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Knockdown of the ?(1) integrin subunit reduces primary tumor growth and inhibits pancreatic cancer metastasis.

ABSTRACT: To address the role of ?(1) integrins in pancreatic cancer progression, we stably knocked down ?(1) integrin subunit expression in human FG-RFP pancreatic cancer cells using lentiviral-based RNA interference. We then examined the effects of ?(1) integrin subunit knockdown on pancreatic cancer cell adhesion, migration and proliferation on tumor microenvironment-specific extracellular matrix proteins in vitro and on tumor progression in vivo using a clinically relevant fluorescent orthotopic mouse model of pancreatic cancer. Knockdown of the ?(1) integrin subunit inhibited cell adhesion, migration and proliferation on types I and IV collagen, fibronectin and laminin in vitro. In vivo, knockdown of the ?(1) integrin subunit reduced primary tumor growth by 50% and completely inhibited spontaneously occurring metastasis. These observations indicate a critical role for the ?(1) integrin subunit in pancreatic cancer progression and metastasis in particular. Our results suggest the ?(1) integrin subunit as a therapeutic target for the treatment of pancreatic cancer, especially in the adjuvant setting to prevent metastasis of this highly aggressive cancer.

SUBMITTER: Grzesiak JJ

PROVIDER: S-EPMC3167925 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Knockdown of the β(1) integrin subunit reduces primary tumor growth and inhibits pancreatic cancer metastasis.

Grzesiak John J JJ Tran Cao Hop S HS Burton Douglas W DW Kaushal Sharmeela S Vargas Fabian F Clopton Paul P Snyder Cynthia S CS Deftos Leonard J LJ Hoffman Robert M RM Bouvet Michael M

International journal of cancer 20110413 12

To address the role of β(1) integrins in pancreatic cancer progression, we stably knocked down β(1) integrin subunit expression in human FG-RFP pancreatic cancer cells using lentiviral-based RNA interference. We then examined the effects of β(1) integrin subunit knockdown on pancreatic cancer cell adhesion, migration and proliferation on tumor microenvironment-specific extracellular matrix proteins in vitro and on tumor progression in vivo using a clinically relevant fluorescent orthotopic mo ...[more]

PMID: 21491421

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Project description:BACKGROUND:Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with basal features, lacking the expression of receptors targeted successfully in other breast cancer subtypes. Treatment response to adjuvant and neoadjuvant chemotherapy is often short-lived and metastatic spread occurs at higher rates than other subtypes within the first five years after diagnosis. TNBCs exhibit stem cell features and are enriched for cancer stem cell (CSC) populations. E1A Binding Protein P300 (EP300) is a large protein with multiple cellular functions, including as an effector in stem cell biology. METHODS:We used a genetic knockdown (KD) model of EP300 in TNBC cell lines to investigate the effect on CSC phenotype, tumor growth and metastasis. Side population assay and tumorsphere suspension culture were used in vitro. Xenograft mouse models were used for in vivo studies. We performed in silico analysis of publicly available gene expression data sets to investigate CSC gene expression and molecular pathways as well as survival outcomes associated with EP300 expression in patients with TNBC and basal-like BC. RESULTS:EP300 KD abolished the CSC phenotype by reducing ABCG2 expression, side population cells and tumorsphere formation capacity in vitro as well as tumor formation in a xenograft mouse model in vivo. Metastatic capacity was markedly reduced in EP300 KD cells in vivo, with no detection of circulating tumor cells. TCGA data analysis demonstrated that genes positively correlated with EP300 expression in TNBC and basal-like BC were associated with CSC biology. Survival analysis demonstrated that EP300 expression predicts poor recurrence free survival in TNBC and basal BC. CONCLUSION:We report a novel oncogenic role for EP300 in driving CSC phenotype representing a potential target to address tumor initiation and metastatic spread in TNBC and basal-like BC. EP300 might serve as a prognostic marker and potential therapeutic target in TNBC.

Dataset Information

Knockdown of the ?(1) integrin subunit reduces primary tumor growth and inhibits pancreatic cancer metastasis.

Publications

Knockdown of the β(1) integrin subunit reduces primary tumor growth and inhibits pancreatic cancer metastasis.

Similar Datasets

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