Dataset Information

Targeting of surface alpha-enolase inhibits the invasiveness of pancreatic cancer cells.

ABSTRACT: Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by rapid progression, invasiveness and resistance to treatment. We have previously demonstrated that most PDAC patients have circulating antibodies against the glycolytic enzyme alpha-enolase (ENO1), which correlates with a better response to therapy and survival. ENO1 is a metabolic enzyme, also expressed on the cell surface where it acts as a plasminogen receptor. ENO1 play a crucial role in cell invasion and metastasis by promoting plasminogen activation into plasmin, a serine-protease involved in extracellular matrix degradation. The aim of this study was to investigate the role of ENO1 in PDAC cell invasion. We observed that ENO1 was expressed on the cell surface of most PDAC cell lines. Mouse anti-human ENO1 monoclonal antibodies inhibited plasminogen-dependent invasion of human PDAC cells, and their metastatic spreading in immunosuppressed mice was inhibited. Notably, a single administration of Adeno-Associated Virus (AAV)-expressing cDNA coding for 72/1 anti-ENO1 mAb reduced the number of lung metastases in immunosuppressed mice injected with PDAC cells. Overall, these data indicate that ENO1 is involved in PDAC cell invasion, and that administration of an anti-ENO1 mAb can be exploited as a novel therapeutic option to increase the survival of metastatic PDAC patients.

SUBMITTER: Principe M

PROVIDER: S-EPMC4484442 | biostudies-other | 2015 May

REPOSITORIES: biostudies-other

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Targeting of surface alpha-enolase inhibits the invasiveness of pancreatic cancer cells.

Principe Moitza M Ceruti Patrizia P Shih Neng-Yao NY Chattaragada Michelle S MS Rolla Simona S Conti Laura L Bestagno Marco M Zentilin Lorena L Yang Sheng-Hui SH Migliorini Paola P Cappello Paola P Burrone Oscar O Novelli Francesco F

Oncotarget 20150501 13

Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by rapid progression, invasiveness and resistance to treatment. We have previously demonstrated that most PDAC patients have circulating antibodies against the glycolytic enzyme alpha-enolase (ENO1), which correlates with a better response to therapy and survival. ENO1 is a metabolic enzyme, also expressed on the cell surface where it acts as a plasminogen receptor. ENO1 play a crucial role in cell invasion a ...[more]

PMID: 25860938

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Project description:MicroRNAs (miRNAs, micro ribonucleic acids) are pivotal post-transcriptional regulators of gene expression. These endogenous small non-coding RNAs play significant roles in tumorigenesis and tumor progression. miR-142-3p expression is dysregulated in several breast cancer subtypes. We aimed at investigating the role of miR-142-3p in breast cancer cell invasiveness. Supported by transcriptomic Affymetrix array analysis and confirmatory investigations at the mRNA and protein level, we demonstrate that overexpression of miR-142-3p in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells leads to downregulation of WASL (Wiskott-Aldrich syndrome-like, protein: N-WASP), Integrin-?V, RAC1, and CFL2, molecules implicated in cytoskeletal regulation and cell motility. ROCK2, IL6ST, KLF4, PGRMC2 and ADCY9 were identified as additional targets in a subset of cell lines. Decreased Matrigel invasiveness was associated with the miR-142-3p-induced expression changes. Confocal immunofluorescence microscopy, nanoscale atomic force microscopy and digital holographic microscopy revealed a change in cell morphology as well as a reduced cell volume and size. A more cortical actin distribution and a loss of membrane protrusions were observed in cells overexpressing miR-142-3p. Luciferase activation assays confirmed direct miR-142-3p-dependent regulation of the 3'-untranslated region of ITGAV and WASL. siRNA-mediated depletion of ITGAV and WASL resulted in a significant reduction of cellular invasiveness, highlighting the contribution of these factors to the miRNA-dependent invasion phenotype. While knockdown of WASL significantly reduced the number of membrane protrusions compared to controls, knockdown of ITGAV resulted in a decreased cell volume, indicating differential contributions of these factors to the miR-142-3p-induced phenotype. Our data identify WASL, ITGAV and several additional cytoskeleton-associated molecules as novel invasion-promoting targets of miR-142-3p in breast cancer.

Project description:Background: Alpha-enolase is an important glycolytic enzyme, and its aberrant expression has been associated with multiple tumor progression. However, few studies investigated the expression of alpha-enolase and its clinical significance in pancreatic cancer (PC). Objectives: To evaluate alpha-enolase level in PC tissues by immunohistochemical (IHC) analysis, and investigate the association of alpha-enolase expression with clinicopathologic features. Methods: The alpha-enolase levels in pancreatic cancer tissues were analyzed by using the Oncomine database. The expression of alpha-enolase, Ki67 and p53 in pancreatic cancer and adjacent normal tissues were evaluated by IHC using the corresponding primary antibodies on the commercial tissue arrays. We also examined their association with clinicopathologic parameters, and explored their prognostic value in PC. Results: We identified an elevation of alpha-enolase mRNA level in pancreatic cancer independent datasets from Oncomine. IHC analysis showed that alpha-enolase protein levels were elevated in 47% (n=100) PC tissue samples, but there was weak or no staining in the normal tissues. Statistical analysis revealed that high levels of alpha-enolase were significantly associated with Stage and Lymph node metastasis. Correlation analysis indicated that over-expression of alpha-enolase was positively associated with Ki67 expression and inversely correlated with p53 expression. Furthermore, membranous expression of alpha-enolase was also observed in 29.8% (14/47) total alpha-enolase positive samples, and was significantly associated with Lymph node metastasis. Kaplan-Meier survival analysis demonstrated that high total alpha-enolase expression was significantly associated with unfavorable survival, while membranous alpha-enolase expression was significantly associated with better survival of PC patients. Multivariate Cox analysis demonstrated that total alpha-enolase expression was an independent prognostic factor for PC patients. Conclusions: Our results suggested that alpha-enolase level was significantly elevated in pancreatic cancer tissues, which was closely associated with PC progression. It might be a candidate target for targeted pancreatic cancer treatments.

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Targeting of surface alpha-enolase inhibits the invasiveness of pancreatic cancer cells.

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Targeting of surface alpha-enolase inhibits the invasiveness of pancreatic cancer cells.

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