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MicroRNA alteration and putative target genes in high-grade prostatic intraepithelial neoplasia and prostate cancer: STAT3 and ZEB1 are upregulated during prostate carcinogenesis.

 Yoon Jin Cha  ;  Joo Hyun Lee  ;  Hyun Ho Han  ;  Baek Gil Kim  ;  Suki Kang  ;  Young Deuk Choi  ;  Nam Hoon Cho 
 Prostate, Vol.76(10) : 937-947, 2016 
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Adult ; Aged ; Aged, 80 and over ; Carcinogenesis/genetics ; Cell Line ; Cell Line, Tumor ; Gene Expression Profiling ; Humans ; Lymphatic Metastasis/genetics ; Male ; MicroRNAs/analysis* ; MicroRNAs/genetics* ; Middle Aged ; Prostatic Intraepithelial Neoplasia/genetics* ; Prostatic Intraepithelial Neoplasia/pathology ; Prostatic Neoplasms/genetics* ; Prostatic Neoplasms/pathology ; RNA, Messenger/analysis ; STAT3 Transcription Factor/genetics* ; Up-Regulation ; Zinc Finger E-box-Binding Homeobox 1/genetics*
STAT3 ; ZEB1 ; microRNAs ; prostate cancer ; prostatic intraepithelial neoplasia
BACKGROUND: We aimed to identify alteration of cancer-related miRNAs in HGPIN and PCa, and to investigate the clinical implications of HGPIN as a precancerous lesion of PCa. METHODS: Clinicopathologic analysis based on the status of HGPIN was performed in 388 patients who received radical prostatectomy between January 2005 and December 2008 in Severance Hospital. Among them, 10 paired HGPIN and PCa were prepared to perform miRNA microarray and quantitative real-time PCR. Fifty-two prostatectomy specimens were used to further validation of protein expression that was assessed by immunohistochemical staining (IHC) in matched non-neoplastic prostatic tissue (NPT), HGPIN, and PCa. Functional analysis was performed using a prostate normal cell line (RWPE-1) and two prostate cancer cell lines (LNCaP, PC-3) for comparison of expression of miR-155 and STAT3 mRNA before and after treatment of miR-155 mimetics/antagomir into each cell line. RESULTS: Patients with HGPIN had significantly less lymphovascular invasion, less lymph node metastasis, lower tumor volume, lower Gleason score, lower incidence of death, and longer overall survival compared to patients without HGPIN. MiR-155, miR-210, miR-153, and miR-200c were downregulated in HGPIN and PCa in common, compared to NPT. As putative target mRNAs, mRNA expression level of STAT3, ZEB1, and BACH1 was increased in PCa and HGPIN compared to NPT. mRNA expression level of ephrin-A3 was increased in PCa compared to NPT, and FGFRL1 was decreased in PCa compared to HGPIN and NPT. Protein expression assessed by IHC showed correlated results in STAT3, ZEB1, and ephrin-A3. Moreover, STAT3 and ZEB1 increased in a stepwise manner, from NPT to PCa. Treatment of miR-155 antagomir increased STAT3 mRNA expression in RWPE-1 cells, whereas treatment of miR-155 mimetics into PC-3 cells significantly decreased STAT3 expression. CONCLUSIONS: STAT3 and ZEB1 could be the key molecules altered at the early stages of carcinogenesis, especially in HGPIN. Prostate 76:937-947, 2016. © 2016 Wiley Periodicals, Inc.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
Yonsei Authors
강숙희(Kang, Suki) ORCID logo https://orcid.org/0000-0002-9957-3479
김백길(Kim, Baek Gil) ORCID logo https://orcid.org/0000-0001-6270-1433
조남훈(Cho, Nam Hoon) ORCID logo https://orcid.org/0000-0002-0045-6441
차윤진(Cha, Yoon Jin) ORCID logo https://orcid.org/0000-0002-5967-4064
최영득(Choi, Young Deuk) ORCID logo https://orcid.org/0000-0002-8545-5797
한현호(Han, Hyun Ho) ORCID logo https://orcid.org/0000-0002-6268-0860
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