Serine peptidase inhibitor Kazal type 1 (SPINK1) as novel downstream effector of the cadherin-17/β-catenin axis in hepatocellular carcinoma

Shek, Felix H.; Luo, Ruibang; Lam, Brian; Sung, Wing-Kin; Lam, Tak Wah; Luk, John M.; Leung, Ming Sum; Chan, Kin; Wang, Hector K.; Chan, Chung Man; Poon, Ronnie Tung‐Ping; Lee, Nikki P.

doi:10.1007/s13402-017-0332-x

Cited by 14 publications

(9 citation statements)

References 45 publications

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“… 30 SPINK-1 is a serine peptidase inhibitor involved in tumorigenesis that has been found upregulated in a number of tumors, including HCC, where it may promote epithelial to mesenchymal transition phenomena. 31 Finally, ITGA2 is a transmembrane receptor for collagens and related proteins that mediates the adhesion of platelets and other cell types to the extracellular matrix and has been shown to be one of the key genes involved in HCC development. 32 In fact, patients with NAFLD and NAFLD-related HCC have increased platelet activation and adhesion within the liver and blockade of platelet activation prevents HCC development in a murine model of NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization of chronic liver disease dynamics: From liver fibrosis to acute-on-chronic liver failure

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Molecular characterization of chronic liver disease dynamics: From liver fibrosis to acute-on-chronic liver failure

et al. 2022

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“…Furthermore, accumulating evidence indicates the significance of aberrant enhancer-mediated transcriptional dysregulation in the formation and maintenance of multiple tumors ( 117 , 118 ), including HCC ( 25 ). In the present study, we identified abundant hypomethylated enhancer-associated activated HCC-related genes such as MUC13 ( 119 ), SPINK1 ( 105 ), and KIF2C ( 97 ), plus hypermethylated enhancer-associated repression of known HCC suppressors like DUSP1 ( 80 ) and ADI1 ( 83 ). Additionally, we found aberrant enhancer-associated dysregulation of genes whose functions are uncharacterized in cancer but harbor possibly essential biological functions.…”

Section: Discussionmentioning

confidence: 60%

Integrative Analysis of Epigenome and Transcriptome Data Reveals Aberrantly Methylated Promoters and Enhancers in Hepatocellular Carcinoma

Huang

Han

et al. 2021

Front. Oncol.

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DNA methylation is a key transcription regulator, whose aberration was ubiquitous and important in most cancers including hepatocellular carcinoma (HCC). Whole-genome bisulfite sequencing (WGBS) was conducted for comparison of DNA methylation in tumor and adjacent tissues from 33 HCC patients, accompanying RNA-seq to determine differentially methylated region-associated, differentially expressed genes (DMR-DEGs), which were independently replicated in the TCGA-LIHC cohort and experimentally validated via 5-aza-2-deoxycytidine (5-azadC) demethylation. A total of 9,867,700 CpG sites showed significantly differential methylation in HCC. Integrations of mRNA-seq, histone ChIP-seq, and WGBS data identified 611 high-confidence DMR-DEGs. Enrichment analysis demonstrated activation of multiple molecular pathways related to cell cycle and DNA repair, accompanying repression of several critical metabolism pathways such as tyrosine and monocarboxylic acid metabolism. In TCGA-LIHC, we replicated about 53% of identified DMR-DEGs and highlighted the prognostic significance of combinations of methylation and expression of nine DMR-DEGs, which were more efficient prognostic biomarkers than considering either type of data alone. Finally, we validated 22/23 (95.7%) DMR-DEGs in 5-azadC-treated LO2 and/or HepG2 cells. In conclusion, integration of epigenome and transcriptome data depicted activation of multiple pivotal cell cycle-related pathways and repression of several metabolic pathways triggered by aberrant DNA methylation of promoters and enhancers in HCC.

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“…Moreover, SPINK1 is significantly upregulated in HCC tissues compared with corresponding nonmalignant tissues ( 25 , 26 ). It also causes the epithelial-mesenchymal transition (EMT) via MEK/ERK pathway ( 27 ) and acts as a downstream effector of the CDH17/β-catenin axis in HCC ( 28 ). By analyzing the GEO database, we found that SPINK1 was upregulated in the HCC tissues; this was further verified using qRT-PCR in 25 paired HCC tumors and adjacent nontumors.…”

Section: Discussionmentioning

confidence: 99%

circRPS16 Promotes Proliferation and Invasion of Hepatocellular Carcinoma by Sponging miR-876-5p to Upregulate SPINK1

Lin

et al. 2021

Front. Oncol.

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The roles of serine protease inhibitor Kazal type 1 (SPINK1) in multiple types of cancers have been significantly documented. However, its specific roles in hepatocellular carcinoma (HCC) remain to be investigated. This study found that SPINK1 is upregulated in HCC and its upregulation correlates with poor prognosis. Besides, functional assays revealed that SPINK1 promotes cell proliferation, cell cycle, and invasion in vitro. Through bioinformatics analysis, we speculate that circRPS16 regulates SPINK1 expression by sponging miR-876-5p. This was further verified by the dual-luciferase reporter and fluorescent in situ hybridization (FISH) assays. Subsequently, rescue assays verified that circRPS16 promotes cell proliferation, cell cycle, and invasion through miR-876-5p. Importantly, silencing circRPS16 inhibited tumor growth by downregulating SPINK1 expression in vivo. Collectively, our results confirm that SPINK1 is a downstream target of circRPS16. Besides, circRPS16 and SPINK1 are oncogenic factors in HCC progression; they provide novel diagnostic and therapeutic targets for HCC patients.

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Serine peptidase inhibitor Kazal type 1 (SPINK1) as novel downstream effector of the cadherin-17/β-catenin axis in hepatocellular carcinoma

Abstract: Our current data substantiate our knowledge on the role of CDH17 in the biology of HCC and suggest that components of the CDH17/β-catenin axis may serve as therapeutic targets in CDH17 over-expressing HCC patients.

Cited by 14 publications

References 45 publications

Molecular characterization of chronic liver disease dynamics: From liver fibrosis to acute-on-chronic liver failure

Molecular characterization of chronic liver disease dynamics: From liver fibrosis to acute-on-chronic liver failure

Integrative Analysis of Epigenome and Transcriptome Data Reveals Aberrantly Methylated Promoters and Enhancers in Hepatocellular Carcinoma

circRPS16 Promotes Proliferation and Invasion of Hepatocellular Carcinoma by Sponging miR-876-5p to Upregulate SPINK1

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