Cholesterol Metabolism and Prostate Cancer Lethality.
Cholesterol Metabolism and Prostate Cancer Lethality.
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DOI：
10.1158/0008-5472.can-16-0903
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发表时间：
2016-08-15
期刊：
影响因子：
11.2
通讯作者：
Rider JR
中科院分区：
文献类型：
--
作者：
Stopsack KH;Gerke TA;Sinnott JA;Penney KL;Tyekucheva S;Sesso HD;Andersson SO;Andrén O;Cerhan JR;Giovannucci EL;Mucci LA;Rider JR
胆固醇代谢与前列腺癌的发病机制有关。在这里，我们评估了诊断时肿瘤标本中胆固醇合成酶、转运蛋白和调节蛋白的肿瘤内mRNA表达与致死性前列腺癌的相关性，致死性前列腺癌定义为死亡率或前列腺癌转移，而非致死性疾病在随访至少8年后没有转移的证据。我们分析了健康专业人员随访研究（n = 249）和医生健康研究（n = 153）中的前瞻性前列腺癌队列，以及瑞典观察等待研究（n = 338）中的预期管理患者。在所有三个队列中，角鲨烯单加氧酶（SQLE）的表达与致死性癌症相关。SQLE高表达的男性（高于平均值1个标准差）与SQLE平均表达水平的男性相比，尽管接受了治疗，但仍有8.3倍（95%置信区间，3.5至19.7）的可能性患有致命癌症。SQLE绝对表达与致死性癌症相关，与Gleason分级和分期无关，肿瘤与周围良性前列腺组织的SQLE表达比率也是如此。较高的SQLE表达与血管生成的组织学标志物增加密切相关。总的来说，这项研究建立了肿瘤内胆固醇合成的预后价值，通过SQLE，其第二限速酶测量。SQLE表达在癌症诊断是预后的致死性前列腺癌后根治性切除术和在一个观察等待设置，可能通过促进微转移疾病。
Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to non-lethal disease without evidence of metastases after at least eight years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians’ Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared to men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease.