Expression of Gadd45a and p53 proteins in human pancreatic cancer: Potential effects on clinical outcomes

Dong, Ming; Dong, Qi; Zhang, Hao; Zhou, Jianping; Tian, Yue; Dong, Yuting

doi:10.1002/jso.20684

Cited by 19 publications

(20 citation statements)

References 7 publications

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“…Hollander et al (1999) could demonstrate that GADD45A is a component of the p53 pathway, contributing to the maintenance of genomic stability. Both p53 and GADD45A are highly expressed in human pancreatic cancer and may be associated with pivotal biological features of pancreatic cancer (Dong et al, 2005). Downregulation of GADD45A, as in our setting, reduces proliferation and induces apoptosis in pancreatic cancer cells .…”

Section: Discussionmentioning

confidence: 53%

Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model

et al. 2007

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The prognosis of pancreatic adenocarcinoma is affected by early metastases and local tumour invasion beyond surgical margins. Gene expression profiling in pancreatic cancer tissue is complicated due to the high amount of RNAses being present in human tissue and that of suitable models. In order to demonstrate early metastases, the models should take into account the anatomical environment of the tumour. Using the orthotopic transplantation of pancreatic tumour cells in SCID (severe combined immunodeficiency) mice, these interactions are taken into consideration. In order to identify genes associated with local tumour invasion and metastases in ductal pancreatic cancer, we investigated a human pancreatic tumour cell line derived from an orthopic pancreatic tumour model in SCID mice. Differential gene expression was performed on the basis of microarray technique. The human MiaPaca-2 cell line was implanted orthotopically in SCID mice. Transcriptional profiling was performed on fresh frozen tissue derived from the primary tumour, the tumour invasion front and the liver metastases. Differentially expressed genes were identified using statistical analyses, and were validated with external databases and with immunohistochemistry. A total of 1066 of 14 500 genes were significantly differentially expressed. Comparing the primary tumour with the tumour invasion front, there were 614 statistically significant up-and 348 downregulated genes. Twenty-five statistically significant up-and 181 downregulated genes were identified comparing the liver metastases with the primary tumour. Eight genes (PAI-1, BNIP3l, VEGF, NSE, RGS4, HSP27, GADD45A, PTPN14) were chosen and validated in a semi-quantitative immunohistochemical analysis, which revealed a positive correlation to the array data. Overrepresentation analyses revealed a total of 66 significantly regulated pathways associated with cell proliferation, cell stress, cell communication metabolic and cytokine function. In conclusion, model marker genes for local invasion and liver metastases can be identified using transcriptional profiling in the SCID mouse. Overrepresentation analysis secures a good and fast overview about the significantly regulated genes and can assign genes to certain pathways. These marker genes can be related to the apoptotic cascade, angiogenesis and cell interaction.

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Section: Discussionmentioning

confidence: 53%

Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model

et al. 2007

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“…GADD45α and p53 expression in clinical samples of invasive pancreatic ductal carcinomas correlated with lower survival rates for patients with GADD45α (+) subgroup compared to GADD45α (-) subgroup, suggesting a link between GADD45α and p53 expression and poor prognosis for pancreatic cancer patients [117]. Supporting this data, GADD45 proteins are highly detected in pancreatic cancer samples and those patients with positive expression of p53 and GADD45α have shorter post-operative survival rates [135]. Moreover, in pancreatic ductal adenocarcinoma, GADD45α knockdown reduces cell proliferation and induces apoptosis [136].…”

Section: Gadd45 Expression Is Deregulated In Various Types Of Cancermentioning

confidence: 93%

GADD45 Proteins: Central Players in Tumorigenesis

Tamura

Vasconcellos²,

Sarkar³

et al. 2012

CMM

273

198

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The Growth Arrest and DNA Damage-inducible 45 (GADD45) proteins have been implicated in regulation of many cellular functions including DNA repair, cell cycle control, senescence and genotoxic stress. However, the pro-apoptotic activities have also positioned GADD45 as an essential player in oncogenesis. Emerging functional evidence implies that GADD45 proteins serve as tumor suppressors in response to diverse stimuli, connecting multiple cell signaling modules. Defects in the GADD45 pathway can be related to the initiation and progression of malignancies. Moreover, induction of GADD45 expression is an essential step for mediating anti-cancer activity of multiple chemotherapeutic drugs and the absence of GADD45 might abrogate their effects in cancer cells. In this review, we present a comprehensive discussion of the functions of GADD45 proteins, linking their regulation to effectors of cell cycle arrest, DNA repair and apoptosis. The ramifications regarding their roles as essential and central players in tumor growth suppression are also examined. We also extensively review recent literature to clarify how different chemotherapeutic drugs induce GADD45 gene expression and how its up-regulation and interaction with different molecular partners may benefit cancer chemotherapy and facilitate novel drug discovery.

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“…Whether these mutations have also a prognostic significance remains unclear. Few researchers have suggested a shorter overall survival in pancreatic cancer patients carrying p53 mutation compared to p53(-) patients [9,11,39,45]. In other studies though no correlation of p53 with prognosis was demonstrated [46,47].…”

Section: P-53mentioning

confidence: 95%

“…Commonly mutated genes in pancreatic cancer include K-ras (in 74-100% of cases), p16INK4a (up to 98%), p53 (43 to 76%), DPC4 (about 50%), HER-2/neu (in about 65%) and FHIT (found in 70% of cases) [9][10][11][12][13][14][15]. Other genes involved are notch1, Akt-2, BRCA2 and COX-2.…”

Section: Molecular Pathogenesis Of Pancreatic Cancermentioning

confidence: 99%

Pancreatic cancer: from molecular pathogenesis to targeted therapy

Strimpakos

Saif

Syrigos

2008

Cancer Metastasis Rev

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Pancreatic cancer is a deadly malignancy with still high mortality and poor survival despite the significant advances in understanding, diagnosis, and access to conventional and novel treatments. Though cytotoxic chemotherapy based on the purine analogue gemcitabine remains the standard approach in adjuvant and palliative setting the need for novel agents aiming at the main pathophysiological abnormalities and molecular pathways involved remains soaring. So far, evidence of clinical benefit, though small, exists only from the addition of the targeted agent erlotinib on the standard gemcitabine chemotherapy. Apart from the popular monoclonal antibodies and small molecules tyrosine kinase inhibitors, other novel compounds being tested in preclinical and clinical studies target mTOR, NF-kappaB, proteasome and histone deacetylase. These new drugs along with gene therapy and immunotherapy, which are also under clinical evaluation, may alter the unfavorable natural course of this disease. In this review we present the main pathophysiological alterations met in pancreatic cancer and the results of the florid preclinical and clinical research with regards to the targeted therapy associated to these abnormalities.

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Expression of Gadd45a and p53 proteins in human pancreatic cancer: Potential effects on clinical outcomes

Abstract: p53 and Gadd45a proteins are both highly expressed in pancreatic cancer. The overexpression of p53 and Gadd45a may have connection with the malignant biologic behavior of pancreatic cancer.

Cited by 19 publications

References 7 publications

Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model

Gene expression profiling of liver metastases and tumour invasion in pancreatic cancer using an orthotopic SCID mouse model

GADD45 Proteins: Central Players in Tumorigenesis

Pancreatic cancer: from molecular pathogenesis to targeted therapy

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