In this review, we summarize the role of several miRNAs that regulate various oncogenes (KRAS) and tumor suppressor genes (p53, p16, SMAD4, etc.) involved in PC development, their prospective roles as diagnostic and prognostic markers and as a therapeutic targets.
The Loss of <i>SMAD4/DPC4</i> Expression Associated with a Strongly Activated Hedgehog Signaling Pathway Predicts Poor Prognosis in Resected Pancreatic Cancer.
Loss of Dpc4 expression occurs biologically late in the neoplastic progression that leads to the development of infiltrating pancreatic cancer, at the stage of histologically recognizable carcinoma.
Inactivating mutations of the tumour suppressor genes TP53, CDKN2 and SMAD4 are also frequently observed and this constellation of genetic defects sets pancreatic cancer apart from other types of cancer, a feature which could have important implications for molecular diagnosis.
As a central player in TGF-β signal transduction, SMAD4 (also known as DPC4) is frequently mutated or deleted in gastrointestinal and pancreatic cancer.
Mechanisms of resistance to TGF-beta caused by modulation of cell cycle regulators and/or inactivation of components of the TGF-beta signaling transduction pathway such as C-myc and Smad4 have been demonstrated in human pancreatic cancer and squamous cell carcinoma cell lines.
No mutations in the coding sequences of the DPC4 gene were found; hence, it appears that germline mutations in DPC4 cannot account for many of the familial aggregations of pancreatic carcinoma.
Our findings identify miR-483-3p as a potent regulator of DPC4/Smad4, which may provide a novel therapeutic strategy for the treatment of DPC4/Smad4-driven pancreatic cancer.
We have tested nanopore sequencing to detect a series of well-characterized SVs, including large deletions, inversions, and translocations that inactivate the CDKN2A/p16 and SMAD4/DPC4 tumor suppressor genes in pancreatic cancer.
Utility of Assessing the Number of Mutated KRAS, CDKN2A, TP53, and SMAD4 Genes Using a Targeted Deep Sequencing Assay as a Prognostic Biomarker for Pancreatic Cancer.
The combination of mutant KRAS with a single inactivating TP53, SMAD4 or CDKN2A mutation in genetically engineered mouse models (GEMMs) showed that these mutations exert different synergistic effects in PC.
These results indicate that whereas DPC4 inactivation is prevalent in pancreatic carcinoma (48%), it is distinctly uncommon (< 10%) in the other tumor types examined.
The most consistently mutated genes are <i>KRAS, CDKN2A, TP53</i>, and <i>SMAD4/DPC4</i> Study of familial PDAC has led to the recognition that a variety of defects in DNA repair genes can be associated with the emergence of pancreatic cancer.
In this report, using the deleted in pancreatic cancer locus 4 (DPC4) gene in pancreatic cancer as an example, we show the feasibility of a novel screening strategy, which we have named Pharmacological Synthetic Lethal Screening, for the identification of agents that selectively target cancer cells with loss-of-function mutations.