Kao Kenneth R, Popadiuk Paul, Thoms John, Aoki Satoko, Anwar Shahgul, Fitzgerald Emily, Andrews Phillip, Voisey Kim, Gai Luis, Challa Satya, He Zhijian, Gonzales-Aguirre Paola, Simmonds Andrea, Popadiuk Catherine
Division of Anatomical Pathology, Laboratory Medicine Program, Eastern Health, St. John's, Canada.
Biomedical Sciences, Memorial University, St. John's, NL, Canada.
J Clin Pathol. 2018 May;71(5):402-411. doi: 10.1136/jclinpath-2017-204718. Epub 2017 Sep 18.
Prostate cancer (PrCa) is the most frequently diagnosed non-cutaneous cancer in men. Without clear pathological indicators of disease trajectory at diagnosis, management of PrCa is challenging, given its wide-ranging manifestation from indolent to highly aggressive disease. This study examines the role in PrCa of the Pygopus (PYGO)2 chromatin effector protein as a risk stratification marker in PrCa.
RNA expression was performed in PrCa cell lines using Northern and RT-PCR analyses. Protein levels were assessed using immunoblot and immunofluorescence. Immunohistochemistry was performed on tissue microarrays constructed from radical prostatectomies with 5-year patient follow-up data including Gleason score tumour staging, margin and lymph node involvement and prostate serum antigen (PSA) levels. Biochemical recurrence (BR) was defined as a postoperative PSA level of >0.2 nL. Univariate and multivariate analyses were performed using SAS and Kaplan-Meier curves using graphPad (Prism).
In vitro depletion of PYGO2 by RNAi in both androgen receptor positive and negative PrCa cell lines attenuated growth and reduced Ki67 and 47S rRNA expression, while PYGO2 protein was localised to the nuclei of tumours as determined by immunohistochemistry. High expression levels of PYGO2 in tumours (n=156) were correlated with BR identified as PSA progression, after 7-year follow-up independent of other traditional risk factors. Most importantly, high PYGO2 levels in intermediate grade tumours suggested increased risk of recurrence over those with negative or weak expression.
Our data suggest that elevated PYGO2 expression in primary prostate adenocarcinoma is a potential risk factor for BR.
前列腺癌（PrCa）是男性中最常被诊断出的非皮肤癌。由于在诊断时缺乏明确的疾病发展病理指标，且PrCa从惰性疾病到高度侵袭性疾病的表现范围广泛，其治疗颇具挑战性。本研究探讨了Pygopus（PYGO）2染色质效应蛋白在PrCa中作为风险分层标志物的作用。
使用Northern和RT-PCR分析在PrCa细胞系中进行RNA表达检测。使用免疫印迹和免疫荧光评估蛋白质水平。对由根治性前列腺切除术构建的组织微阵列进行免疫组织化学分析，并收集患者5年随访数据，包括 Gleason评分、肿瘤分期、切缘和淋巴结受累情况以及前列腺特异性抗原（PSA）水平。生化复发（BR）定义为术后PSA水平>0.2 nL。使用SAS进行单因素和多因素分析，并使用GraphPad（Prism）绘制Kaplan-Meier曲线。
在雄激素受体阳性和阴性的PrCa细胞系中，通过RNAi体外消耗PYGO2可减弱细胞生长并降低Ki67和47S rRNA表达，而免疫组织化学确定PYGO2蛋白定位于肿瘤细胞核。在7年随访后，与其他传统风险因素无关，肿瘤（n = 156）中PYGO2的高表达水平与被确定为PSA进展的BR相关。最重要的是，中级肿瘤中高PYGO2水平表明与那些表达阴性或弱阳性的肿瘤相比，复发风险增加。
我们的数据表明，原发性前列腺腺癌中PYGO2表达升高是BR的潜在风险因素。
