Highly repetitive tandem arrays such as satellite sequences in the centromeric and pericentromeric regions of chromosomes, which were previously considered to be silent, are actively transcribed in various biological processes, including
cancers. In the pancreas, this aberrant expression occurs even in Kras-mutated pancreatic intraepithelial
neoplasia (PanIN) tissues, which are precancerous lesions. To determine the
biological role of
satellite RNAs in
carcinogenesis in vivo, we constructed mouse major satellite (MajSAT)
RNA-expressing transgenic mice. However, these transgenic mice did not show spontaneous malignant
tumor formation under normal breeding. Importantly, however, DNA damage was increased in pancreatic tissues induced by
caerulein treatment or high-fat diet, which may be due to impaired nuclear localization of
Y-Box Binding Protein 1 (YBX1), a component of the DNA damage repair machinery. In addition, when crossed with pancreas-specific Kras-mutant mice, MajSAT
RNA expression resulted in an earlier increase in PanIN formation. These results suggest that aberrant MajSAT
RNA expression accelerates
oncogenesis by increasing the probability of a second driver mutation, thus accelerating cells to exit from the breakthrough phase to the expansion phase.Implications: Aberrant expression of
satellite RNAs accelerates
oncogenesis through a mechanism involving increased DNA damage. Mol
Cancer Res; 16(8); 1255-62. ©2018 AACR.