Chinnam Meenalakshmi, Wang Yanqing, Zhang Xiaojing, Gold David L, Khoury Thaer, Nikitin Alexander Yu, Foster Barbara A, Li Yanping, Bshara Wiam, Morrison Carl D, Payne Ondracek Rochelle D, Mohler James L, Goodrich David W
Department of Pharmacology & Therapeutics (MC, YW, XZ, BAF, DWG), Department of Biostatistics (DLG), Department of Pathology (TK, WB, CDM), Department of Cancer Prevention and Population Science (RDPO), Department of Urology (JLM), Roswell Park Cancer Institute, Buffalo, NY; Department of Biomedical Sciences, Cornell University, Ithaca, NY (AYN); Department of Pathology, Virginia Commonwealth University, Richmond, VA (YL). Current affiliation: MedImmune LLC, Gaitherburg, MD.
Current affiliation: MedImmune LLC, Gaitherburg, MD.
J Natl Cancer Inst. 2014 Oct 8;106(11). doi: 10.1093/jnci/dju306. Print 2014 Nov.
The majority of newly diagnosed prostate cancers will remain indolent, but distinguishing between aggressive and indolent disease is imprecise. This has led to the important clinical problem of overtreatment. THOC1 encodes a nuclear ribonucleoprotein whose expression is higher in some cancers than in normal tissue. The hypothesis that THOC1 may be a functionally relevant biomarker that can improve the identification of aggressive prostate cancer has not been tested.
THOC1 protein immunostaining was evaluated in a retrospective collection of more than 700 human prostate cancer specimens and the results associated with clinical variables and outcome. Thoc1 was conditionally deleted in an autochthonous mouse model (n = 22 or 23 per genotype) to test whether it is required for prostate cancer progression. All statistical tests were two-sided.
THOC1 protein immunostaining increases with higher Gleason score and more advanced Tumor/Node/Metastasis stage. Time to biochemical recurrence is statistically significantly shorter for cancers with high THOC1 protein (log-rank P = .002, and it remains statistically significantly associated with biochemical recurrence after adjusting for Gleason score, clinical stage, and prostate-specific antigen levels (hazard ratio = 1.61, 95% confidence interval = 1.03 to 2.51, P = .04). Thoc1 deletion prevents prostate cancer progression in mice, but has little effect on normal tissue. Prostate cancer cells deprived of Thoc1 show gene expression defects that compromise cell growth.
Thoc1 is required to support the unique gene expression requirements of aggressive prostate cancer in mice. In humans, high THOC1 protein immunostaining associates with prostate cancer aggressiveness and recurrence. Thus, THOC1 protein is a functionally relevant molecular marker that may improve the identification of aggressive prostate cancers, potentially reducing overtreatment.
大多数新诊断出的前列腺癌将保持惰性，但区分侵袭性和惰性疾病并不精确。这导致了过度治疗这一重要的临床问题。THOC1编码一种核糖核蛋白，其在某些癌症中的表达高于正常组织。THOC1可能是一种功能相关的生物标志物，可改善侵袭性前列腺癌的识别这一假说尚未得到验证。
在一项回顾性收集的700多例人类前列腺癌标本中评估THOC1蛋白免疫染色，并将结果与临床变量和预后相关联。在一个原位小鼠模型中条件性敲除Thoc1（每种基因型n = 22或23），以测试它是否是前列腺癌进展所必需的。所有统计检验均为双侧检验。
THOC1蛋白免疫染色随着Gleason评分升高和肿瘤/淋巴结/转移分期进展而增加。THOC1蛋白水平高的癌症患者生化复发时间在统计学上显著更短（对数秩检验P = 0.002，在调整Gleason评分、临床分期和前列腺特异性抗原水平后，它与生化复发仍在统计学上显著相关（风险比 = 1.61，95%置信区间 = 1.03至2.51，P = 0.04）。敲除Thoc1可阻止小鼠前列腺癌进展，但对正常组织影响很小。缺乏Thoc1的前列腺癌细胞表现出损害细胞生长的基因表达缺陷。
Thoc1是支持小鼠侵袭性前列腺癌独特基因表达需求所必需的。在人类中，高THOC1蛋白免疫染色与前列腺癌侵袭性和复发相关。因此，THOC1蛋白是一种功能相关的分子标志物，可能改善侵袭性前列腺癌的识别，潜在地减少过度治疗。
