SPINK1 as a plasma marker for tumor hypoxia and a therapeutic target for radiosensitization.
SPINK1 as a plasma marker for tumor hypoxia and a therapeutic target for radiosensitization.
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DOI：
10.1172/jci.insight.148135
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发表时间：
2021-11-08
期刊：
影响因子：
8
通讯作者：
Harada H
中科院分区：
文献类型：
--
作者：
Suwa T;Kobayashi M;Shirai Y;Nam JM;Tabuchi Y;Takeda N;Akamatsu S;Ogawa O;Mizowaki T;Hammond EM;Harada H
缺氧与肿瘤放射抵抗有关；因此，寻求肿瘤缺氧的预测指标和合理的治疗靶点，实现个体化放疗。在这里，我们发现丝氨酸蛋白酶抑制剂Kazal I型（SPINK1）符合这两个标准。缺氧（O2 < 0.1%）诱导转录起始水平的SPINK1表达以hif依赖的方式表达，导致分泌的SPINK1水平增加。SPINK1蛋白在异种移植物和临床肿瘤组织缺氧区内部和周围均被检测到，其血浆水平随着异种移植物供氧减少而升高。即使在正常环境下，分泌的SPINK1蛋白也以egfr依赖和核因子红系2相关因子2依赖（nrf2依赖）的方式增强癌细胞的放射抵抗，并加速放疗后肿瘤的生长。抗spink1中和抗体具有放射增敏作用。这些结果表明，缺氧细胞分泌的SPINK1以旁分泌的方式保护周围和相对氧化的癌细胞免受辐射，证明了SPINK1作为放射增敏靶点和预测肿瘤缺氧的血浆标记物是合理的。
Hypoxia is associated with tumor radioresistance; therefore, a predictive marker for tumor hypoxia and a rational target to overcome it have been sought to realize personalized radiotherapy. Here, we show that serine protease inhibitor Kazal type I (SPINK1) meets these 2 criteria. SPINK1 expression was induced upon hypoxia (O2 < 0.1%) at the transcription initiation level in a HIF-dependent manner, causing an increase in secreted SPINK1 levels. SPINK1 proteins were detected both within and around hypoxic regions of xenografted and clinical tumor tissues, and their plasma levels increased in response to decreased oxygen supply to xenografts. Secreted SPINK1 proteins enhanced radioresistance of cancer cells even under normoxic conditions in EGFR-dependent and nuclear factor erythroid 2–related factor 2–dependent (Nrf2-dependent) manners and accelerated tumor growth after radiotherapy. An anti-SPINK1 neutralizing antibody exhibited a radiosensitizing effect. These results suggest that SPINK1 secreted from hypoxic cells protects the surrounding and relatively oxygenated cancer cells from radiation in a paracrine manner, justifying the use of SPINK1 as a target for radiosensitization and a plasma marker for predicting tumor hypoxia.
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