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Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis.

ABSTRACT: Mucus injury associated with goblet cell (GC) depletion constitutes an early event in inflammatory bowel disease (IBD). Using single-cell sequencing to detect critical events in mucus dysfunction, we discover that the Kazal-type serine protease inhibitor SPINK4 is dynamically regulated in colitic intestine in parallel with disease activities. Under chemically induced colitic conditions, the grim status in Spink4-conditional knockout mice is successfully rescued by recombinant murine SPINK4. Notably, its therapeutic potential is synergistic with existing TNF-α inhibitor infliximab in colitis treatment. Mechanistically, SPINK4 promotes GC differentiation using a Kazal-like motif to modulate EGFR-Wnt/β-catenin and -Hippo pathways. Microbiota-derived diacylated lipoprotein Pam2CSK4 triggers SPINK4 production. We also show that monitoring SPINK4 in circulation is a reliable noninvasive technique to distinguish IBD patients from healthy controls and assess disease activity. Thus, SPINK4 serves as a serologic biomarker of IBD and has therapeutic potential for colitis via intrinsic EGFR activation in intestinal homeostasis.

SUBMITTER: Wang Y

PROVIDER: S-EPMC11245600 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis.

Wang Ying Y Han Jing J Yang Guang G Zheng Shuhui S Zhou Gaoshi G Liu Xinjuan X Cao Xiaocang X Li Guang G Zhang Bowen B Xie Zhuo Z Li Li L Zhang Mudan M Li Xiaoling X Chen Minhu M Zhang Shenghong S

Nature communications 20240712 1

Mucus injury associated with goblet cell (GC) depletion constitutes an early event in inflammatory bowel disease (IBD). Using single-cell sequencing to detect critical events in mucus dysfunction, we discover that the Kazal-type serine protease inhibitor SPINK4 is dynamically regulated in colitic intestine in parallel with disease activities. Under chemically induced colitic conditions, the grim status in Spink4-conditional knockout mice is successfully rescued by recombinant murine SPINK4. Nota ...[more]

PMID: 38997284

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Project description:BackgroundWe aimed to characterize serine protease inhibitor Kazal type 1 (SPINK1) as a gene signature for the early diagnosis, molecular targeting, and prediction of immune checkpoint blockade (ICB) treatment response of hepatocellular carcinoma (HCC).MethodsThe transcriptomics, proteomics, and phenotypic analyses were performed separately or in combination.ResultsWe obtained the following findings on SPINK1. Firstly, in the transcriptomic training dataset, which included 279 stage I and II tumor samples (out of 1,884 stage I-IV HCC specimens) and 259 normal samples, significantly higher area under curve (AUC) values and increased integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were demonstrated for HCC discrimination in SPINK1-associated models compared with those of alpha-fetoprotein (AFP). The calibration of both SPINK1-related curves fitted significantly better than that of AFP. In the two independent transcriptomic validation datasets, which included 201, 103 stage I-II tumor and 192, 169 paired non-tumor specimens, respectively, the obtained results were consistent with the above-described findings. In the proteomic training dataset, which included 98 stage I and II tumor and 165 normal tissue samples, the analyses also revealed better AUCs and increased IDI and NRI in the aforementioned SPINK1-associated settings. A moderate calibration was shown for both SPINK1-associated models relative to the poor results of AFP. Secondly, in the in vitro and/or in vivo murine models, the wet-lab experiments demonstrated that SPINK1 promoted the proliferation, clonal formation, migration, chemoresistance, anti-apoptosis, tumorigenesis, and metastasis of HCC cells, while the anti-SPINK1 antibody inhibited the growth of the cells, suggesting that SPINK1 has "tumor marker" and "targetable" characteristics in the management of HCC. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that SPINK1 was engaged in immunity-related pathways, including T-cell activation. Thirdly, in the transcriptomic analyses of the 368 HCC specimens from The Cancer Genome Atlas (TCGA) cohort, the high abundance of SPINK1 was positively correlated with the high levels of activated tumor-infiltrating CD4+ and CD8+ T lymphocytes and dendritic and natural killer cells, while there were also positive correlations between SPINK1 and immune checkpoints, including PD-1, LAG-3, TIM-3, TIGIT, HAVCR2, and CTLA-4. The ESTIMATE algorithm calculated positive correlations between SPINK1 and the immune and ESTIMATE scores, suggesting a close correlation between SPINK1 and the immunogenic microenvironment within HCC tissues, which may possibly help in predicting the response of patients to ICB therapy.ConclusionsSPINK1 could be a potential biomarker for the early detection, targeted therapy, and prediction of ICB treatment response in the management of HCC.

Dataset Information

Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis.

Publications

Therapeutic potential of the secreted Kazal-type serine protease inhibitor SPINK4 in colitis.

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