MiR-23a/-24-induced gene silencing results in mesothelial cell integration of pancreatic cancer
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MiR-23a/-24-induced gene silencing results in mesothelial cell integration of pancreatic cancer. / Listing, H; Mardin, W A; Wohlfromm, S; Mees, S T; Haier, J.
In: BRIT J CANCER, Vol. 112, No. 1, 06.01.2015, p. 131-9.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - MiR-23a/-24-induced gene silencing results in mesothelial cell integration of pancreatic cancer
AU - Listing, H
AU - Mardin, W A
AU - Wohlfromm, S
AU - Mees, S T
AU - Haier, J
PY - 2015/1/6
Y1 - 2015/1/6
N2 - BACKGROUND: Invasion of the surrounding tissue is part of the metastatic cascade. Here, we examined the invasion of pancreatic ductal adenocarcinoma (PDAC) cells into the mesothelial barrier and identified the related microRNA (miRNA) expression profiles.METHODS: The interactions between PDAC cells and mesothelial monolayers were characterised and quantified using a specific time-lapse videomicroscopy assay. Pancreatic ductal adenocarcinoma cells were further evaluated using the adhesion assay, and miRNA, mRNA and protein expressions were determined using microarray, q-RT-PCR and western blots, respectively. These data were correlated with in vivo dissemination scores.RESULTS: Two groups of PDAC cell lines were distinguished by their integration capacity into the mesothelial monolayer using mean elongation factors (MEFs). Adhesion assays showed a concordant relation between adhesive properties and integration capacity. The distant metastases scores were reverse correlated with MEFs. Microarray analysis of these groups revealed that miR-23a and/or miR-24 target for FZD5, HNF1B and/or TMEM92, respectively, and that they are significantly deregulated.CONCLUSIONS: MiR-23a and/or miR-24 overexpression leads to gene silencing of FZD5, TMEM92 and/or HNF1B. Their downregulation induces deregulated expression and degradation of E-cadherin and β-catenin causing destabilisation of the cadherin/catenin complex, and altered the expression of Wnt-related genes. We propose a molecular (epi)genetic mechanism by which increased EMT-like cell shape transformation and integration into mesothelial monolayers of PDAC cells can be observed.
AB - BACKGROUND: Invasion of the surrounding tissue is part of the metastatic cascade. Here, we examined the invasion of pancreatic ductal adenocarcinoma (PDAC) cells into the mesothelial barrier and identified the related microRNA (miRNA) expression profiles.METHODS: The interactions between PDAC cells and mesothelial monolayers were characterised and quantified using a specific time-lapse videomicroscopy assay. Pancreatic ductal adenocarcinoma cells were further evaluated using the adhesion assay, and miRNA, mRNA and protein expressions were determined using microarray, q-RT-PCR and western blots, respectively. These data were correlated with in vivo dissemination scores.RESULTS: Two groups of PDAC cell lines were distinguished by their integration capacity into the mesothelial monolayer using mean elongation factors (MEFs). Adhesion assays showed a concordant relation between adhesive properties and integration capacity. The distant metastases scores were reverse correlated with MEFs. Microarray analysis of these groups revealed that miR-23a and/or miR-24 target for FZD5, HNF1B and/or TMEM92, respectively, and that they are significantly deregulated.CONCLUSIONS: MiR-23a and/or miR-24 overexpression leads to gene silencing of FZD5, TMEM92 and/or HNF1B. Their downregulation induces deregulated expression and degradation of E-cadherin and β-catenin causing destabilisation of the cadherin/catenin complex, and altered the expression of Wnt-related genes. We propose a molecular (epi)genetic mechanism by which increased EMT-like cell shape transformation and integration into mesothelial monolayers of PDAC cells can be observed.
KW - Carcinoma, Pancreatic Ductal
KW - Cell Communication
KW - Cell Line, Tumor
KW - Epithelium
KW - Gene Silencing
KW - Humans
KW - MicroRNAs
KW - Pancreatic Neoplasms
KW - Tissue Array Analysis
U2 - 10.1038/bjc.2014.587
DO - 10.1038/bjc.2014.587
M3 - SCORING: Journal article
C2 - 25422915
VL - 112
SP - 131
EP - 139
JO - BRIT J CANCER
JF - BRIT J CANCER
SN - 0007-0920
IS - 1
ER -