Beyene Desta A, Naab Tammey J, Kanarek Norma F, Apprey Victor, Esnakula Ashwini, Khan Farahan A, Blackman Marc R, Brown Collis A, Hudson Tamaro S
Research Service, Veteran Affairs Medical Center, Washington, District of Columbia.
Howard University Cancer Center, Washington, District of Columbia.
Prostate. 2018 Aug;78(11):801-811. doi: 10.1002/pros.23537. Epub 2018 Apr 22.
Although studies have observed several markers correlate with progression of prostate cancer (PCa), no specific markers have been identified that accurately predict the progression of this disease, even in African American (AA) men who are generally at higher risk than other ethnic groups. The primary goal of this study was to explore whether three markers could predict the progression of PCa.
We investigated protein expression of Annexin 2 (ANX2), serine peptidase inhibitor, kazal type 1(SPINK1)/tumor-associated trypsin inhibitor (TATI), and heat shock protein 60 (Hsp60) in 79 archival human prostate trans-rectal ultrasound (TRUS) biopsy tissues according to a modified World Health Organization (WHO) classification: normal (WHO1a), Gleason Score (GS6 (WHO1b), GS7 subgroups (WHO2 = 3 + 4, WHO3 = 4 + 3), GS8 (WHO4), and GS9-10 (WHO5). AA men aged 41-90 diagnosed from 1990 to 2013 at Howard University were included. Automated staining assessed expression of each biomarker. Spearman correlation assessed the direction and relationship between biomarkers, WHO and modified WHO GS, age, and 5-year survival. A two-tailed t-test and ANOVA evaluated biomarkers expression in relationship to WHO normal and other GS levels, and between WHO GS levels. A logistic and linear regression analysis examined the relationship between biomarker score and WHO GS categories. Kaplan-Meier curves graphed survival.
ANX2 expression decreased monotonically with the progression of PCa while expression of SPINK1/TATI and Hsp60 increased but had a more WHO GS-specific effect; SPINK1/TATI differed between normal and GS 2-6 and HSP60 differed between GS 7 and GS 2-6. WHO GS was found to be significantly and negatively associated with ANX2, and positively with SPINK1/TATI and Hsp60 expression. High SPINK1/TATI expression together with the low ANX2 expression at higher GS exhibited a bi-directional relationship that is associated with PCa progression and survival.
Importantly, the data reveal that ANX2, and SPINK1/TAT1 highly associate with WHO GS and with the transition from one stage of PrCa to the next in AA men. Future research is needed in biracial and larger population studies to confirm this dynamic relationship between ANX2 and SPINK1 as independent predictors of PCa progression in all men.
尽管多项研究观察到几种标志物与前列腺癌（PCa）进展相关，但尚未确定能准确预测该疾病进展的特异性标志物，即便在通常比其他种族群体风险更高的非裔美国（AA）男性中也是如此。本研究的主要目的是探究三种标志物能否预测PCa的进展。
我们根据改良的世界卫生组织（WHO）分类，对79份存档的人类前列腺经直肠超声（TRUS）活检组织中的膜联蛋白2（ANX2）、丝氨酸蛋白酶抑制剂 Kazal 型1（SPINK1）/肿瘤相关胰蛋白酶抑制剂（TATI）和热休克蛋白60（Hsp60）的蛋白表达进行了研究：正常（WHO1a）、 Gleason评分（GS6（WHO1b）、GS7亚组（WHO2 = 3 + 4，WHO3 = 4 + 3）、GS8（WHO4）和GS9 - 10（WHO5）。纳入了1990年至2013年在霍华德大学诊断出的41 - 90岁的AA男性。采用自动染色评估每种生物标志物的表达。Spearman相关性分析评估生物标志物、WHO和改良WHO Gleason评分、年龄及5年生存率之间的方向和关系。双尾t检验和方差分析评估生物标志物表达与WHO正常水平及其他Gleason评分水平之间，以及WHO Gleason评分水平之间的关系。逻辑回归和线性回归分析检验生物标志物评分与WHO Gleason评分类别之间的关系。绘制Kaplan - Meier曲线以描绘生存率。
随着PCa进展，ANX2表达呈单调下降，而SPINK1/TATI和Hsp60的表达增加，但具有更特定于WHO Gleason评分的效应；SPINK1/TATI在正常与GS 2 - 6之间存在差异，HSP60在GSGS7与GS 2 - 6之间存在差异。发现WHO Gleason评分与ANX2显著负相关，与SPINK1/TATI和Hsp60表达显著正相关。在较高的Gleason评分下，高SPINK1/TATI表达与低ANX2表达呈现出与PCa进展和生存相关的双向关系。
重要的是，数据显示ANX2以及SPINK1/TAT1与WHO Gleason评分以及AA男性中前列腺癌从一个阶段向下一个阶段的转变高度相关。需要在双种族和更大规模的人群研究中进一步开展研究，以证实ANX2和SPINK1之间的这种动态关系可作为所有男性PCa进展的独立预测指标。
