Ratio of the expression levels of androgen receptor splice variant 7 to androgen receptor in castration refractory prostate cancer

Sekine,Yoshitaka; Nakayama,Hiroshi; Miyazawa,Yoshiyuki; Arai,Seiji; Koike,Hidekazu; Matsui,Hiroshi; Shibata,Yasuhiro; Ito,Kazuto; Suzuki,Kazuhiro

doi:10.3892/ol.2021.13092

Ratio of the expression levels of androgen receptor splice variant 7 to androgen receptor in castration refractory prostate cancer

Authors:
- Yoshitaka Sekine
- Hiroshi Nakayama
- Yoshiyuki Miyazawa
- Seiji Arai
- Hidekazu Koike
- Hiroshi Matsui
- Yasuhiro Shibata
- Kazuto Ito
- Kazuhiro Suzuki
View Affiliations

Affiliations: Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371‑8511, Japan
Published online on: October 13, 2021 https://doi.org/10.3892/ol.2021.13092
Article Number: 831
Copyright: © Sekine et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In clinical samples, the expression of androgen receptor (AR) and of AR splice variant 7 (AR‑V7) is higher in castration‑resistant prostate cancer (CRPC) compared with that in hormone‑sensitive prostate cancer (PCa). However, there are only a few reports on the ratio of the expression levels of AR‑V7 to AR (AR‑V7/AR) in prostate tissue. The present study evaluated AR‑V7/AR expression in various types of human prostate tissues and CRPC cells. Pretreatment prostate tissue samples from patients with benign prostatic hyperplasia (BPH; n=18), Gleason score 7 (n=17), and Gleason score 8‑10 (n=26) were collected at the time of prostate biopsy, and tissue samples from CRPC patients (n=10) were collected at the time of transurethral resection of the prostate. Furthermore, androgen‑independent LNCaP cells were established. The mRNA expression levels of AR and AR‑V7, cell proliferation and prostate‑specific antigen (PSA) production were evaluated by reverse transcription quantitative PCR, MTS assay and chemiluminescent enzyme immunoassay, respectively. There was a significant difference in AR‑V7/AR expression ratios between the CRPC group and the BPH and pre‑treatment PCa groups (CRPC, 7%; BPH and pre‑treatment PCa, 1%). Subsequently, we compared the AR and AR‑V7 expression levels in CRPC samples with those in the pretreatment prostate tissues from the same patients. The results demonstrated that the AR‑V7/AR ratio increased from 3 to 9% after CRPC onset. Furthermore, in vitro experiment demonstrated that AR‑V7 expression in LNCaP cells was increased after transforming into CRPC cells. The AR‑V7/AR ratio also increased from 0.05 to 0.3%. In addition, small interfering (si)‑RNA‑mediated knockdown of AR inhibited the proliferation of and PSA production from androgen‑independent LNCaP cells; however, AR‑V7 knockdown had no effect. Conversely, siRNA‑mediated knockdown of both AR and AR‑V7 inhibited the proliferation of VCAP cells. In summary, the findings from the present study demonstrated that AR‑V7 expression and AR‑V7/AR ratio were increased after the onset of CRPC, which had a limited role in CRPC cell proliferation. Further investigation is required to clarify the roles of AR other splice variants and AR‑V7 in CRPC.

View Figures

View References

1	Heinlein CA and Chang C: Androgen receptor in prostate cancer. Endocr Rev. 25:276–308. 2004. View Article : Google Scholar : PubMed/NCBI
2	Scher HI and Sawyers CL: Biology of progressive, castration-resistant prostate cancer: Directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 23:8253–8261. 2005. View Article : Google Scholar : PubMed/NCBI
3	Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, et al: A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 69:2305–2313. 2009. View Article : Google Scholar : PubMed/NCBI
4	Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, Humphreys E, Han M, Partin AW, Vessella RL, Isaacs WB, et al: Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 69:16–22. 2009. View Article : Google Scholar : PubMed/NCBI
5	Claessens F, Denayer S, Van Tilborgh N, Kerkhofs S, Helsen C and Haelens A: Diverse roles of androgen receptor (AR) domains in AR-mediated signaling. Nucl Recept Signal. 6:e0082008. View Article : Google Scholar : PubMed/NCBI
6	Yu Z, Chen S, Sowalsky AG, Voznesensky OS, Mostaghel EA, Nelson PS, Cai C and Balk SP: Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res. 20:1590–1600. 2014. View Article : Google Scholar : PubMed/NCBI
7	Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, et al: AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 371:1028–1038. 2014. View Article : Google Scholar : PubMed/NCBI
8	Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA and Dehm SM: Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 73:483–489. 2013. View Article : Google Scholar : PubMed/NCBI
9	Korpal M, Korn JM, Gao X, Rakiec DP, Ruddy DA, Doshi S, Yuan J, Kovats SG, Kim S, Cooke VG, et al: An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov. 3:1030–1043. 2013. View Article : Google Scholar : PubMed/NCBI
10	Scher HI, Lu D, Schreiber NA, Louw J, Graf RP, Vargas HA, Johnson A, Jendrisak A, Bambury R, Danila D, et al: Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol. 2:1441–1449. 2016. View Article : Google Scholar : PubMed/NCBI
11	Liu LL, Xie N, Sun S, Plymate S, Mostaghel E and Dong X: Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene. 33:3140–3150. 2014. View Article : Google Scholar : PubMed/NCBI
12	Gleason DF: Classification of prostatic carcinomas. Cancer Chemother Rep. 50:125–128. 1966.PubMed/NCBI
13	Suzuki K, Koike H, Matsui H, Ono Y, Hasumi M, Nakazato H, Okugi H, Sekine Y, Oki K, Ito K, et al: Genistein, a soy isoflavone, induces glutathione peroxidase in the human prostate cancer cell lines LNCaP and PC-3. Int J Cancer. 99:846–852. 2002. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
15	Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, Miller K, Logothetis CJ, Shore ND, Small EJ, et al COU-AA-302 Investigators, : Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): Final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 16:152–160. 2015. View Article : Google Scholar : PubMed/NCBI
16	Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, et al AFFIRM Investigators, : Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 367:1187–1197. 2012. View Article : Google Scholar : PubMed/NCBI
17	Rathkopf DE, Morris MJ, Fox JJ, Danila DC, Slovin SF, Hager JH, Rix PJ, Chow Maneval E, Chen I, Gönen M, et al: Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin Oncol. 31:3525–3530. 2013. View Article : Google Scholar : PubMed/NCBI
18	Fizazi K, Massard C, Bono P, Jones R, Kataja V, James N, Garcia JA, Protheroe A, Tammela TL, Elliott T, et al ARADES study group, : Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): An open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial. Lancet Oncol. 15:975–985. 2014. View Article : Google Scholar : PubMed/NCBI
19	Yamashita S, Lai KP, Chuang KL, Xu D, Miyamoto H, Tochigi T, Pang ST, Li L, Arai Y, Kung HJ, et al: ASC-J9 suppresses castration-resistant prostate cancer growth through degradation of full-length and splice variant androgen receptors. Neoplasia. 14:74–83. 2012. View Article : Google Scholar : PubMed/NCBI
20	Scher HI, Graf RP, Schreiber NA, McLaughlin B, Lu D, Louw J, Danila DC, Dugan L, Johnson A, Heller G, et al: Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic castration-resistant prostate cancer. Eur Urol. 71:874–882. 2017. View Article : Google Scholar : PubMed/NCBI
21	Bernemann C, Schnoeller TJ, Luedeke M, Steinestel K, Boegemann M, Schrader AJ and Steinestel J: Expression of AR-V7 in circulating tumour cells does not preclude response to next generation androgen deprivation therapy in patients with castration resistant prostate cancer. Eur Urol. 71:1–3. 2017. View Article : Google Scholar : PubMed/NCBI
22	Wadosky KM and Koochekpour S: Androgen receptor splice variants and prostate cancer: From bench to bedside. Oncotarget. 8:18550–18576. 2017. View Article : Google Scholar : PubMed/NCBI
23	Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR and Humphrey PA; Grading Committee, : The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of grading patterns and proposal for a new grading system. Am J Surg Pathol. 40:244–252. 2016. View Article : Google Scholar : PubMed/NCBI