The Activity of KV11.1 Potassium Channel Modulates F-Actin Organization During Cell Migration of Pancreatic Ductal Adenocarcinoma Cells

Manoli, Sagar S.; Coppola, Stefano; Duranti, Claudia; Lulli, Matteo; Magni, Lara; Kuppalu, Nirmala; Nielsen, Nikoline Juul; Schmidt, Thomas; Schwab, Albrecht; Becchetti, Andrea; Arcangeli, Annarosa

doi:10.3390/cancers11020135

Cited by 39 publications

(22 citation statements)

References 40 publications

(68 reference statements)

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“…At points of ECM-cell contact, specialized structures are formed, which are termed focal adhesions. Some components of focal adhesions contribute to cell migration in PDAC and participate in structural links between the actin cytoskeleton and membrane receptors, whereas others are signaling molecules (Manoli et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Identifying MMP14 and COL12A1 as a potential combination of prognostic biomarkers in pancreatic ductal adenocarcinoma using integrated bioinformatics analysis

Ding

Liu

Lai

2020

PeerJ

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Background Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignant neoplasm. It is necessary to improve the understanding of the underlying molecular mechanisms and identify the key genes and signaling pathways involved in PDAC. Methods The microarray datasets GSE28735, GSE62165, and GSE91035 were downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified by integrated bioinformatics analysis, including protein–protein interaction (PPI) network, Gene Ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The PPI network was established using the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software. GO functional annotation and KEGG pathway analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery. Hub genes were validated via the Gene Expression Profiling Interactive Analysis tool (GEPIA) and the Human Protein Atlas (HPA) website. Results A total of 263 DEGs (167 upregulated and 96 downregulated) were common to the three datasets. We used STRING and Cytoscape software to establish the PPI network and then identified key modules. From the PPI network, 225 nodes and 803 edges were selected. The most significant module, which comprised 11 DEGs, was identified using the Molecular Complex Detection plugin. The top 20 hub genes, which were filtered by the CytoHubba plugin, comprised FN1, COL1A1, COL3A1, BGN, POSTN, FBN1, COL5A2, COL12A1, THBS2, COL6A3, VCAN, CDH11, MMP14, LTBP1, IGFBP5, ALB, CXCL12, FAP, MATN3, and COL8A1. These genes were validated using The Cancer Genome Atlas (TCGA) and Genotype–Tissue Expression (GTEx) databases, and the encoded proteins were subsequently validated using the HPA website. The GO analysis results showed that the most significantly enriched biological process, cellular component, and molecular function terms among the 20 hub genes were cell adhesion, proteinaceous extracellular matrix, and calcium ion binding, respectively. The KEGG pathway analysis showed that the 20 hub genes were mainly enriched in ECM–receptor interaction, focal adhesion, PI3K-Akt signaling pathway, and protein digestion and absorption. These findings indicated that FBN1 and COL8A1 appear to be involved in the progression of PDAC. Moreover, patient survival analysis performed via the GEPIA using TCGA and GTEx databases demonstrated that the expression levels of COL12A1 and MMP14 were correlated with a poor prognosis in PDAC patients (p < 0.05). Conclusions The results demonstrated that upregulation of MMP14 and COL12A1 is associated with poor overall survival, and these might be a combination of prognostic biomarkers in PDAC.

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Section: Discussionmentioning

confidence: 99%

Identifying MMP14 and COL12A1 as a potential combination of prognostic biomarkers in pancreatic ductal adenocarcinoma using integrated bioinformatics analysis

Ding

Liu

Lai

2020

PeerJ

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“…This indicates that Kv11.1 could function as an oncogene in PDAC and be a potential target of miR-96 (Feng et al, 2014). Further investigations showed that Kv11.1 promotes pancreatic cancer cell migration, by modulation of F-actin organization and dynamics (Lastraioli et al, 2015b) suggesting its involvement in cancer metastasis (Arcangeli et al, 2014;Manoli et al, 2019).…”

Section: Kv Channelsmentioning

confidence: 97%

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancerrelated deaths in United States and Europe. It is predicted that PDAC will become the second leading cause of cancer-related deaths during the next decades. The development of PDAC is not well understood, however, studies have shown that dysregulated exocrine pancreatic fluid secretion can contribute to pathologies of exocrine pancreas, including PDAC. The major roles of healthy exocrine pancreatic tissue are secretion of enzymes and bicarbonate rich fluid, where ion channels participate to fine-tune these biological processes. It is well known that ion channels located in the plasma membrane regulate multiple cellular functions and are involved in the communication between extracellular events and intracellular signaling pathways and can function as signal transducers themselves. Hereby, they contribute to maintain resting membrane potential, electrical signaling in excitable cells, and ion homeostasis. Despite their contribution to basic cellular processes, ion channels are also involved in the malignant transformation from a normal to a malignant phenotype. Aberrant expression and activity of ion channels have an impact on essentially all hallmarks of cancer defined as; uncontrolled proliferation, evasion of apoptosis, sustained angiogenesis and promotion of invasion and migration. Research indicates that certain ion channels are involved in the aberrant tumor growth and metastatic processes of PDAC. The purpose of this review is to summarize the important expression, localization, and function of ion channels in normal exocrine pancreatic tissue and how they are involved in PDAC progression and development. As ion channels are suggested to be potential targets of treatment they are furthermore suggested to be biomarkers of different cancers. Therefore, we describe the importance of ion channels in PDAC as markers of diagnosis and clinical factors.

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“…hERG1 was shown to modulate β1-integrin mediated VEGF-A secretion through the recruitment of PI3K and AKT[72]. In PC hERG1 over-expression was reported in 59% of tumors[66] where it promoted cancer cell migration via modulation of F-actin organization[64]. hERG1 expression was also associated with lymph node involvement, tumor grade, TNM stage and poor patient prognosis[66].…”

Section: Potassium Channelsmentioning

confidence: 99%

Role of ion channels in gastrointestinal cancer

Anderson¹,

Cormier²,

Scott³

2019

WJG

136

103

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In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity c...

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The Activity of KV11.1 Potassium Channel Modulates F-Actin Organization During Cell Migration of Pancreatic Ductal Adenocarcinoma Cells

Cited by 39 publications

References 40 publications

Identifying MMP14 and COL12A1 as a potential combination of prognostic biomarkers in pancreatic ductal adenocarcinoma using integrated bioinformatics analysis

Identifying MMP14 and COL12A1 as a potential combination of prognostic biomarkers in pancreatic ductal adenocarcinoma using integrated bioinformatics analysis

Ion Channel Signature in Healthy Pancreas and Pancreatic Ductal Adenocarcinoma

Role of ion channels in gastrointestinal cancer

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