DNA methylation changes in extracellular remodeling pathway genes during the transformation of human mesenchymal stem cells

Abstract

Extracellular matrix (ECM) molecules are essential structural components that exhibit important functional roles in the control of key cellular events, including cell adhesion, migration, proliferation, differentiation, and survival. The ECM remodeling pathway is also important for tumorigenesis and the metastatic progression of cancer. In this study, we determined the methylation pattern of nineteen ECM genes in colon cancer cell lines and demonstrated that these genes were frequently hypermethylated in primary colon tissues. Upon extracting gene expression profile data of the mouse epithelium and mesenchymal compartments, we found that several ECM genes (CD109, EVL, FBN2, FLNC, IGFBP3, MMP2, and LAMA1) were highly expressed in the mesenchymal compartment. These results were confirmed via reverse transcription polymerase chain reaction analysis. Moreover, we demonstrated the correlation between transcriptional silencing and the promoter hypermethylation of LAMA1, FBN2, and IGFBP3 during the transformation of the mesenchymal stem cell model system using key genetic alterations that develop during human malignance. Interestingly, MMP2, IGFBP3, and LAMA1 mRNA levels were significantly decreased during the transformation. In terms of transcriptional silencing by promoter DNA hypermethylation, the lack of LAMA1 mRNA expression was associated with its promoter hypermethylation in the last step of transformation, which develops to malignancies. Overall, our data suggest that ECM alterations by hypermethylated genes may contribute to carcinogenesis through the silencing of ECM pathway genes by epigenetic alterations.