Molecular genetics of pancreatic intraepithelial neoplasia

Feldmann, Georg; Beaty, Robert M.; Hruban, Ralph H.; Maitra, Anirban

doi:10.1007/s00534-006-1166-5

Cited by 233 publications

(186 citation statements)

References 69 publications

Supporting

Mentioning

182

Contrasting

Unclassified

Order By: Relevance

“…Pancreatic cancer is an aggressive as well as malignant disease and is advanced by the successive and accumulated mutations of genes, including oncogenes KRAS2 and tumor-suppressor genes, INK4A, TP53 and DPC4/Smad4 [5,6]. The involvement of miRNAs in various human tumors suggests that they could also have regulatory functions in pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In most pancreatic cancers, there are several pathways, such as TGF-b, K-RAS, JNK, Intergrin, and Hedgehog signalings etc, and processes, including control of G1/S phase transition and DNA damage, whose component genes are genetically altered [4]. The deregulation of many tumor-suppressor genes is one of the critical reasons for the initiation and advancement of pancreatic cancer [5,6]. However, it remains unknown whether there is any miRNA targeting the tumor-suppressor gene in pancreatic carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, there have been important advances in the understanding of the molecular biology of pancreatic cancer, and genetic analyses have shown that the genetic basis of this dismal disease is extremely complex and heterogeneous [4]. It has been suggested that pancreatic cancer is associated with the successive accumulation of gene mutations such as oncogene KRAS2 and tumor-suppressor genes INK4A, TP53 and DPC4/Smad4 [5,6]. Despite extensive research efforts, the prognosis for pancreatic cancer is the worst among all cancers due to minimal improvements in its prevention and treatment, and the 5-year relative survival rate over the past decades has remained at only 5% for all stages of this disease [1,3].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer

et al. 2010

View full text Add to dashboard Cite

a b s t r a c tBoth deregulation of tumor-suppressor genes and misexpression of microRNAs (miRNAs) have been implicated in the development of pancreatic cancer, but their relationship during this process remains less clear. Here, we report that the expression of miR-483-3p is strongly enhanced in pancreatic cancer tissues compared to side normal tissues using a miRNA-array differential analysis. Furthermore, DPC4/Smad4 is identified as a target of miR-483-3p and their expression levels are inversely correlated in human clinical specimens. Ectopic expression of miR-483-3p significantly represses DPC4/Smad4 protein levels in pancreatic cancer cell lines, and simultaneously promotes cell proliferation and colony formation in vitro. 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer

et al. 2010

View full text Add to dashboard Cite

show abstract

“…The reported genetic alterations in PanINs include activating point mutations in the KRAS2 oncogene 4 and inactivation of p16/CDKN2A, 5 TP53, 6 SMAD4/DPC4, 6,7 and BRCA2. 2,8,9 Most of these genetic alterations have been detected in the histologically more advanced PanIN lesions (PanIN-2 and PanIN-3), and the initiating events in neoplastic progression within the pancreatic ducts remains unknown. In addition, telomere shortening is a common genetic abnormality observed in all stages of PanINs including the vast majority of earliest lesions (PanIN-1A).…”

mentioning

confidence: 99%

“…1,2 Characterization of molecular basis for these precursor lesions may refine our understanding of pancreatic ductal carcinogenesis and also provide important insight into early pancreatic cancer detection strategies and novel targets for chemoprevention. 3 Many of the genetic abnormalities observed in invasive pancreatic cancer have also been observed in PanIN lesions.…”

mentioning

confidence: 99%

CpG island methylation profile of pancreatic intraepithelial neoplasia

et al. 2008

View full text Add to dashboard Cite

Infiltrating adenocarcinoma of the pancreas is thought to develop through well-defined precursor lesions called pancreatic intraductal neoplasia (PanIN). Despite the exponential growth in our understanding of genetic events that characterize the progression of PanINs to invasive carcinoma, little is known about the role of epigenetic alterations in these precursor lesions. To define the timing and prevalence of methylation abnormalities during early pancreatic carcinogenesis, we investigated the CpG island methylation profile in the various grades of PanINs. Using methylation-specific PCR, we analyzed DNA samples from 65 PanIN lesions for methylation status of eight genes recently identified by microarray approach as aberrantly hypermethylated in invasive pancreatic cancer. Aberrant methylation at any of the eight genes was identified in 68% of all the PanIN lesions examined, and, notably, aberrant methylation was identified in more than 70% of the earliest lesions (PanIN-1A). The average number of methylated loci was 1.1 in PanIN-1A, 0.8 in PanIN-1B, 1.1 in PanIN-2, and 2.9 in PanIN-3 lesions (P ¼ 0.01 for PanIN -3 vs earlier PanINs). Among the genes analyzed, NPTX2 demonstrated an increase in methylation prevalence from PanIN-1 to PanIN-2 (P ¼ 0.0008), and from PanIN-2 to PanIN-3 for SARP2 (P ¼ 0.001), Reprimo (P ¼ 0.01), and LHX1 (P ¼ 0.03). These results suggest that aberrant CpG island hypermethylation begins in early stages of PanINs, and its prevalence progressively increases during neoplastic progression. Keywords: PanIN; pancreatic cancer; methylation specific PCR; DNA methylation Accumulating evidence supports the hypothesis that infiltrating adenocarcinoma of the pancreas develops from noninvasive precursor lesions in the small ducts and ductules, called pancreatic intraductal neoplasia (PanIN). 1,2 Characterization of molecular basis for these precursor lesions may refine our understanding of pancreatic ductal carcinogenesis and also provide important insight into early pancreatic cancer detection strategies and novel targets for chemoprevention. 3 Many of the genetic abnormalities observed in invasive pancreatic cancer have also been observed in PanIN lesions. The reported genetic alterations in PanINs include activating point mutations in the KRAS2 oncogene 4 and inactivation of p16/CDKN2A, 5 TP53, 6 SMAD4/DPC4, 6,7 and BRCA2. 2,8,9 Most of these genetic alterations have been detected in the histologically more advanced PanIN lesions (PanIN-2 and PanIN-3), and the initiating events in neoplastic progression within the pancreatic ducts remains unknown. In addition, telomere shortening is a common genetic abnormality observed in all stages of PanINs including the vast majority of earliest lesions (PanIN-1A). 10 PanIN lesions may be particularly important in patients with a strong family history of pancreatic cancer. [11][12][13] Pancreata in patients with a strong family history of pancreatic cancer are remarkable for the presence of multifocal PanIN lesions, and these PanIN lesions are characteristi...

show abstract

Protease‐activated receptor 1 drives and maintains ductal cell fates in the premalignant pancreas and ductal adenocarcinoma

et al. 2021

View full text Add to dashboard Cite

Pancreatic acinar cells have high plasticity and can transdifferentiate into ductal-like cells. This acinar-to-ductal metaplasia (ADM) contributes to tissue maintenance but may also contribute to the premalignant transformation that can eventually progress to pancreatic ductal adenocarcinoma (PDAC). Macrophages are key players in ADM, and macrophage secreted matrix metalloproteinase (MMP)-9 induces ADM through yet unknown mechanisms. As we previously identified MMP9 as a novel agonist of protease-activated receptor 1 (PAR1), a receptor that is known to orchestrate the cross-talk between macrophages and tumor cells in PDAC, we here assessed the contribution of PAR1 to pancreatic cell fates. We found that genetic deficiency for PAR1 increases acinar gene expression programs in the healthy pancreas and that PAR1 deficiency limits ductal transdifferentiation in experimental systems for ADM. Moreover, PAR1 silencing in PDAC cells increases acinar marker expression. Changes in PDAC cell lines were associated with a downregulation of known Myc-target genes, and Myc inhibition mimics PAR1 deficiency in enhancing acinar programs in healthy organoids and PDAC cells. Overall, we identify the PAR1-Myc axis as a driver of ductal cell fates in premalignant pancreas and PDAC. Moreover, we show that cellular plasticity is not unique to acinar cells and that ductal regeneration into acinar-like cells is possible even in the context of oncogenic KRAS activation.

show abstract

Molecular genetics of pancreatic intraepithelial neoplasia

Abstract: Background-Recent evidence suggests that noninvasive precursor lesions, classified as pancreatic intraepithelial neoplasia (PanIN), can progress to invasive pancreatic cancer. This review will discuss the major genetic alterations in PanIN lesions.

Cited by 233 publications

References 69 publications

MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer

MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer

CpG island methylation profile of pancreatic intraepithelial neoplasia

Protease‐activated receptor 1 drives and maintains ductal cell fates in the premalignant pancreas and ductal adenocarcinoma

Contact Info

Product

Resources

About