412 research outputs found
Hypermethylation of O6-methylguanine-DNA methyltransferase promoter as a good predictor for colorectal cancer patients receiving chemotherapy
No full textAbstract 5503: Interplay between the transcription factors PRRX1 and FOXM1 in pancreatic cancer
No full textAbstract
Introduction: We have identified previously the Paired Related Homeobox 1 gene (Prrx1) as a key regulator of embryonic ductal development, acinar-to-ductal metaplasia (ADM) and pre-cancerous lesion (PanIN)/pancreatic ductal adenocarcinoma (PDAC) progression (Reichert M. et al Genes & Dev 2013). We discovered an isoform switch between PRRX1A and PRRX1B occurring in EMT-MET plasticity in pancreatic tumorigenesis (EMT) and metastatic colonization of the liver (MET) (Takano S. et al Genes & Dev 2016). The transcription factor FOXM1 is also implicated in EMT of pancreatic cancer cells. Interestingly, both transcription factors, FOXM1 and PRRX1, are overexpressed in PDAC. The aim of this study was to investigate if PRRX1, specifically its isoforms, might interact with FOXM1, to regulate gene transcription in pancreatic cancer.
Methods: Experiments were performed in human pancreatic cancer cells (PANC1, MIA PaCa2 and BxPC3), and HEK293T cells. Epitope-tagged PRRX1 and FOXM1 proteins (wild type or deletion mutants) were either transiently or stably expressed in these cells. Immunoprecipitation and western blot were performed to evaluate potential interaction between PRRX1 and FOXM1. As a functional readout, the TnC and 6xFOXM1 luciferase reporters were used to measure Tenascin C and FOXM1 transcriptional activities.
Results: Immunoprecipitation of tagged-PRRX1 or endogenous FOXM1 showed co-binding of both PRRX1 isoforms (A and B) with FOXM1 in pancreatic cancer cells. We further characterized this interaction using deletion mutants of PRRX1 C-terminal region, FOXM1 binds to the 200-222 amino acid region of PRRX1. Similarly, using deletion mutants of the FOXM1 N-terminal region we mapped PRRX1 binding to the winged helix DNA binding domain of FOXM1. Interestingly, we also observed co-binding of HA-tagged PRRX1A with either Flag-tagged PRRX1A or PRRX1B suggesting homo and heterodimerization of the PRRX1 isoforms. Next, we found that co-expression of PRRX1 and FOXM1 cooperatively induced transcriptional activity of a known PRRX1 target gene, Tenascin C. Furthermore, co-expression of PRRX1A and FOXM1 cooperatively induced FOXM1 transcriptionnal activity. FOXM1 has been reported to regulate Wnt signaling in glioblastomas (Zhang N. et al. Cancer Cell 2011). Given the importance of Wnt signaling in early pancreatic carcinogenesis, we observed co-binding of PRRX1 and FOXM1 with beta-catenin.
Conclusion: Our results provides new insights in the interaction of PRRX1 and FOXM1 with functional activation of FOXM1 mediated transcriptional activity, and potential regulation of the Wnt pathway.
Citation Format: Benoit Marchand, Maximilian Reichert, Meredith A. Collins, Anil K. Rustgi. Interplay between the transcription factors PRRX1 and FOXM1 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5503. doi:10.1158/1538-7445.AM2017-5503</jats:p
Investigation of Crohn's Disease Risk Loci in Ulcerative Colitis Further Defines Their Molecular Relationship
No full textBACKGROUND & AIMS: Identifying shared and disease-specific susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. METHODS: We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. RESULTS: Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 x 10(-8); odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. CONCLUSIONS: Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis
Identification of prognostic phenotypes of esophageal adenocarcinoma in two independent cohorts
No full textBackground & Aims: most
patients with esophageal adenocarcinoma (EAC) present de novo. Although
this could be due to inadequate screening strategies, the precise
reason for this observation is not clear. We compared survival of
patients with prevalent EAC with and without synchronous Barrett
esophagus (BE) with intestinal metaplasia (IM) at the time of EAC
diagnosis.Methods: clinical
data were studied using Cox proportional hazards regression to evaluate
the effect of synchronous BE-IM on EAC survival independent of age,
sex, TNM stage, and tumor location. Two cohorts from the Mayo Clinic and
a UK multicenter prospective cohort were included.Results: the
Mayo Clinic cohort had 411 patients with EAC, and 49.3% with BE-IM
showed a survival benefit compared with those without (hazard ratio [HR]
0.44, 95% confidence interval [CI] 0.34–0.57, P < .001). In
a multivariable analysis, BE-IM was associated with better survival
independent of age, sex, stage, and tumor location and length (adjusted
HR 0.66, 95% CI 0.5–0.88, P = .005). The UK cohort included1417
patients, and 45% with BE-IM showed a survival benefit compared with
those without (hazard ratio 0.59, 95% CI 0.5–0.69, P <
.001), with continued significance in multivariable analysis that
included age, sex, stage, and tumor location (adjusted HR 0.77, 95% CI
0.64–0.93, P = .006).Conclusion: two
types of EAC can be characterized based on the presence or absence of
Barrett epithelium. These findings have implications for understanding
the etiology of EAC, determining prognosis, and developing optimal
clinical strategies to identify patients at risk
ETS-Transcription Factor ETV1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer
No full textBACKGROUND & AIMS: The ETS-transcription factor ETV1 is involved in epithelial-mesenchymal transition during pancreatic development and is induced in mouse pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). We investigated the function of ETV1 in stromal expansion of PDAC and metastasis, as well as its effects on a novel downstream target Sparc, which encodes a matricellular protein found in PDAC stroma that has been associated with invasiveness, metastasis and poor patient outcomes. METHODS: Pancreatic ductal cells were isolated from Pdx1Cre; Kras(G12D/+) mice (PanIN), Pdx1Cre; Kras(G12D/+); p53(fl/+) and Pdx1Cre; Kras(G12D/+); p53(fl/+); Rosa26(YFP) mice (PDAC), and Pdx1Cre; Kras(G12D/+); p53(fl/+); Sparc(-/-) mice. Cells were grown in 3-dimensional organoid culture to analyze morphology, proliferation, and invasion. Human PanIN and PDAC tissues were evaluated for ETV1 expression. Orthotopic pancreatic transplants of ETV1-overexpressing PDAC and respective control cells were performed. RESULTS: ETV1 expression was significantly increased in human PanINs and, even more so, in primary and metastatic PDAC. Analyses of mouse orthotopic xenografts revealed that ETV1 induced significantly larger primary tumors than controls, with significantly increased stromal expansion, ascites and metastases. In 3-dimensional organoids, ETV1 disrupted cyst architecture, induced EMT, and increased invasive capacity. Furthermore, we identified Sparc as a novel functional gene target of Etv1 by luciferase assays, and SPARC and ETV1 proteins co-localized in vivo. Disruption of Sparc abrogates the phenotype of stromal expansion and metastasis found with ETV1 overexpression in vivo. We identified hyaluronan synthase 2 (Has2) as another novel downstream factor of Etv1; that may mediate ETV1's significant expansion of hyaluronic acid in PDAC stroma. Conversely, disruption of Etv1 in PDAC mice (Pdx1Cre; Kras(G12D/+); p53(fl/+); Rosa26(YFP); Cre; Etv1(fl/fl)) reduced levels of SPARC and hyaluronic acid in the stroma. CONCLUSIONS: ETV1 is critical in the desmoplastic stromal expansion and metastatic progression of pancreatic cancer in mice, mediated functionally in part through Sparc and Has2
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