MicroRNA-dependent regulation in the preceding step of prostate cancer

Abstract

Background: Prostatic intraepithelial neoplasia (PIN), convincingly acceptable precursor lesion of prostate cancer (PCa), is characterized by obvious cytologic atypia in luminal cells with preserved basal cells. However, molecular association between PIN and PCa has been vaguely clarified. We aimed to identify miRNAs and surrogate target mRNA specific to regulate development of PIN and PCa, and to identify clinical implication of PIN as precancerous lesion of PCa.

Materials and methods: Among the 388 radical prostatectomy patients, 69.3% harbored PIN, and large PIN was observed in 56 patients. Clinicopathologic analysis was performed based on the PIN status. To anlaysis miRNAs and surrogate target mRNAs, PIN clusters were obtained by macrodisseciton or laser capture microdissection from formalin-fixed paraffin embedded tissue. Using miRNA microarray screening analysis for each PIN or PCa to compare with normal prostatic tissue, top-ranked miRNAs with relatively lower expression were selected. Immunohistochemistry for FGFRL1, BACH1, ephrin-A3, STAT3, and ZEB1was performed, and expression level of the proteins in PCa, PIN, and normal prostatic tissue was analyzed.

Results: Patients harbored PIN showed significant less lymphovascular invasion, less lymph node metastasis, lower tumor volume, lower Gleason score, lower death rate, longer overall survival compared to patients without PIN. Significant downregulation of miR-155, miR-210, miR-153, and miR-200c was observed. Subsequent validation step using immunohistochemistry against the candidate gene products revealed significant high expression of STAT3, ephrin-A3 and ZEB1 in PCa compared to PIN and normal prostatic tissue. Significant stepwise increase in expression of STAT3 and ZEB1 was observed from normal prostatic tissue to PCa.

Conclusion: More favorable clinicopathologic parameters and longer overall survival in patients with PIN imply disease progression from PIN to PCa. Furthermore, downregulation of cancer-related miRNAs - miR-155, miR-210, miR-153, and miR-200c- in both PIN and PCa and stepwise increased expression of STAT3 and ZEB1 support that PIN is a preceding lesion of PCa and early carcinogenesis starts at the molecular level.