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Citations to this article

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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Total citations by year

Year: 2025 2024 2023 2022 Total
Citations: 1 4 2 4 11
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article (11)

Title and authors Publication Year
UPR-induced intracellular C5aR1 promotes adaptation to the hypoxic tumour microenvironment by regulating tumour cell fate
Tatsuya Suwa, Kelly Lee, Ian Jie Chai, Heather Clark, David J. MacLean, Nicole Machado, Gonzalo Berriguete, Geoff S Higgins, Ester Hammond, Monica Olcina
Cell death & disease 2025
An integrative proteomics approach identifies tyrosine kinase KIT as a therapeutic target for SPINK1-positive prostate cancer
Manzar N, Khan UK, Goel A, Carskadon S, Gupta N, Palanisamy N, Ateeq B
iScience 2024
Single-cell transcriptome reveals the heterogeneity of malignant ductal cells and the prognostic value of REG4 and SPINK1 in primary pancreatic ductal adenocarcinoma
Ji Y, Xu Q, Wang W
PeerJ 2024
Hypoxia- and Postirradiation reoxygenation-induced HMHA1/ARHGAP45 expression contributes to cancer cell invasion in a HIF-dependent manner
Lee PW, Suwa T, Kobayashi M, Yang H, Koseki LR, Takeuchi S, Chow CC, Yasuhara T, Harada H
British Journal of Cancer 2024
Myriad factors and pathways influencing tumor radiotherapy resistance
Mi L, Zhang H
Open Life Sciences 2024
Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions
Chen Z, Han F, Du Y, Shi H, Zhou W
Signal Transduction and Targeted Therapy 2023
A positive feedback loop between ID3 and PPARγ via DNA damage repair regulates the efficacy of radiotherapy for rectal cancer
Huang C, Wang L, Chen H, Fu W, Shao L, Zhou D, Wu J, Ye Y
BMC Cancer 2023
SPINKs in Tumors: Potential Therapeutic Targets
C Liao, Q Wang, J An, M Zhang, J Chen, X Li, L Xiao, J Wang, Q Long, J Liu, X Guan
Frontiers in Oncology 2022
Lung transcriptome of nonhuman primates exposed to total- and partial-body irradiation.
Vellichirammal NN, Sethi S, Pandey S, Singh J, Wise SY, Carpenter AD, Fatanmi OO, Guda C, Singh VK
2022
Cuproptosis identifies respiratory subtype of renal cancer that confers favorable prognosis.
Li K, Tan L, Li Y, Lyu Y, Zheng X, Jiang H, Zhang X, Wen H, Feng C
Apoptosis : an international journal on programmed cell death 2022
Prognostic Factors for the Efficiency of Radiation Therapy in Dogs with Oral Melanoma: A Pilot Study of Hypoxia in Intraosseous Lesions.
Noguchi S, Yagi K, Okamoto N, Wada Y, Tanaka T
Veterinary Sciences 2022

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