Loss of PLZF Expression in Prostate Cancer by Immunohistochemistry Correlates with Tumor Aggressiveness and Metastasis

Abstract

PLZF is a transcription repressor, which plays a critical role in development, spermatogenesis and oncogenesis. Down-regulation of PLZF has been found in various tumor cell lines. There has been virtually no tissue study on the expression of PLZF in prostate cancer (PCa). PCa is a heterogeneous disease, most of which are indolent and non-lethal. Currently there are no biomarkers that distinguish indolent from aggressive PCa; therefore there is an urgent need for such markers to provide clinical decision support. This study aimed to investigate the expression of PLZF by immunohistochemistry in different grade as well as metastatic PCa and to correlate the alteration of PLZF expression with PCa aggressiveness. We studied a total of 83 primary PCa from biopsies, 43 metastatic PCa and 8 paired primary and metastatic PCa from radical prostatectomies with lymph node dissection. Our results demonstrated that PLZF was strongly expressed in almost all (~100%) benign luminal cells (n=77) and low grade (Gleason pattern 3) PCa (n=70) and weak or absent (100%) in basal cells (n=70). Decreased or lost expression of PLZF was evidenced in 26% of high-grade (Gleason 4 and 5) primary PCa (n=70) and 84% metastatic PCa (n=43). The primary high grade PCa in the prostatectomies shared similar PLZF loss/decrease and histomorphology to that of paired parallel lymph node metastases. These data demonstrated that down-regulation of PLZF is an important molecular process for tumor progression and loss of PLZF expression detected by routine immunohistochemistry is a promising and valuable biomarker for PCa aggressiveness and metastasis in the personalized care of PCa.

Impact of Therapy on Genomics and Transcriptomics in High-Risk Prostate Cancer Treated with Neoadjuvant Docetaxel and Androgen Deprivation Therapy

“…However, there were some unusual events including a deep deletion of ZBTB16 in the biopsy and RP specimen from one patient (case 5346), and an amplification of CDK6 in both the biopsy and RP specimen from another patient (case 6803) (Supplementary Figure 6). Homozygous deletions of the transcriptional repressor and putative tumor suppressor ZBTB16 ( PLZF ) were recently identified in CRPC (8,26). …”

ZBTB16: a novel sensitive and specific biomarker for yolk sac tumor

“…Except carcinoid and prostatic adenocarcinoma, 25,44 ZBTB16 nuclear expression is barely seen in other tumors, including those from respiratory, gastrointestinal and biliary tracts, pancreas, kidney, bladder, and female genital tract. 45 Despite only a few cases studied, the strong reactivity of anti-ZBTB16 with ovarian yolk sac tumor, metastatic yolk sac tumor, as well as extragonadal (mediastinal) yolk sac tumor also confirmed its potential value in distinguishing extra-testicular and metastatic yolk sac tumor from its other tumor mimics.…”

“…[18][19][20] Zinc finger and BTB domain containing 16 (ZBTB16), first identified in a patient with acute promyelocytic leukemia, is a zinc finger transcription factor belonging to the POZ-Krüppel family that binds to specific DNA sequences with its C-terminal zinc fingers and suppresses transcription by recruiting co-repressors with its aminoterminal POZ domain. 21,22 ZBTB16 affects diverse signaling pathways including cell cycle, differentiation, and programmed cell death pathways in hematopoietic cells and in solid tumors as well, [22][23][24][25] and is involved in major developmental and biological processes such as spermatogenesis and stem cell maintenance, hind limb formation, hematopoiesis, immune regulation, and oncogenesis. 21,22,26,27 In the testes, ZBTB16 is expressed specifically in undifferentiated spermatogonia.…”

An Integrative Analysis of Preeclampsia Based on the Construction of an Extended Composite Network Featuring Protein-Protein Physical Interactions and Transcriptional Relationships

“…ZBTB16 is a member of the kruppel-like zinc finger protein family involved in a multitude of biological processes including spermatogenesis, hematopoiesis, myeloid differentiation lymphoid development, cytokine production, programming and maturation of NKT and INKT cells, cellular proliferation and apoptosis [47, 48]. Due to its role in limiting cell-cycle progression and cellular proliferation PLZF is known as a tumor suppressor [49]. Recruitment of co-repressors and subsequent chromatin remodeling has been shown to underlie the repressor function of ZBTB16 [48, 50].…”