Involvement of CD40 targeting miR-224 and miR-486 on the progression of pancreatic ductal adenocarcinomas
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Involvement of CD40 targeting miR-224 and miR-486 on the progression of pancreatic ductal adenocarcinomas. / Mees, Soeren Torge; Mardin, Wolf Arif; Sielker, Sonja; Willscher, Edith; Senninger, Norbert; Schleicher, Christina; Colombo-Benkmann, Mario; Haier, Joerg.
In: ANN SURG ONCOL, Vol. 16, No. 8, 08.2009, p. 2339-50.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Involvement of CD40 targeting miR-224 and miR-486 on the progression of pancreatic ductal adenocarcinomas
AU - Mees, Soeren Torge
AU - Mardin, Wolf Arif
AU - Sielker, Sonja
AU - Willscher, Edith
AU - Senninger, Norbert
AU - Schleicher, Christina
AU - Colombo-Benkmann, Mario
AU - Haier, Joerg
PY - 2009/8
Y1 - 2009/8
N2 - BACKGROUND: Genetic and epigenetic alterations during development of pancreatic ductal adenocarcinomas (PDAC) are well known. Genetic and epigenetic data were correlated with tumor biology to find specific alterations responsible for invasion and metastasis in pancreatic ductal adenocarcinomas.METHODS: A total of 16 human PDAC cell lines were used in murine orthotopic PDAC models. By means of standardized dissemination scores, local invasion and metastatic spread were assessed. mRNA and microRNA expression were studied by microarray and TaqMan low-density array. Quantitative real-time-polymerase chain reaction and flow cytometry were used for expression validation.RESULTS: CD40 was detected as a relevant target gene for differentially expressed miRNAs observed in highly invasive and metastatic PDAC only. A significant overexpression (P < .05) of CD40-related miRNAs miR-224 and miR-486 was detected in highly invasive and metastatic PDAC, whereas CD40 mRNA expression was not significantly altered. Instead, CD40 protein expression at cell surfaces of these highly invasive and metastatic PDAC was significantly reduced (P < .01).CONCLUSIONS: Epigenetic alterations with upregulated CD40-targeting miR-224 and miR-486 are related to downregulated CD40 protein expression at cell surfaces in highly invasive and metastatic PDAC. Thus, miRNA-regulated CD40 expression seems to play an important role in progression of PDAC. These data suggest a diagnostic and therapeutic potential for CD40 and/or its targeting miRNAs in PDAC.
AB - BACKGROUND: Genetic and epigenetic alterations during development of pancreatic ductal adenocarcinomas (PDAC) are well known. Genetic and epigenetic data were correlated with tumor biology to find specific alterations responsible for invasion and metastasis in pancreatic ductal adenocarcinomas.METHODS: A total of 16 human PDAC cell lines were used in murine orthotopic PDAC models. By means of standardized dissemination scores, local invasion and metastatic spread were assessed. mRNA and microRNA expression were studied by microarray and TaqMan low-density array. Quantitative real-time-polymerase chain reaction and flow cytometry were used for expression validation.RESULTS: CD40 was detected as a relevant target gene for differentially expressed miRNAs observed in highly invasive and metastatic PDAC only. A significant overexpression (P < .05) of CD40-related miRNAs miR-224 and miR-486 was detected in highly invasive and metastatic PDAC, whereas CD40 mRNA expression was not significantly altered. Instead, CD40 protein expression at cell surfaces of these highly invasive and metastatic PDAC was significantly reduced (P < .01).CONCLUSIONS: Epigenetic alterations with upregulated CD40-targeting miR-224 and miR-486 are related to downregulated CD40 protein expression at cell surfaces in highly invasive and metastatic PDAC. Thus, miRNA-regulated CD40 expression seems to play an important role in progression of PDAC. These data suggest a diagnostic and therapeutic potential for CD40 and/or its targeting miRNAs in PDAC.
KW - Adenocarcinoma
KW - Animals
KW - Antigens, CD40
KW - Carcinoma, Pancreatic Ductal
KW - Disease Progression
KW - Flow Cytometry
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Male
KW - Mice
KW - Mice, Nude
KW - MicroRNAs
KW - Oligonucleotide Array Sequence Analysis
KW - Pancreatic Neoplasms
KW - RNA, Messenger
KW - Tumor Cells, Cultured
KW - Xenograft Model Antitumor Assays
U2 - 10.1245/s10434-009-0531-4
DO - 10.1245/s10434-009-0531-4
M3 - SCORING: Journal article
C2 - 19475450
VL - 16
SP - 2339
EP - 2350
JO - ANN SURG ONCOL
JF - ANN SURG ONCOL
SN - 1068-9265
IS - 8
ER -