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New markers for the epithelial and proliferative or mesenchymal invasive phenotype of human neoplasias

a technology of epithelial and mesenchymal invasive phenotype and new markers, which is applied in the field of new ena/vasp protein isoforms, can solve the problem of no molecular markers or pathologic prognostic criteria capable of predicting the clinical evolution of tumour lesion in human patients

Inactive Publication Date: 2013-07-18
INSTI FISIOTERAPICI OSPITALERI IFO INST REGINA ELENA PER LO STUDIO E LA CURA DEI TUMORI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The inventors conducted experiments that showed the presence of two proteins, hMenaΔv6 and hMena11a, are associated with the ability of cells to move and invade. These proteins are also alternately expressed with each other, meaning cells that express hMenaΔv6 do not express hMena11a, and vice versa. The absence of hMena11a expression is a strong predictor of individual patient risk in early non-small-cell lung cancer (NSCLC). These findings can help clinicians better identify patients at higher risk of the disease and improve treatment outcomes.

Problems solved by technology

Unfortunately, despite the progress related to the understanding of molecular mechanisms underlying the carcinogenesis, there are no molecular markers or pathologic prognostic criteria capable to predict the clinical evolution of a tumour lesion in human patient.

Method used

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  • New markers for the epithelial and proliferative or mesenchymal invasive phenotype of human neoplasias
  • New markers for the epithelial and proliferative or mesenchymal invasive phenotype of human neoplasias
  • New markers for the epithelial and proliferative or mesenchymal invasive phenotype of human neoplasias

Examples

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example 1

Molecular Cloning and Characterization of hMenaΔv6 Coding Sequence

[0178]RT-PCR experiments on the breast cancer cell line MDA-MB-231 with two primers designed on the human Mena coding sequence and possessing the ATG and the stop codon respectively were performed. PCR products sequencing revealed that these cells express hMena (1713 nt) and in addition, a not yet described transcript of 1602 nucleotides from the ATG to the stop codon. This sequence is identical to hMena, but lacks the internal exon 6 of 111 nucleotides, thus we named this splice variant hMena Δv6 (GenBank, Accession: 1030575), SED ID NO 1.

[0179]hMena Δv6cDNA encodes a protein of 533aa (SEQ ID 2) without an internal peptide of 37aa located between the LERER and the Proline-rich region of hMena (FIG. 1). The absence of this peptide physically approaches, in the protein, the LERER domain with the pro-rich domain. Upon protein alignment, hMena Δv6displays an identity of 88% with the 526aa Rattus norvegicus ENAH(NCBI Acce...

example 2

hMena11a and hMena Δv6 are Alternatively Expressed and Correlate with an Epithelial and Mesenchymal Phenotype Respectively

[0181]We then analyzed by RT-PCR experiments the expression of hMena, hMena11a and hMenaΔv6 by two primers located in the exons 5 and 12 respectively (MTC1f; MTC4r) on a panel of breast cancer cell lines. Whereas hMena is always present, the two splice variants hMena11a and hMena Δv6 are mutually exclusive expressed (FIG. 1 panels B, C). As shown in the FIG. 1, two luminal breast cancer cell lines MCF7 and SBT express hMena11a and not hMena Δv6, which is conversely present in basal breast cancer cells MDA-MB-231 and BT549, lacking the epithelial hMena11a isoform, suggesting that the hMena Δv6 expression is peculiar of mesenchymal phenotype.

[0182]At protein level the characterization of hMena isoform expression lines with specific antibodies we produced demonstrate, in a large panel of cell, that hMena11a and hMena Δv6 correlate with an epithelial or mesenchymanl ...

example 3

hMena11a Transfection Inhibits Matrigel Invasion of hMena11a Negative Breast Cancer Cells

[0185]In order to understand whether the lack of hMena11a contributes to the invasive and migratory behaviour of hMena Δv6 expressing cells, we have transfected MDA-MB-231 cells with hMena11a. Matrigel invasion assays, demonstrate a very significant inhibition of invasion in MDA-MB-231-hMena11a transfected cells respect to the control (FIG. 6 panel A). In addition, results of wound healing migration assay clearly show that, in contrast to the behaviour of control cells (pcDNA3), MDA-MB-231-hMena11a transfected cells do not scatter and do not migrate into the wound either after 24 h or, more evident after 48 h. A significant reduction of the invasive properties determined by hMena11a transfection was also observed in the highly invasive BT549 cells, as shown in FIG. 6 panel B.

[0186]Immunofluorescence analysis (FIG. 6 panel D) show cytoskeletal changes following the exogeneous expression of hMena1...

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Abstract

The present invention relates to a new Ena / VASP protein isoform, uses thereof, diagnostic methods and kits comprising the same.

Description

BACKGROUND OF THE INVENTION[0001]The present invention was granted a foreign filing license issued by the Ministero dello sviluppo economico UIBM, on the 30, Apr. 2010, Protocol number 40718.[0002]The present invention relates to a new Ena / VASP protein isoform, uses thereof, diagnostic methods and kits comprising the same.[0003]Carcinogenesis and progression of a tumour lesion are characterized by different gene expression patterns. These expression patterns are defined by different splice-variants and in particular, alternative splicing events frequently affect genes controlling the cytoskeleton organization in tumour cells (Wang G S, Cooper T A. 2007; Gardina P J et al. 2006).[0004]It has been reported that regulatory pathways controlling actin cytoskeleton dynamics are deregulated in cancer cells, and altered expression of proteins controlling actin polymerization frequently occurs affecting growth, survival and migration of tumor cells (Olson M F, Sahai E. Clin Exp Metastasis. 2...

Claims

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Application Information

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IPC IPC(8): C07K14/435G01N33/574C12Q1/68
CPCC12Q1/6886G01N33/57492C12Q2600/136C12Q2600/158G01N33/5011G01N33/57407G01N33/57415G01N33/57419G01N33/57423G01N33/5743G01N33/57434G01N33/57438G01N33/57446G01N33/57449C07K14/435C12Q2600/118
Inventor NISTICO, PAOLADI MODUGNO, FRANCESCA
Owner INSTI FISIOTERAPICI OSPITALERI IFO INST REGINA ELENA PER LO STUDIO E LA CURA DEI TUMORI
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