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The HMGA1-COX-2 axis: a key molecular pathway and potential target in pancreatic adenocarcinoma.

ABSTRACT: Although pancreatic cancer is a common, highly lethal malignancy, the molecular events that enable precursor lesions to become invasive carcinoma remain unclear. We previously reported that the high-mobility group A1 (HMGA1) protein is overexpressed in >90% of primary pancreatic cancers, with absent or low levels in early precursor lesions.Here, we investigate the role of HMGA1 in reprogramming pancreatic epithelium into invasive cancer cells. We assessed oncogenic properties induced by HMGA1 in non-transformed pancreatic epithelial cells expressing activated K-RAS. We also explored the HMGA1-cyclooxygenase (COX-2) pathway in human pancreatic cancer cells and the therapeutic effects of COX-2 inhibitors in xenograft tumorigenesis.HMGA1 cooperates with activated K-RAS to induce migration, invasion, and anchorage-independent cell growth in a cell line derived from normal human pancreatic epithelium. Moreover, HMGA1 and COX-2 expression are positively correlated in pancreatic cancer cell lines (r(2) = 0.93; p < 0.001). HMGA1 binds directly to the COX-2 promoter at an AT-rich region in vivo in three pancreatic cancer cell lines. In addition, HMGA1 induces COX-2 expression in pancreatic epithelial cells, while knock-down of HMGA1 results in repression of COX-2 in pancreatic cancer cells. Strikingly, we also discovered that Sulindac (a COX-1/COX-2 inhibitor) or Celecoxib (a more specific COX-2 inhibitor) block xenograft tumorigenesis from pancreatic cancer cells expressing high levels of HMGA1.Our studies identify for the first time an important role for the HMGA1-COX-2 pathway in pancreatic cancer and suggest that targeting this pathway could be effective to treat, or even prevent, pancreatic cancer.

SUBMITTER: Hillion J

PROVIDER: S-EPMC3466102 | biostudies-literature | 2012 Jul-Aug

REPOSITORIES: biostudies-literature

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The HMGA1-COX-2 axis: a key molecular pathway and potential target in pancreatic adenocarcinoma.

Hillion Joelle J Smail Shamayra S SS Di Cello Francescopaolo F Belton Amy A Shah Sandeep N SN Huso Tait T Schuldenfrei Andrew A Nelson Dwella Moton DM Cope Leslie L Campbell Nathaniel N Karikari Collins C Aderinto Abimbola A Maitra Anirban A Huso David L DL Resar Linda M S LM

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 20120529 4

<h4>Context</h4>Although pancreatic cancer is a common, highly lethal malignancy, the molecular events that enable precursor lesions to become invasive carcinoma remain unclear. We previously reported that the high-mobility group A1 (HMGA1) protein is overexpressed in >90% of primary pancreatic cancers, with absent or low levels in early precursor lesions.<h4>Methods</h4>Here, we investigate the role of HMGA1 in reprogramming pancreatic epithelium into invasive cancer cells. We assessed oncogeni ...[more]

PMID: 22898640

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most complicated and fatally pathogenic human malignancies. Therefore, there is an urgent need to improve our understanding of the underlying molecular mechanism that drives the initiation, progression, and metastasis of PDAC. The aim of the present study was to identify the key genes and signaling pathways associated with PDAC using bioinformatics analysis. Four transcriptome microarray datasets (GSE15471, GSE55643, GSE62165 and GSE91035) were acquired from Gene Expression Omnibus datasets, which included 226 PDAC samples and 65 normal pancreatic tissue samples. We screened differentially expressed genes (DEGs) with GEO2R and investigated their biological function by Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) analysis. The overall survival data was obtained from UALCAN, which calculated the data shared with The Cancer Genome Atlas. In addition, a protein-protein interaction (PPI) network of the DEGs was constructed by STRING and Cytoscape software. The four sets of DEGs exhibited an intersection consisting of 205 genes (142 up-regulated and 63 down-regulated), which may be associated with PDAC. GO analysis showed that the 205 DEGs were significantly enriched in the plasma membrane, cell adhesion molecule activity and the Energy pathways, and glycine, serine, threonine metabolism were the most enriched pathways according to KEGG pathway analysis. Kaplan-Meier survival analysis revealed that 22 of 205 common genes were significantly associated with the overall survival of pancreatic cancer patients. In the PPI network and sub-network, DKK1 and HMGA2 were considered as hub genes with high connectivity degrees. DKK1 and HMGA2 are strongly associated with WNT3A and TP53 separately, which indicates that they may play an important role in the Wnt and P53 signaling pathways. Using integrated bioinformatics analysis, we identified DKK1 and HMGA2 as candidate genes in PDAC, which may improve our understanding of the mechanisms of the pathogenesis and integration; the two genes may be therapeutic targets and prognostic markers for PDAC.

Project description:BackgroundPancreatic adenocarcinoma (PAAD) is an aggressive solid tumour characterised by few early symptoms, high mortality, and lack of effective treatment. Therefore, it is important to identify new potential therapeutic targets and prognostic biomarkers of PAAD.MethodsThe Cancer Genome Atlas and Genotype-Tissue Expression databases were used to identify the expression and prognostic model of protocadherin 1 (PCDH1). The prognostic performance of risk factors and diagnosis of patients with PAAD were evaluated by regression analysis, nomogram, and receiver operating characteristic curve. Paraffin sections were collected from patients for immunohistochemistry (IHC) analysis. The expression of PCDH1 in cells obtained from primary tumours or metastatic biopsies was identified using single-cell RNA sequencing (scRNA-seq). Real-time quantitative polymerase chain reaction (qPCR) and western blotting were used to verify PCDH1 expression levels and the inhibitory effects of the compounds.ResultsThe RNA and protein levels of PCDH1 were significantly higher in PAAD cells than in normal pancreatic ductal cells, similar to those observed in tissue sections from patients with PAAD. Aberrant methylation of the CpG site cg19767205 and micro-RNA (miRNA) hsa-miR-124-1 may be important reasons for the high PCDH1 expression in PAAD. Up-regulated PCDH1 promotes pancreatic cancer cell metastasis. The RNA levels of PCDH1 were significantly down-regulated following flutamide treatment. Flutamide reduced the percentage of PCDH1 RNA level in PAAD cells Panc-0813 to < 50%. In addition, the PCDH1 protein was significantly down-regulated after Panc-0813 cells were incubated with 20 µM flutamide and proves to be a potential therapeutic intervention for PAAD.ConclusionPCDH1 is a key prognostic biomarker and promoter of PAAD metastasis. Additionally, flutamide may serve as a novel compound that down-regulates PCDH1 expression as a potential treatment for combating PAAD progression and metastasis.

Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed and treated in advanced tumor stages with poor prognosis. More effective screening programs and novel therapeutic means are urgently needed. Recent studies have regarded tight junction protein claudin 18.2 (CLDN18.2) as a candidate target for cancer treatment, and zolbetuximab (formerly known as IMAB362) has been developed against CLDN18.2. However, there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC.AimTo investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC.MethodsThe Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue. Second, we analyzed the expression of CLDN18.2 in 93 primary PDACs, 86 para-cancer tissues, and 13 normal pancreatic tissues by immunohistochemistry. Immunostained tissues were assessed applying the histoscore. subsequently, they fell into two groups according to the expression state of CLDN18.2. Furthermore, the correlations between CLDN18.2 expression and diverse clinicopathological characteristics, including survival, were investigated.ResultsThe gene expression of CLDN18 was statistically higher (P < 0.01) in pancreatic tumors than in normal tissues. However, there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients. CLDN18.2 was expressed in 88 (94.6%) of the reported PDACs. Among these tumors, 50 (56.8%) cases showed strong immunostaining. The para-cancer tissues were positive in 81 (94.2%) cases, among which 32 (39.5%) of cases were characterized for strong staining intensities. Normal pancreatic tissue was identified solely via weak immunostaining. Finally, CLDN18.2 expression significantly correlated with lymph node metastasis, distant metastasis, nerve invasion, stage, and survival of PDAC patients, while there was no correlation between CLDN18.2 expression and localization, tumor size, patient age and sex, nor any other clinicopathological characteristic.ConclusionCLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in PDAC.

Dataset Information

The HMGA1-COX-2 axis: a key molecular pathway and potential target in pancreatic adenocarcinoma.

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The HMGA1-COX-2 axis: a key molecular pathway and potential target in pancreatic adenocarcinoma.

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