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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 8

SPINK1 in plasma reflects the degree of hypoxia within tumor tissue in vivo.

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SPINK1 in plasma reflects the degree of hypoxia within tumor tissue in v...
(A) A scatter plot for correlation analysis between mRNA levels of SPINK1 and CA9 in 36 HeLa tumor xenografts showed a good coefficient of determination, R2 = 0.9458. (B and C) After blood flow to the HeLa tumor xenografts was decreased by ligaturing the leg for the indicated times, levels of SPINK1 mRNA (B) and SPINK1 protein (C) in the tumor tissues were quantified by qPCR and the ELISA assay, respectively. (D–I) After anemia treatment by phenylhydrazine administration, mRNA levels of EPO in the kidneys (D and E) and those of CA9 (E–H) and SPINK1 (F) in tumor tissues were quantified by qPCR. SPINK1 protein levels in tumors (G) and plasma (H and I) and the tumor volume (I) were measured by the ELISA assay and digital calipers, respectively. Scatter plots for correlation analysis between the 2 indicated factors (E–I). Data are represented as mean ± SD (B–D; n = 36 in A, n = 9–10 in B and C, n = 5 in D–I). Two-tailed Student’s t test (D). One-way ANOVA with Dunnett’s test (B and C). *P < 0.05, ***P < 0.001. SPINK1, serine peptidase inhibitor Kazal type 1; EV, empty vector; CA9, carbonic anhydrase 9; EPO, erythropoietin.

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