding site. (B) Hsa-miR-765 interacts with 3′UTR of HMGA1 in a targeting reporter assay. DU145 cells were transfected with either pMIR-empty or pMIR-HMGA1-3UTR in which 3′ UTR of HMGA1 (+8026–+9332) was cloned into the 3′ end of luciferase. Reporter activities of the pMIR-HMGA1-3UTR transfected cells treated with hsa-miR-765 mimic or negative-control mimic are compared (n = 3). (C) Hsa-miR-765 mimic reduced HMGA1 protein expression in DU145 cells. Protein and mRNA levels of HMGA1 in the hsa-miR-765 mimic- and negative-control mimic-treated cells were determined by Western blot analysis (upper) and real-time RT-PCR analysis (lower), respectively. Results from miR-765 mimic vs negative control mimic are compared (n = 3). (D) Fulvestrant reduces HMGA1 protein expression in DU145 cells. Protein level of HMGA1 and β-actin in the fulvestrant-treated and ethanol-treated control (CTL) cells were determined by Western blot analysis. (E) Ectopic expression of HMGA1 blocks fulvestrant-induced DU145 cell growth inhibition. The relative cell growth was determined after 4 days of treatment with fulvestrant or ethanol after stable transfection of HMGA1 (or empty vector for control) for a week. Protein levels of HMGA1 were shown in Figure S6. The cell growth of fulvestrant-treated cells with HMGA1 overexpression vs empty vector are compared (n = 8). Student's t-test was performed to determine significance between groups using a cutoff p value of 0.05. **p<0.01; bar = S.D.

Figure 6. Significant reduction of HMGA1 protein…

Figure 6. Significant reduction of HMGA1 protein correlates with enhanced expression of hsa-miR-765 in fulvestrant-treated…

Figure 6. Significant reduction of HMGA1 protein correlates with enhanced expression of hsa-miR-765 in fulvestrant-treated clinical PCa specimens.
(A) Higher level of hsa-miR-765 is detected in fulvestrant-treated clinical PCa specimens. Relative fold changes between expression of hsa-miR-765 in the fulvestrant-treated (n = 7) and untreated (n = 7) clinical specimen are presented. Student's t-test was performed to determine significance between two groups. *p<0.05; bar = S.E.M. (B) Nuclear expression of HMGA1 and AR is reduced in fulvestrant-treated clinical PCa specimens. HMGA1 immunostaining was performed in the clinical PCa specimens from the fulvestrant-treated (n = 5) and untreated (n = 5) patients. Representative micrographs (100×) are shown. In upper panel, a magnified view (400×) of a selected region (dashed rectangle) in each micrograph is shown as a small insert to show the immunostaining of HGMA1 in the nuclei of Gleason grade 3/4 cancer foci. Imunnopositivity of nuclear AR is reduced in fulvestrant-treated Gleason grade 3/4 foci as shown in lower panel (400×). (C) Expression of both HMGA1 and AR is significantly reduced in fulvestrant-treated clinical PCa specimens when compared with their respective untreated samples (*p<0.05; **p<0.01; n = 9 (from 5 patients) for untreated samples; n = 10 (from 5 patients) for fulvestrant-treated samples, bar = S.E.M).
Figure 2. Fulvestrant upregulates hsa-miR-765 expression in…
Figure 2. Fulvestrant upregulates hsa-miR-765 expression in DU145 cells.
(A) Hsa-miR-765 is highly expressed in fulvestrant-treated DU145 cells. Total RNAs of treated cells were labeled directly and arrayed on the NCode Human miRNA Microarray. The median- and linear regression-normalized data are presented in a scatterplot. (B) Hsa-miR-765 is induced by fulvestrant in two prostate cancer cell lines. The hsa-miR-765 in the fulvestrant- and ethanol-treated control DU145 and PC-3 cells was quantified by miRNA qRT-PCR analysis. Relative fold changes between the expression of hsa-miR-765 in the fulvestrant-treated and control cells are presented. Student t-test was performed to determine their significance using a cutoff p value of 0.05 (n = 3). **p<0.01; bars = S.D.
Figure 3. Hsa-miR-765 suppresses DU145 cell growth,…
Figure 3. Hsa-miR-765 suppresses DU145 cell growth, migration, and invasion.
(A) Hsa-miR-765 mimic effectively recognizes reporter with complementary sequence of hsa-miR-765 in DU145 cells. Fold changes of luciferase activities of the hsa-miR-765 mimic treated cells relative to the cells treated with the negative-control mimic are presented (n = 3). Transfection reagents were used as control. (B) Hsa-miR-765 mimic reduces DU145 cell growth. MTS assay was performed on the cells treated with hsa-miR-765 mimic or negative-control mimic or transfection control for 4 days (n = 8). (C) Hsa-miR-765 mimic significant reduces G0/G1 to G2/M ratio in DU145. Representative DNA histograms (n = 3) are presented. (D) Hsa-miR-765 mimic treatment causes up-regulation of cyclin A, cyclin B, and phosphorylated-cdc2 expression in DU145 cells. Protein expression levels of cell cycle regulator proteins were determined by Western blot analyses. Two independent experiments were performed and one representative set of data was presented. (E) Hsa-miR-765 mimic suppresses DU145 cell migration and invasion as shown in transwell migration assay (top left) and invasion assay (top right), respectively. Representative micrographs of the cells after transwell migration (top left) or invasion assay (top right) are presented. Fold changes of migration (bottom left) and invasion (bottom right) of DU145 cells with either hsa-miR-765 mimic or negative-control mimic relative to the control cells with negative-control mimic are presented (n = 3). (F) Hsa-miR-765 mimic significantly reduces stress fibers and filopodia formations in DU145 cells. Representative micrographs and the percentages of the cells with intense stress fibers and the filopodial cells (n = 3) are presented. Student's t-test was used for comparisons with a cutoff p value of 0.05. ** p<0.01; bar = S.D.
Figure 4. ERβ is involved in fulvestrant-induced…
Figure 4. ERβ is involved in fulvestrant-induced upregulation of hsa-miR-765 expression.
(A) ERβ siRNA knockdown blocks fulvestrant-induced upregulation of hsa-miR-765 expression in DU145 cells. Expression levels of hsa-miR-765 determined by qRT-PCR analysis of the fulvestrant-treated cells with ERβ-siRNA (siERβ) or scramble negative-control (siNeg) were compared (n = 3). (B) SiRNA knockdown of ERβ blocks fulvestrant-induced transactivation of the 5′ upstream regulatory region of hsa-miR-765 in DU145 cells. 5′ upstream regulatory region of hsa-miR-765 was cloned into a luciferase vector. The reporter activities with ERβ-knockdown (siERβ) or scramble negative-control (siNeg) in the presence of fulvestrant were compared (n = 3). (C) Deletion mapping analysis defines a fulvestrant-responsive segment in hsa-miR-765 regulatory region in DU145 cells. The 5′ upstream DNA sequence of hsa-miR-765 from nt. −3208 to +100 was analyzed using luciferase reporter system. Serial deletions from the 5′ end of the cloned sequence in the vector were conducted. Reporter activities were compared between the fulvestrant-treated (Fulvestrant) and control (ETOH) cells for each reporter vector (n = 3). (D) Fulvestrant-induces recruitment of ERβ onto the putative hsa-miR-765 regulatory region. Chromatin-immunoprecipitation revealed the recruitment of ERβ to a sequence in the 5′-regulatory region of hsa-miR765. Mouse IgG and RNA polymerase II serve as negative and positive control, respectively. Fulvestrant induced 17 fold increase in ERβ recruitment when compared with non-ERβ binding region (the 0N promoter of ERβ [33], [41]). Student's t-test was performed to determine significance of between groups using a cutoff p value of 0.05. ** p<0.01; bar = S.D.
Figure 5. HMGA1 is a direct target…
Figure 5. HMGA1 is a direct target of hsa-miR-765.
(A) The 3′UTR of HMGA1 from +8910 to +8929 is predicted to be hsa-miR-765 binding site. (B) Hsa-miR-765 interacts with 3′UTR of HMGA1 in a targeting reporter assay. DU145 cells were transfected with either pMIR-empty or pMIR-HMGA1-3UTR in which 3′ UTR of HMGA1 (+8026–+9332) was cloned into the 3′ end of luciferase. Reporter activities of the pMIR-HMGA1-3UTR transfected cells treated with hsa-miR-765 mimic or negative-control mimic are compared (n = 3). (C) Hsa-miR-765 mimic reduced HMGA1 protein expression in DU145 cells. Protein and mRNA levels of HMGA1 in the hsa-miR-765 mimic- and negative-control mimic-treated cells were determined by Western blot analysis (upper) and real-time RT-PCR analysis (lower), respectively. Results from miR-765 mimic vs negative control mimic are compared (n = 3). (D) Fulvestrant reduces HMGA1 protein expression in DU145 cells. Protein level of HMGA1 and β-actin in the fulvestrant-treated and ethanol-treated control (CTL) cells were determined by Western blot analysis. (E) Ectopic expression of HMGA1 blocks fulvestrant-induced DU145 cell growth inhibition. The relative cell growth was determined after 4 days of treatment with fulvestrant or ethanol after stable transfection of HMGA1 (or empty vector for control) for a week. Protein levels of HMGA1 were shown in Figure S6. The cell growth of fulvestrant-treated cells with HMGA1 overexpression vs empty vector are compared (n = 8). Student's t-test was performed to determine significance between groups using a cutoff p value of 0.05. **p<0.01; bar = S.D.
Figure 6. Significant reduction of HMGA1 protein…
Figure 6. Significant reduction of HMGA1 protein correlates with enhanced expression of hsa-miR-765 in fulvestrant-treated clinical PCa specimens.
(A) Higher level of hsa-miR-765 is detected in fulvestrant-treated clinical PCa specimens. Relative fold changes between expression of hsa-miR-765 in the fulvestrant-treated (n = 7) and untreated (n = 7) clinical specimen are presented. Student's t-test was performed to determine significance between two groups. *p<0.05; bar = S.E.M. (B) Nuclear expression of HMGA1 and AR is reduced in fulvestrant-treated clinical PCa specimens. HMGA1 immunostaining was performed in the clinical PCa specimens from the fulvestrant-treated (n = 5) and untreated (n = 5) patients. Representative micrographs (100×) are shown. In upper panel, a magnified view (400×) of a selected region (dashed rectangle) in each micrograph is shown as a small insert to show the immunostaining of HGMA1 in the nuclei of Gleason grade 3/4 cancer foci. Imunnopositivity of nuclear AR is reduced in fulvestrant-treated Gleason grade 3/4 foci as shown in lower panel (400×). (C) Expression of both HMGA1 and AR is significantly reduced in fulvestrant-treated clinical PCa specimens when compared with their respective untreated samples (*p<0.05; **p<0.01; n = 9 (from 5 patients) for untreated samples; n = 10 (from 5 patients) for fulvestrant-treated samples, bar = S.E.M).

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