In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3121-3121
Abstract:
Prognosis for pancreatic cancer is especially poor, with a 5% survival rate. Current FDA-approved therapeutics gemcitabine and erlotinib extend patient survival by a mere two months. As the disease is asymptomatic, patients are generally diagnosed at later stages of the disease. Consequentially, only 15-20% of patients present with resectable tumors. Further, aggressive metastasis often occurs after surgical intervention, resulting in the death of 75% of patients within five years. These statistics indicate an unmet need for more effective therapeutic strategies to combat pancreatic cancer. c-Jun is a component of the AP-1 early response transcription factor. It is expressed in 87% of primary pancreatic cancer lesions and in several pancreatic cancer cell lines. c-Jun overexpression has been linked to metastasis in numerous cancer models and previous work in our laboratory has demonstrated the efficacy of a DNAzyme against c-Jun for the suppression of tumor growth and angiogenesis in in vivo models of basal and squamous cell carcinoma. We sought to explore the role of c-Jun in pancreatic cancer and the therapeutic potential of gene silencing of endogenous c-Jun. We confirmed serum-inducible c-Jun expression at the mRNA level using qRT-PCR in two in vitro models of pancreatic adenocarcinoma, PANC-1 and MIA PaCa-2. This is consistent with Western blot data, which confirm expression of both c-Jun as well as its phosphorylated form (p-c-Jun) at the protein level. Optimal uptake of a FITC-labeled siRNA into these cell lines was achieved using DOTAP/DOPE transfection reagent. We subsequently demonstrated that the effective blockade of c-Jun and p-c-Jun could be achieved with siRNA targeting human endogenous c-Jun. At the functional level, while blockade of c-Jun had no apparent effect on cell proliferation, PANC-1 and MIA PaCa-2 cell migration and invasion were markedly reduced. This was demonstrated using transwell assays. Interestingly, this effect was enhanced in cells that were also treated with gemcitabine. Further, we showed that MMP-1 expression was inhibited in MIA PaCa-2 cells treated with siRNA targeting c-Jun. We have also identified Cystatin F, MDM2, MET, MMP-13 and NF2 as potential downstream targets of c-Jun using a human tumor metastasis PCR array. This in vitro data confirms the expression and activation of c-Jun in pancreatic cancer cells, and demonstrate a functional role for c-Jun in pancreatic cancer cell migration and invasion, which underpin metastasis. We are in the process of validating these results in vivo employing shRNA to generate a stable knockdown of c-Jun in pancreatic cancer cells (MIA PaCa-2). Citation Format: Anjali V. Sheahan, Levon M. Khachigian. c-Jun as a target in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3121. doi:10.1158/1538-7445.AM2013-3121
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2013-3121
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2013
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
