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SPINK1 as a plasma marker for tumor hypoxia and a therapeutic target for radiosensitization
Tatsuya Suwa, … , Ester M. Hammond, Hiroshi Harada
Tatsuya Suwa, … , Ester M. Hammond, Hiroshi Harada
Published November 8, 2021
Citation Information: JCI Insight. 2021;6(21):e148135. https://doi.org/10.1172/jci.insight.148135.
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Research Article Cell biology Oncology Article has an altmetric score of 6

SPINK1 as a plasma marker for tumor hypoxia and a therapeutic target for radiosensitization

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Abstract

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.

Authors

Tatsuya Suwa, Minoru Kobayashi, Yukari Shirai, Jin-Min Nam, Yoshiaki Tabuchi, Norihiko Takeda, Shusuke Akamatsu, Osamu Ogawa, Takashi Mizowaki, Ester M. Hammond, Hiroshi Harada

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Figure 4

SPINK1 accelerates tumor growth after radiotherapy.

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SPINK1 accelerates tumor growth after radiotherapy.
(A–C) DU145/EV and D...
(A–C) DU145/EV and DU145/SPINK1 cells were cultured under the indicated oxygen conditions for 48 hours and subjected to qPCR (A) and the ELISA assay (B) or treated with the indicated dose of γ-ray irradiation for the clonogenic survival assay (C). (D and E) DU145/EV or SPINK1 xenografts were locally irradiated at a dose of 0 (solid lines) or 10 (dotted lines) Gy. When the volumes of the xenografts reached the same sizes as those on day 0, plasma SPINK1 levels were quantified by ELISA assays (D). Tumor growth was analyzed after the treatment (E). Data are represented as mean ± SD (n = 3 in A and B, n = 6 in C, n = 5 in D, and n = 9–10 in E). Two-tailed Student’s t test. ***P < 0.001. SPINK1, serine peptidase inhibitor Kazal type 1; EV, empty vector.

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