AI Article Synopsis
- GSK-3β is a protein that interacts with the oncogene KRas and accumulates in the nucleus of pancreatic ductal adenocarcinoma (PDA), playing a role in cancer development.
- Research using special genetically modified mice shows that the interaction between nuclear GSK-3β and KRas leads to significant changes in pancreatic cells, such as loss of acinar cells and the formation of cystic-like lesions resembling intraductal papillary mucinous neoplasm (IPMN).
- RNA sequencing revealed that proliferating ductal cells express genes like AQP5, which is also found in human IPMN, suggesting that these findings could help to identify biomarkers for pancreatic cancer progression and provide insights into its development
Article Abstract
Glycogen synthase kinase-3β (GSK-3β) is a downstream target of oncogenic KRas and can accumulate in the nucleus in pancreatic ductal adenocarcinoma (PDA). To determine the interplay between oncogenic KRas and nuclear GSK-3β in PDA development, we generated Lox-STOP-Lox (LSL) nuclear-targeted GSK-3β animals and crossed them with LSL-KRas mice under the control of the Pdx1-cre transgene-referred to as KNGC. Interestingly, 4-week-old KNGC animals show a profound loss of acinar cells, the expansion of ductal cells, and the rapid development of cystic-like lesions reminiscent of intraductal papillary mucinous neoplasm (IPMN). RNA-sequencing identified the expression of several ductal cell lineage genes including AQP5. Significantly, the Aqp5 ductal cell pool was proliferative, phenotypically distinct from quiescent pancreatic ductal cells, and deletion of AQP5 limited expansion of the ductal pool. Aqp5 is also highly expressed in human IPMN along with GSK-3β highlighting the putative role of Aqp5 ductal cells in human preneoplastic lesion development. Altogether, these data identify nGSK-3β and KRas as an important signaling node promoting the retention of pancreatic ductal progenitor cells, which could be used to further characterize pancreatic ductal development as well as lineage biomarkers related to IPMN and PDA.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136019 | PMC |
| http://dx.doi.org/10.3389/fcell.2022.853003 | DOI Listing |
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