Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter

Su, Zhao-zhong; Sarkar, Devanand; Emdad, Luni; Duigou, Gregory J.; Young, C. S. H.; Ware, Joy L.; Randolph, Aaron; Valerie, Kristoffer; Fisher, Paul B.

doi:10.1073/pnas.0409141102

Cited by 77 publications

(107 citation statements)

References 41 publications

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“…58 The cancer-specific activity of this promoter is governed by Pea3 binding sites on the promoter, and this Pea3-progression-elevated gene 3 link promotes the transformation of rat embryonic cells. 59,60 The importance of Pea3 group transcription factors in tumorigenesis is further strengthened by a recent study demonstrating that Pea3 and Erm are required for the tumorigenesis of mammary cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

Yuen

McCrudden

Chan

et al. 2011

The American Journal of Pathology

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The transcription factors Pea3, Erm, and Er81 can promote cancer initiation and progression in various types of solid tumors. However, their role in esophageal squamous cell carcinoma (ESCC) has not been elucidated. In this study, we found that the expression levels of Pea3 and Erm, but not that of Er81, were significantly higher in ESCC compared with nontumor esophageal epithelium. A high level of Pea3 expression was significantly correlated with a shorter overall survival in a cohort of 81 patients with ESCC and the subgroup with N1 stage tumor (WilcoxonGehan test, P ‫؍‬ 0.016 and P ‫؍‬ 0.001, respectively). Pea3 was overexpressed in seven ESCC cell lines compared with two immortalized esophageal cell lines. Pea3 knockdown reduced cell proliferation and suppressed nonadherent growth, migration, and invasion in ESCC cells in vitro. In addition, Pea3 knockdown in ESCC cells resulted in a down-regulation of phospho-Akt and matrix metalloproteinase 13, whereas a significant positive correlation in the expression levels was observed between Pea3 and phospho-Akt (r ‫؍‬ 0.281, P < 0.013) and between Pea3 and matrix metalloproteinase 13 in the human specimens (r ‫؍‬ 0.462, P < 0.001). Moreover, Pea3 modulated the sensitivity of EC109 cells to doxorubicin, probably via reduced activity of the phosphatidylinositol 3-kinase-Akt-mammalian target of Rapamycin complex 1 pathway on Pea3 knockdown. In conclusion, our results suggest that Pea3 plays an important role in the progression of ESCC. Esophageal squamous cell carcinoma (ESCC) is common among Asian populations. 1 Despite recent advances in the detection of the premalignant lesions and the development of combination therapies, its incidence is increasing, and its outcome remains poor. [2][3][4] Given the poor prognosis of ESCC and its high incidence rate, it is increasingly important to understand the initiation and progression of this type of cancer and to identify the associated prognostic factors.Pea3, Erm, and Er81 belong to the Pea3 subgroup of the Ets transcription factor family. This group of proteins contains several functional domains, and the individual members demonstrate extensive amino acid sequence similarities. 5 The roles of these proteins in mammary gland development and tumorigenesis have also been extensively studied and reviewed. 6 -8 Pea3 group transcription factors promote metastatic development and cancer progression through transcriptional activation of metastasis-related genes, such as matrix metalloproteinases (MMPs) 9 -13 and cyclooxygenase (COX)-2. 14,15 Overexpression of Pea3 also increases the motility and invasiveness of lung cancer cells via activation of the pathway and an increase in COX-2 expression. 16 -18 The prognostic significance of Pea3 has also been demonstrated in various solid tumors. Pea3 is overexpressed in mouse metastatic mammary adenocarcinoma 19 and in human breast cancer, in which its overexpression is also correlated with HER-2 expression and poor prognosis. 20 -23

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Section: Discussionmentioning

confidence: 99%

The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

Yuen

McCrudden

Chan

et al. 2011

The American Journal of Pathology

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“…PEG-GFP or Ad.CMV-GFP, as described previously. 39 Luciferase assays were performed as described previously. 39,44,45 GFP expression was determined following infection with the appropriate viruses 2 days postinfection.…”

Section: Construction Of a Conditional Replication-competent Adenovirusmentioning

confidence: 99%

“…This approach employs a genetically modified adenovirus, CTV, in which replication is controlled by a minimal active region of the promoter of progression-elevated gene-3 (PEG-3), which expresses selectively in diverse cancer cells with limited activity in normal cells. 21,[39][40][41] The PEG-3 gene was cloned using subtraction hybridization as an upregulated transcript from a transformation progression rodent cancer model. 42,43 Of direct relevance for gene therapy applications, activity of the PEG-3 promoter (PEG-Prom) is significantly and often markedly elevated not only in rodent but also in human cancer cells of diverse origin when compared to normal cells.…”

Section: Introductionmentioning

confidence: 99%

“…42,43 Of direct relevance for gene therapy applications, activity of the PEG-3 promoter (PEG-Prom) is significantly and often markedly elevated not only in rodent but also in human cancer cells of diverse origin when compared to normal cells. 21,[39][40][41] The mechanism underlying the cancer-specific expression of the PEG-Prom implicates two transcription factors, AP-1 and PEA-3, which are expressed at elevated levels, either singly or in combination, in virtually all types of cancers. 21,[39][40][41][42][43][44][45] Using the PEG-Prom to transcriptionally regulate green fluorescence protein (GFP) or luciferase gene expression via a replication-incompetent Ad confirmed targeted cancer-cell-selective transgene expression in human prostate and breast cancer cells, as well as in malignant glioma cells.…”

Section: Introductionmentioning

confidence: 99%

“…21,[39][40][41][42][43][44][45] Using the PEG-Prom to transcriptionally regulate green fluorescence protein (GFP) or luciferase gene expression via a replication-incompetent Ad confirmed targeted cancer-cell-selective transgene expression in human prostate and breast cancer cells, as well as in malignant glioma cells. 39 Considering these findings, we investigated the use of the PEG-Prom to drive expression of the E1A gene, necessary for Ad replication, to create cancer-cell-specific CRCAs. 21,40,41 One of the engineered CRCAs, which we generated, simultaneously expresses mda-7/IL-24 in the E3 region (Ad.PEG-E1A-mda-7; CTV), thereby inducing robust production of this cytokine as a function of adenoviral replication.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A cancer terminator virus eradicates both primary and distant human melanomas

Sarkar

et al. 2008

Cancer Gene Ther

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The prognosis and response to conventional therapies of malignant melanoma inversely correlate with disease progression. With increasing thickness, melanomas acquire metastatic potential and become inherently resistant to radiotherapy and chemotherapy. These harsh realities mandate the design of improved therapeutic modalities, especially those targeting metastases. To develop an approach to effectively treat this aggressive disease, we constructed a conditionally replication-competent adenovirus in which expression of the adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of progression-elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7), a cancer terminator virus (CTV). This CTV produces large quantities of MDA-7/IL-24 protein as a function of adenovirus replication uniquely in cancer cells. Infection of Ad.PEG-E1A-mda-7 (CTV) in normal human immortal melanocytes and human melanoma cells demonstrates cancer cell-selective adenoviral replication, mda-7/IL-24 expression, growth inhibition and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 CTV into xenografts derived from MeWo human metastatic melanoma cells in athymic nude mice completely eliminated not only primary treated tumors but also distant non-treated tumors (established in the opposite flank), thereby implementing a cure. These provocative findings advocate potential therapeutic applications of this novel virus for treating patients with advanced melanomas with metastases.

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Cancer Gene Therapy by Tissue‐specific and Cancer‐targeting Promoters

Hsu

Huo

et al. 2014

Cancer Gene Therapy by Viral and Non‐viral Vectors

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Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter

Cited by 77 publications

References 41 publications

The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

The Role of Pea3 Group Transcription Factors in Esophageal Squamous Cell Carcinoma

A cancer terminator virus eradicates both primary and distant human melanomas

Cancer Gene Therapy by Tissue‐specific and Cancer‐targeting Promoters

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