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Downregulation of Notch3 links TIMP3 inhibition to suppress aggressive phenotypes of pancreatic ductal adenocarcinoma.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), one of the most deadly digestive cancers, has a poor 5-year survival rate and is resistant to chemotherapeutic agents, such as gemcitabine. Notch3 plays an important role in cancer progression, and its expression facilitates chemoresistance in cancers. This study examined the clinical significance of Notch3 and explored the mechanisms through which it may affect disease progression in PDAC. We found Notch3 to be upregulated in PDAC patients in whom it correlated with lymph node stage and poor survival. In vitro and in vivo, functional assays indicated that silencing Notch3 could suppress the growth, migration, invasion of PDAC cells and sensitize PDAC cells to gemcitabine. QPCR array, which was performed to elucidate the Notch3-regulated pathway, revealed that inhibition of Notch3 decreased the transcription and secretion of TIMP3 in PDAC cells. Overexpression of TIMP3 reversed the impaired growth, migration, invasion, and chemosensitivity induced by Notch3 silencing. We also found a positive correlation between Notch3 mRNA expression and TIMP3 expression in patients with PDAC. We concluded that blocking Notch3/TIMP3 pathway could considered a potentially new therapeutic strategy for treating PDAC.

SUBMITTER: Chiu TJ

PROVIDER: S-EPMC8640811 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Downregulation of Notch3 links TIMP3 inhibition to suppress aggressive phenotypes of pancreatic ductal adenocarcinoma.

Chiu Tai-Jan TJ Chen Yi-Ju YJ Lan Jui J Chen Yen-Yang YY Chen Yueh-Chiu YC Lin Hsiao-Wu HW Tsai Hsin-Ting HT Lin Yu-Sheng YS Hsiao Chang-Chun CC Chen Chang-Han CH

American journal of cancer research 20211115 11

Pancreatic ductal adenocarcinoma (PDAC), one of the most deadly digestive cancers, has a poor 5-year survival rate and is resistant to chemotherapeutic agents, such as gemcitabine. Notch3 plays an important role in cancer progression, and its expression facilitates chemoresistance in cancers. This study examined the clinical significance of Notch3 and explored the mechanisms through which it may affect disease progression in PDAC. We found Notch3 to be upregulated in PDAC patients in whom it cor ...[more]

PMID: 34873483

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Project description:BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is usually incurable. Contrary to genetic mechanisms involved in PDAC pathogenesis, epigenetic alterations are ill defined. Here we determine the contribution of epigenetically silenced genes to the development of PDAC. METHODS: We investigated methylated DNAs from PDACs, chronic pancreatitis and normal pancreatic tissues using Methyl-CpG immunoprecipitation followed by microarray hybridization. Promoter methylation of selected genes was confirmed with the Epityper assay. Expression levels were evaluated by quantitative RT-PCR. WNK2 was further investigated in tissue microarrays, methylation analysis of early pancreatic intraepithelial neoplasia (PanINs), mouse models for PDAC and pancreatitis, re-expression studies after demethylation, and cell growth assays using WNK2 overexpression. RESULTS: A total of 3.8% of 27.800 interrogated CpG islands were hypermethylated in PDAC versus normal and chronic pancreatitis tissues. Hypermethylation was confirmed in 12 out of 13 selected islands and was associated with gene silencing in 4 of them. The most prominently hypermethylated gene, WNK2, was further investigated. Demethylation assays confirmed the link between methylation and expression. WNK2 hypermethylation was higher in pancreatic tumor cells than in surrounding inflamed tissues and was observed in PanIN lesions as well as in a PDAC mouse model. WNK2 mRNA and protein expression were lower in PDAC and chronic pancreatitis compared to normal tissues both in patients and mouse models. Overexpression of WNK2 led to a reduced cell growth and WNK2 expression in tissues correlated negatively with the expression of pERK1/2, a downstream target of WNK2 responsible for cell proliferation. CONCLUSIONS: WNK2 is downregulated by promoter hypermethylation early in PDAC pathogenesis and may support tumor cell growth via the ERK-MAPK pathway. 3 types of pancreatic tissue samples: 5 normals, 2 chronic pancreatitis, 7 tumors (PDAC)

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Downregulation of Notch3 links TIMP3 inhibition to suppress aggressive phenotypes of pancreatic ductal adenocarcinoma.

Publications

Downregulation of Notch3 links TIMP3 inhibition to suppress aggressive phenotypes of pancreatic ductal adenocarcinoma.

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