Gene expression alterations of pancreatic intraepithlial neoplasia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE96784 | GEO | 2018/03/17
REPOSITORIES: GEO
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Project description:Development of systems that reconstitute hallmark features of human pancreatic intraepithelial neoplasia (PanINs), the precursor to pancreatic ductal adenocarcinoma, could generate new strategies for early diagnosis and intervention. However, human cell-based PanIN models with defined mutations are unavailable. Here, we report that genetic modification of primary human pancreatic cells leads to development of lesions resembling native human PanINs. Primary human pancreas duct cells harbouring oncogenic KRAS and induced mutations in CDKN2A, SMAD4 and TP53 expand in vitro as epithelial spheres. After pancreatic transplantation, mutant clones form lesions histologically similar to native PanINs, including prominent stromal responses. Gene expression profiling reveals molecular similarities of mutant clones with native PanINs, and identifies potential PanIN biomarker candidates including Neuromedin U, a circulating peptide hormone. Prospective reconstitution of human PanIN development from primary cells provides experimental opportunities to investigate pancreas cancer development, progression and early-stage detection.
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Project description:Transcriptome analysis of RNA samples from riboflavin deficiency combined with NMBA-induced rat esophageal intraepithelial neoplasia tissues. Epidemiological studies suggest that dietary riboflavin deficiency and environmental exposure to N-nitrosomethylbenzylamine (NMBA) are common in China's high incidence area of esophageal cancer. Riboflavin deficiency has been documented as an important risk factor for esophageal cancer. In this study, we established a F344 rat esophageal tumor model that combines dietary riboflavin deficiency with exposure to NMBA. The results showed that riboflavin deficiency combined with NMBA (R0N+) enhanced the incidence of esophageal intraepithelial neoplasia, including in situ carcinoma, whereas normal levels of riboflavin combined with NMBA (RcN+) mainly induced the occurrence of esophageal benign hyperplasia and small amount of esophageal intraepithelial neoplasia. Oxidative DNA damage (8-OHdG) and DNA double-strand breaks (p-γH2AX) in R0N+ rats were higher than that in RcN+ rats. The aim of the present study is to analyze the mechanism of riboflavin deficiency-induced tumorigenesis. So, we used Affymetrix Clariom D(also known as Rat Transcriptome Array 1.0) to identify genes that were differentially expressed upon R0N+ esophageal intraepithelial neoplasia tissues.
2018-02-28 | GSE111207 | GEO
Project description:Cervical mucus was collected from 86 patients with a normal cervix, cervical intraepithelial neoplasia (CIN), squamous cell carcinoma (SCC), or adenocarcinoma (AD). 76 candidates of miRNAs were selected according to criteria such as absolute value of the signal intensity included more than 20 and the ratio of the SCC/normal or AD/normal included more than four.
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Project description:Serum was collected from 63 patients of Group A with a normal cervix, cervical intraepithelial neoplasia (CIN), squamous cell carcinoma (SCC), or adenocarcinoma (AD) and 33 patients of Group B with a normal cervix or SCC. Three miRNAs (miR-16-5p, -223-3p and -451a) were commonly down-regulated in the Group A and the Group B.
2024-04-18 | GSE229935 | GEO
Project description:Many human cancers are dramatically accelerated in the setting of chronic inflammation. However the specific cellular and molecular elements mediating this effect remain largely unknown. Using a murine model of pancreatic intraepithelial neoplasia (PanIN), we found that KrasG12D induces expression of functional IL-17 receptors on PanIN cells, and stimulates infiltration of the pancreatic stroma by IL-17-producing immune cells. Both effects are augmented by chronic pancreatitis, resulting in functional in vivo changes in gene expression among PanIN epithelial cells. Forced IL-17 overexpression dramatically accelerates PanIN initiation and progression, while inhibition of IL-17 signaling using genetic or pharmacologic techniques effectively prevents PanIN formation. Together, these studies suggest that a hematopoietic-to-epithelial IL-17 signaling axis is a potent and requisite driver of PanIN formation.
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Project description:To determine the molecular basis of gene regulation in pancreatic ductal epithelial cells, we developed methods for the isolation of this cell population during mouse development and normal adult homeostasis, as well as in conditions with ductal features (acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC)). Our technique utilizes the specificity of Dolichos biflorus Agglutinin (DBA) lectin marking the entire normal ductal tree, including terminal intercalated ducts (putative sites of stem or progenitor cells) and ductal structures in ADM and PanIN. We used ferromagnetic-labeled DBA lectin to isolate ductal structures. Ductal cells were isolated under the following conditions: (1) Embryonic Development in wild type mice: E14.5, E15.5, E16.5, and postnatal day 1 (P1); (2) Injury and regeneration (pancreatitis) 0, 1, 3, 5 days following cerulein-induced acute pancreatitis. Cerulein is a cholecystokinin analog which produces a self-limited pancreatitis with injury and subsequent regeneration and repair, completed five days after insult; and (3) Pdx1-Cre;LSL-KrasG12D/+ mice aged 10 and 20 weeks that harbor PanIN lesions and a subset develop PDAC. Ductal/PanIN cells were isolated from these mice and appropriate control mice (Pdx1-Cre;Kras+/+).
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Project description:Biliary intraepithelial neoplasia (BilIN) is a common precursor lesion of distal cholangiocarcinoma (dCCA). However, the sequence leading from a single epithelial layer in normal biliary epithelia to intraepithelial precursor lesions and finally to the invasive tumor is poorly understood. Here, we aimed to elucidate key miRNAs involved in this stepwise process and to identify their possible mRNA target genes in distal cholangiocarcinogenesis. As basis of our study, we conducted Laser Capture Microdissection of FFPE tissue sections of 12 patients with distal cholangiocarcinoma. For each patient, we isolated three matched sample sets, including non-neoplastic biliary epithelia, high grade BilIN (grade 3), and invasive dCCA, thereby representing different stages of distal cholangiocarcinogenesis. This resulted in a total of 36 samples. Total RNA was extracted and the expression of ~800 miRNAs was assessed using the Nanostring® technology. Significantly deregulated miRNAs were validated by quantitative RT-PCR. Target genes were identified using miRWalk2.0 and validated by qRT-PCR and Western blot.
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Project description:The aim of this experiment is to unravel PDAC biology and phospho-print based on aberrant kinase activities and proteome alterations. For this we will perform pTYyrIP, Bravo_IMAC, and protein expression data of n=56 tissues encompassing 47 pancreatic ductal adenocarcinoma (PDAC), 5 cholangiocarcinoma, 1 Intraductal Papillary Mucinous Neoplasm (IPMN), 1 pancreatitis and 1 pancreatitis-Pancreatic Intraepithelial Neoplasia (PanIN) tissue. Pancreatitis, PanIN, and IPMN are seen as early events predecessing PDAC. An equiproportional pool of 5 PDAC cell lines (PANC1, SUIT-2, CFPAC-1, HPAC, MIAPACA2) is also taken along.
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Project description:Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells to precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We found that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity in the pancreas. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to carcinoma. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.
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Project description:Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells to precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We found that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity in the pancreas. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to carcinoma. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.
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