Abstract
Serine Peptidase Inhibitor Kazal Type 1 (SPINK1) is a secreted protein known as a protease inhibitor of trypsin in the pancreas. However, emerging evidence shows its function in promoting cancer progression in various types of cancer. SPINK1 modulated tumor malignancies and induced the activation of the downstream signaling of epidermal growth factor receptor (EGFR) in cancer cells, due to the structural similarity with epidermal growth factor (EGF). The discoverable SPINK1 somatic mutations, expressional signatures, and prognostic significances in various types of cancer have attracted attention as a cancer biomarker in clinical applications. Emerging findings further clarify the direct and indirect biological effects of SPINK1 in regulating cancer proliferation, metastasis, drug resistance, transdifferentiation, and cancer stemness, warranting the exploration of the SPINK1-mediated molecular mechanism to identify a therapeutic strategy. In this review article, we first integrate the transcriptomic data of different types of cancer with clinical information and recent findings of SPINK1-mediated malignant phenotypes. In addition, a comprehensive summary of SPINK1 expression in a pan-cancer panel and individual cell types of specific organs at the single-cell level is presented to indicate the potential sites of tumorigenesis, which has not yet been reported. This review aims to shed light on the roles of SPINK1 in cancer and provide guidance and potential directions for scientists in this field.
Highlights
Serine Peptidase Inhibitor Kazal Type 1 (SPINK1) is a secreted protein known as a protease inhibitor of trypsin in the pancreas
In addition to the frequently reported N34S mutation in the West, a retrospective study in China indicated that the c.194+2T>C mutation of SPINK1 was present in 44.9% of patients with idiopathic chronic pancreatitis [24]
These transcriptomic data were mainly obtained after performing microarray experiments and RNA sequencing (RNA-Seq) on a pan-cancer scale, and the raw data were retrieved from the public database The Cancer Genome Atlas (TCGA), showing relative SPINK1 expression after normalization in various types of cancer (Figure 3)
Summary
Serine peptidase inhibitor Kazal type I (SPINK1) was first discovered in bovine pancreas extracts by Kazal et al, and the molecule was designated a pancreatic secretory trypsin inhibitor (PSTI) [1]. SPINK1 reprograms the expression profile of prostate cancer cells, leading to prominent epithelial–endothelial transition (EET), a phenotypic switch mediated by EGFR signaling [9]. The interaction of SPINK1 with EGFR has attracted attention for its potentially pivotal biological functions, especially in modulating cancer progression. We further review and summarize the recently published data focusing on integrated evidence that illustrates SPINK1 expression levels in a broad range of cancer types together with SPINK1-dependent biological effects on the regulation of several critical. The SPINK1-driven biological effect induced by EGFR signaling was reported factors in processes related to cancer progression, including cancer proliferation, metastain ovarian cells [12]. In addition to the biological in an immunoprecipitation experiment and trigger cancer cell proliferation via activating function of SPINK1 in cancer, its clinical and prognostic significance in multiple cancer. Transcription and position of a stop codon are indicated by green and red arrowheads, respectively
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