Pancreatic carcinoma cells colonizing the liver modulate the expression of their extracellular matrix genes
Khamael M.K. Al-Taee1, Michael Zepp1, Irina Berger2, Martin R. Berger1 and Hassan Adwan1,3
1 Toxicology and Chemotherapy Unit, German Cancer Research Center, Heidelberg, Germany
2 Institute of Pathology, Klinikum Kassel, Mönchebergstraße, Kassel
3 German University of Cairo, Cairo, Egypt
Correspondence:
Martin R. Berger, email:
Keywords: pancreatic ductal adenocarcinoma; ASML cell line; liver metastasis; mRNA and miRNA expression; extracellular matrix
Received: July 06, 2018 Accepted: September 16, 2018 Published: September 23, 2018
Abstract
Liver is the main target of pancreatic ductal adenocarcinoma (PDAC) metastasis. Here, a rat model was used for analysing gene expression modulations during liver colonization. ASML PDAC cells were injected to isogenic rats and re-isolated at various stages of liver colonization for RNA isolation or re-cultivation. Microarrays were used for analysing mRNA and miRNA profiles of expression. The results were partially confirmed by (q) RT-PCR and western blot. Selected genes were knocked down by siRNA transfection and the resulting cell behaviour was analysed.The ratio of up- and down regulated genes decreased from 20:1 (early stage) to 1.2:1 (terminal stage). Activation of cancer relevant gene categories varied between stages of liver colonization, with a nadir in the intermediate stage. The cells’ environment triggered up to hundredfold changed expression for collagens, matrix metalloproteinases and chemokines. These modulations in mRNA expression were related to respective changes at miRNA levels. Gene expression knockdown of Mmp2 and Ccl20, which were highly modulated in vivo, was correlated with reduced proliferation and migration in vitro. Thus, target genes and temporal alterations in expression were identified, which can serve as basis for future therapeutic or diagnostic purposes.
