Dataset Information

KCNN4-mediated Ca²⁺/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma.

ABSTRACT: As a member of the potassium calcium-activated channel subfamily, increasing evidence suggests that KCNN4 was associated with malignancies. However, the roles and regulatory mechanisms of KCNN4 in PDAC have been little explored. In this work, we demonstrated that the level of KCNN4 in PDAC was abnormally elevated, and the overexpression of KCNN4 was induced by transcription factor AP-1. KCNN4 was closely correlated with unfavorable clinicopathologic characteristics and poor survival. Functionally, we found that overexpression of KCNN4 promoted PDAC cell proliferation, migration and invasion. Conversely, the knockdown of KCNN4 attenuated the growth and motility of PDAC cells. In addition to these, knockdown of KCNN4 promoted PDAC cell apoptosis and led to cell cycle arrest in the S phase. In mechanistic investigations, RNA-sequence revealed that the MET-mediated AKT axis was essential for KCNN4, encouraging PDAC cell proliferation and migration. Collectively, these findings reveal a function of KCNN4 in PDAC and suggest it's an attractive therapeutic target and tumor marker. Our studies underscore a better understanding of the biological mechanism of KCNN4 in PDAC and suggest novel strategies for cancer therapy.

SUBMITTER: Mo X

PROVIDER: S-EPMC8888650 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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KCNN4-mediated Ca<sup>2+</sup>/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma.

Mo Xiao X Zhang Cheng-Fei CF Xu Ping P Ding Min M Ma Zhi-Jie ZJ Sun Qi Q Liu Yu Y Bi Hong-Kai HK Guo Xin X Abdelatty Alaa A Hu Chao C Xu Hao-Jun HJ Zhou Guo-Ren GR Jia Yu-Liang YL Xia Hong-Ping HP

Acta pharmacologica Sinica 20210628 3

As a member of the potassium calcium-activated channel subfamily, increasing evidence suggests that KCNN4 was associated with malignancies. However, the roles and regulatory mechanisms of KCNN4 in PDAC have been little explored. In this work, we demonstrated that the level of KCNN4 in PDAC was abnormally elevated, and the overexpression of KCNN4 was induced by transcription factor AP-1. KCNN4 was closely correlated with unfavorable clinicopathologic characteristics and poor survival. Functionall ...[more]

PMID: 34183755

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most common tumor subtype of pancreatic cancer, which exhibits poor patient prognosis due to the lack of effective biomarkers in the diagnosis and treatment. The present study aimed to identify the potential biomarkers of PDAC carcinogenesis and progression using three microarray datasets, GSE15471, GSE16515 and GSE28735, which were downloaded from the Gene Expression Omnibus database. The datasets were analyzed to screen out differentially expressed genes (DEGs) in PDAC tissues and adjacent normal tissues. A total of 143 DEGs were identified, including 132 upregulated genes and 11 downregulated genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional and signaling pathway enrichment analyses were performed on the DEGs, and the Search Tool for the Retrieval of Interacting Genes/Proteins database was used to construct a protein-protein interaction network. The main functions of DEGs include extracellular matrix degradation, and regulation of matrix metalloproteinase activity and the PI3K-Akt signaling pathway. The five hub genes were subsequently screened using Cytoscape software, and survival analysis demonstrated that abnormal expression levels of the hub genes was associated with poor disease-free survival and overall survival. Biological experiments were performed to confirm whether mesenchymal-to-epithelial transition (MET) factors promote the proliferation, migration and invasion of PDAC cells via the PI3K/AKT signaling pathway. In addition, six MET-targeted microRNAs (miRNAs) were identified, four of which had conserved binding sites with MET. Based on the signaling pathway enrichment analysis of these miRNAs, it is suggested that they can affect the progression of PDAC by targeting MET via the PI3K/AKT signaling pathway. In conclusion, the hub genes and miRNAs that were identified in the present study contribute to the molecular mechanisms of PDAC carcinogenesis and progression. They also provide candidate biomarkers for early diagnosis and treatment of patients with PDAC.

Dataset Information

KCNN4-mediated Ca²⁺/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma.

Publications

KCNN4-mediated Ca<sup>2+</sup>/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma.

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Dataset Information

KCNN4-mediated Ca2+/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma.

Publications

KCNN4-mediated Ca<sup>2+</sup>/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

KCNN4-mediated Ca²⁺/MET/AKT axis is promising for targeted therapy of pancreatic ductal adenocarcinoma.