期刊
MOLECULAR CANCER RESEARCH
卷 16, 期 8, 页码 1255-1262出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-18-0139
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan [16H05149, 16KT0109, 26860492, 17K15923, 15H04807]
- Project for Cancer Research And Therapeutic Evolution (P-CREATE) from Japan Agency for Medical Research and Development (AMED) [JP17cm0106419, JP19cm0106602]
- Pancreas Research Foundation of Japan
- Grants-in-Aid for Scientific Research [17K15923, 16H05149, 15H04807, 26860492, 16KT0109] Funding Source: KAKEN
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. (C) 2018 AACR.
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