Serine protease inhibitor Kazal type 1 (<i>SPINK</i><i>1</i>) downregulates E‐cadherin and induces EMT of hepatoma cells to promote hepatocellular carcinoma metastasis via the MEK/ERK signaling pathway

Ying, Hai Yan; Gong, Chao Jie; Feng, Yi; Jing, Da Dao; Lu, Lun Gen

doi:10.1111/1751-2980.12486

Cited by 25 publications

(26 citation statements)

References 26 publications

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“…Experiments involving pharmacological blocking of MEK revealed that suppression of ERK is involved in RAC1B-mediated inhibition of cell migration, prevention of TGF-β1-induced downregulation of CDH1 and TGF-β1-mediated upregulation of SNAI1 (see Figure 5). While MEK-ERK signaling has been implicated before in downregulation of CDH1 by epidermal growth factor, serine protease inhibitor Kazal type 1, and activin B [38][39][40], our observation that TGF-β employs the same pathway to silence CDH1 is novel. The partial reversal of migratory activity in RAC1B knockdown cells and the TGF-β1-dependent decrease in E-cadherin expression by U0126 may be secondary to U0126-mediated inhibition of TGF-β1-induced upregulation of SNAIL since SNAIL is a potent inhibitor of CDH1.…”

Section: Discussionmentioning

confidence: 60%

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Zinn

Otterbein

Lehnert

et al. 2019

Cells

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The small GTPase Ras-related C3 botulinum toxin substrate 1B (RAC1B) has been shown to potently inhibit transforming growth factor (TGF)-β1-induced cell migration and epithelial-mesenchymal transition (EMT) in pancreatic and breast epithelial cells, but the underlying mechanism has remained obscure. Using a panel of pancreatic ductal adenocarcinoma (PDAC)-derived cell lines of different differentiation stages, we show that RAC1B is more abundantly expressed in well differentiated as opposed to poorly differentiated cells. Interestingly, RNA interference-mediated knockdown of RAC1B decreased expression of the epithelial marker protein E-cadherin, encoded by CDH1, and enhanced its TGF-β1-induced downregulation, whereas ectopic overexpression of RAC1B upregulated CDH1 expression and largely prevented its TGF-β1-induced silencing of CDH1. Conversely, knockdown of RAC1B, or deletion of the RAC1B-specific exon 3b by CRISPR/Cas-mediated genomic editing, enhanced basal and TGF-β1-induced upregulation of mesenchymal markers like Vimentin, and EMT-associated transcription factors such as SNAIL and SLUG. Moreover, we demonstrate that knockout of RAC1B enhanced the cells’ migratory activity and derepressed TGF-β1-induced activation of the mitogen-activated protein kinase ERK2. Pharmacological inhibition of ERK1/2 activation in RAC1B-depleted cells rescued cells from the RAC1B knockdown-induced enhancement of cell migration, TGF-β1-induced downregulation of CDH1, and upregulation of SNAI1. We conclude that RAC1B promotes epithelial gene expression and suppresses mesenchymal gene expression by interfering with TGF-β1-induced MEK-ERK signaling, thereby protecting cells from undergoing EMT and EMT-associated responses like acquisition of cell motility.

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Section: Discussionmentioning

confidence: 60%

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

Zinn

Otterbein

Lehnert

et al. 2019

Cells

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“…Low expression of miR‐448 induces EMT and promotes invasion by regulating ROCK2 in HCC . Serine protease inhibitor Kazal type 1 downregulates E‐cadherin and induces EMT of hepatoma cells to promote HCC metastasis via the MEK/ERK signaling pathway . Small nucleolar RNA 47 promotes tumorigenesis by regulating EMT markers in HCC .…”

Section: Discussionmentioning

confidence: 99%

LncRNA CRNDE promotes the epithelial‐mesenchymal transition of hepatocellular carcinoma cells via enhancing the Wnt/β‐catenin signaling pathway

Zhū

et al. 2018

J of Cellular Biochemistry

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Colorectal neoplasia differentially expressed (CRNDE) is a significantly upregulated long noncoding RNA in hepatocellular carcinoma (HCC). CRNDE could promote cell proliferation, migration, and invasion, while its molecular mechanisms were still largely unclear. In this study, we investigated the expression and function of CRNDE. CRNDE was significantly upregulated in tumor tissues compared with adjacent normal tissues. In vitro, we revealed that knockdown of CRNDE inhibited cell proliferation, migration, and cell invasion capacities in HCC. Animal studies indicated that CRNDE knockdown represses both growth and metastasis of HCC tumors in vivo. Moreover, knockdown of CRNDE suppressed the cell epithelial‐mesenchymal transition (EMT) process by increasing the expression of E‐cadherin and ZO‐1, whereas, decreasing the expression of N‐cadherin, slug, twist, and vimentin in HCC cells. We also revealed that knockdown of CRNDE suppressed the Wnt/β‐catenin signaling in HCC. Thus, CRNDE could modulate EMT of HCC cells and knockdown of CRNDE impaired the mesenchymal properties. CRNDE increased invasion of HCC cells might be through activating the Wnt/β‐catenin signaling pathway.

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“…In addition, SPINK1 secreted by cancer cells could coimmmunoprecipitate with serine protease granzyme A (GzmA), a cytolytic granule secreted by natural killer cells and cytotoxic T lymphocytes, thereby suppressing GzmA-mediated apoptosis and establishing a tolerance of cancer cells to the immune surveillance system (32). More importantly, SPINK1, as a growth factor, is aberrantly expressed in multiple human cancers such as ovarian cancer (33), prostatic cancer (36), colorectal cancer (37), hepatocellular carcinoma (38) and pulmonary adenocarcinoma (39). Based on big data analysis, we detected a significant increase of SPINK1 expression in NSCLC tissues.…”

Section: Discussionmentioning

confidence: 99%

“…It has been universally accepted that SPINK1 acting as a pro-survival factor accelerated the progression of multiple cancers by interacting with EGFR ( 25,28,29,38,53). In order to clarify signaling pathways downstream of EGFR mediating the carcinogenic effect of SPINK1 in NSCLC, the phosphorylation levels of MEK1/2, ERK, PI3K and AKT were assessed by western blot.…”

Section: Spink1 Accelerates the Proliferation Of Nsclc Via Activationmentioning

confidence: 99%

Identification and Exploration of Serine Peptidase Inhibitor Kazal Type 1 (SPINK1) as a Potential Biomarker Correlated with the Progression of Non-Small Cell Lung Cancer

Zhang¹,

Ai²,

Ding³

et al. 2020

Preprint

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Background Lung cancer is one of the most common malignancies worldwide and is the leading cause of cancer-related death. Approximately 85% of lung cancer patients represent a group of histological subtypes collectively known as non-small cell lung cancer (NSCLC).Methods To explore the molecular mechanisms underlying tumorigenesis and progression of NSCLC, mRNA expression profiles were downloaded from GEO database (GSE19804, GSE18842, GSE27262, and GSE43458) and differentially expressed genes (DEGs) in NSCLC tissues were analyzed by GEO2R. DEGs in NSCLC tissues were further analysed in TCGA (The Cancer Genome Atlas), GTEx (The Genotype-Tissue Expression Project) and IST (In Silico Transcriptomics) online databases. Serum of NSCLC patients and normal controls were collected and serum concentration of SPINK1 were analysed by ELISA. mRNA and protein expression levels of SPINK1 were analysed by qRT-PCR and western assays. siRNA targeting SPINK1 and normal controls were used for the silence of SPINK1 and GAPDH. CCK-8 assays were employed for cell proliferation detection. Flow cytometric analysis and western blot assays were conducted to assess cell cycle distribution and apoptosis. Western blot assays were performed for the evaluation of cell autophagy and signaling pathways.Results Among these DEGs, SPINK1 was distinctively up-regulated in NSCLC tissues, which was further validated in TCGA, GTEx and IST databases. Furthermore, serum SPINK1 concentration notably increased in NSCLC patients compared with normal controls. Besides, both mRNA and protein expression levels of SPINK1 significantly increased in human NSCLC cell lines A549 and H1299 compared with normal human bronchial epithelial cell line HBE. Silence of SPINK1 significantly inhibited proliferation of NSCLC cell lines, and exogenous addition of rhSPINK1 partially rescued proliferation suppressed by endogenous knockdown of SPINK1. Mechanistically, silence of SPINK1 could inhibit MEK/ERK signaling pathway, while rhSPINK1 could activate MEK/ERK signaling pathway and then promote proliferation of NSCLC cell lines. In addition, silence of SPINK1 also could activate cell autophagy and apoptosis.Conclusions Overall, our results suggested that SPINK1 may be a potential biomarker correlated with the progression of NSCLC.

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Serine protease inhibitor Kazal type 1 (SPINK1) downregulates E‐cadherin and induces EMT of hepatoma cells to promote hepatocellular carcinoma metastasis via the MEK/ERK signaling pathway

Abstract: SPINK1 may be an oncogene that induces EMT via the MEK/ERK pathway and is a potential target for HCC therapy.

Cited by 25 publications

References 26 publications

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

RAC1B: A Guardian of the Epithelial Phenotype and Protector Against Epithelial-Mesenchymal Transition

LncRNA CRNDE promotes the epithelial‐mesenchymal transition of hepatocellular carcinoma cells via enhancing the Wnt/β‐catenin signaling pathway

Identification and Exploration of Serine Peptidase Inhibitor Kazal Type 1 (SPINK1) as a Potential Biomarker Correlated with the Progression of Non-Small Cell Lung Cancer

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