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Smad4 deficiency substitutes Cdkn2b but not Cdkn2a downregulation in pancreatic cancer following induction of genetic events in adult mice
- Source :
- Pancreatology. 21:418-427
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Background Minor progress in pancreatic cancer treatment and prognosis implies that more reliable animal models are urgently needed to decipher its molecular mechanisms and preclinical research. We recently reported a genetically engineered adult mouse model where Cdkn2b downregulation was required together with Cdkn2a downregulation to inactivate the Rb pathway. Besides, the role of Smad4, which is mutated more frequently than Cdkn2b in human pancreatic cancer, was determined critical on the development of the pancreas tumor by some reports. However, the impact of Smad4 deficiency in combination with PDAC-relevant mutations, such as Cdkn2a when induced in adult pancreas has not been completely elucidated in mice. Methods Lentiviral delivered oncogene/tumor suppressors in adult pancreas. The development of pancreatic cancer was monitored. Hematoxylin and eosin staining and immunofluorescence were performed for pathological identification of the pancreatic cancer. Real-time polymerase chain reaction, immunofluorescence and western blot were used to test gene expression. Results Loss of Smad4 could cooperate with alterations of KRAS, Trp53, and Cdkn2a to induce pancreatic cancer in adult mice. The role of Smad4 was mainly in downregulating the expression of Cdkn2b and further inducing phosphorylation of the Rb1 protein. Conclusions These findings show an essential role of Smad4 deficiency in pancreatic ductal adenocarcinoma (PDAC) formation. This model better recapitulates the adult onset, clonal origin, and genetic alterations in human PDAC and can be simply generated on a large-scale.
- Subjects :
- Male
Endocrinology, Diabetes and Metabolism
H&E stain
Down-Regulation
medicine.disease_cause
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
CDKN2A
Pancreatic cancer
CDKN2B
medicine
Animals
Cyclin-Dependent Kinase Inhibitor p16
Cyclin-Dependent Kinase Inhibitor p15
Smad4 Protein
Mice, Knockout
Hepatology
Oncogene
business.industry
Gastroenterology
medicine.disease
digestive system diseases
Specific Pathogen-Free Organisms
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms
Retinoblastoma Binding Proteins
medicine.anatomical_structure
030220 oncology & carcinogenesis
Mutation
Cancer research
030211 gastroenterology & hepatology
KRAS
Pancreas
business
Subjects
Details
- ISSN :
- 14243903
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Pancreatology
- Accession number :
- edsair.doi.dedup.....d3859858e26d9fea833aa90f8e10e506