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Abrogation of junctional adhesion molecule-A expression induces cell apoptosis and reduces breast cancer progression.

Murakami M, Giampietro C, Giannotta M, Corada M, Torselli I, Orsenigo F, Cocito A, d'Ario G, Mazzarol G, Confalonieri S, Di Fiore PP, Dejana E - PLoS ONE (2011)

Bottom Line: Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased.We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis.JAM-A may be considered a negative prognostic factor and a potential therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: IFOM, Foundation FIRC Institute of Molecular Oncology, Milan, Italy.

ABSTRACT
Intercellular junctions promote homotypic cell to cell adhesion and transfer intracellular signals which control cell growth and apoptosis. Junctional adhesion molecule-A (JAM-A) is a transmembrane immunoglobulin located at tight junctions of normal epithelial cells of mammary ducts and glands. In the present paper we show that JAM-A acts as a survival factor for mammary carcinoma cells. JAM-A mice expressing Polyoma Middle T under MMTV promoter develop significantly smaller mammary tumors than JAM-A positive mice. Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased. Tumor cells isolated from JAM-A mice or 4T1 cells incubated with JAM-A blocking antibodies showed reduced growth and increased apoptosis which paralleled altered junctional architecture and adhesive function. In a breast cancer clinical data set, tissue microarray data show that JAM-A expression correlates with poor prognosis. Gene expression analysis of mouse tumor samples showed a correlation between genes enriched in human G3 tumors and genes over expressed in JAM-A +/+ mammary tumors. Conversely, genes enriched in G1 human tumors correlate with genes overexpressed in JAM-A-/- tumors. We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis. JAM-A may be considered a negative prognostic factor and a potential therapeutic target.

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JAM-A and junctional proteins' expression was decreased at the invading tumor edge in vivo and in vitro.A) MMTV-PyVmT/JAM-A+/+ tumor sections show decreased JAM-A and E-cadherin expression level at the invasive edge as compared to tumor nodules and mammary duct. Scale bar; 100 µm; B) In tissue sections, TUNEL positive tumor cells were concentrated at the invasive edge of the tumor. Scale bar; 100 µm; C) In the wound assay (see Fig. 3) cultured MMTV-PyVmT/JAM-A−/− cells show strong TUNEL staining both at the migrating front and in the distal areas while JAM-A+/+ cells presented TUNEL staining only at the leading edge. Quantification is reported at the right panel, data are means +/− SEM of 3 experiments performed in quadruplicates. **p<0.01 by unpaired Student-t test. Scale bar; 300 µm; D) Western blot analysis of JAM-A and ZO-1 expression in 4T1 cells in sparse, sub-confluent, and confluent conditions. Quantification is reported in the right panels. The results are representative of 3 independent experiments.
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pone-0021242-g004: JAM-A and junctional proteins' expression was decreased at the invading tumor edge in vivo and in vitro.A) MMTV-PyVmT/JAM-A+/+ tumor sections show decreased JAM-A and E-cadherin expression level at the invasive edge as compared to tumor nodules and mammary duct. Scale bar; 100 µm; B) In tissue sections, TUNEL positive tumor cells were concentrated at the invasive edge of the tumor. Scale bar; 100 µm; C) In the wound assay (see Fig. 3) cultured MMTV-PyVmT/JAM-A−/− cells show strong TUNEL staining both at the migrating front and in the distal areas while JAM-A+/+ cells presented TUNEL staining only at the leading edge. Quantification is reported at the right panel, data are means +/− SEM of 3 experiments performed in quadruplicates. **p<0.01 by unpaired Student-t test. Scale bar; 300 µm; D) Western blot analysis of JAM-A and ZO-1 expression in 4T1 cells in sparse, sub-confluent, and confluent conditions. Quantification is reported in the right panels. The results are representative of 3 independent experiments.

Mentions: These data were further supported by in vivo observations. In MMTV-PyVmT carcinomas (Fig. 4A) we found that JAM-A is strongly decreased at the tumor invasive edge as compared to tumor nodules (Fig. 4A, compare a and b). The decrease in JAM-A and ZO-1 could be seen also in sparse/subconfluent cell cultures as compared to confluent cells (Fig. 4D). Consistently, when cells invade the surrounding tissue and junctions are partially dismantled, JAM-A expression is significantly reduced.


Abrogation of junctional adhesion molecule-A expression induces cell apoptosis and reduces breast cancer progression.

Murakami M, Giampietro C, Giannotta M, Corada M, Torselli I, Orsenigo F, Cocito A, d'Ario G, Mazzarol G, Confalonieri S, Di Fiore PP, Dejana E - PLoS ONE (2011)

JAM-A and junctional proteins' expression was decreased at the invading tumor edge in vivo and in vitro.A) MMTV-PyVmT/JAM-A+/+ tumor sections show decreased JAM-A and E-cadherin expression level at the invasive edge as compared to tumor nodules and mammary duct. Scale bar; 100 µm; B) In tissue sections, TUNEL positive tumor cells were concentrated at the invasive edge of the tumor. Scale bar; 100 µm; C) In the wound assay (see Fig. 3) cultured MMTV-PyVmT/JAM-A−/− cells show strong TUNEL staining both at the migrating front and in the distal areas while JAM-A+/+ cells presented TUNEL staining only at the leading edge. Quantification is reported at the right panel, data are means +/− SEM of 3 experiments performed in quadruplicates. **p<0.01 by unpaired Student-t test. Scale bar; 300 µm; D) Western blot analysis of JAM-A and ZO-1 expression in 4T1 cells in sparse, sub-confluent, and confluent conditions. Quantification is reported in the right panels. The results are representative of 3 independent experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3117883&req=5

pone-0021242-g004: JAM-A and junctional proteins' expression was decreased at the invading tumor edge in vivo and in vitro.A) MMTV-PyVmT/JAM-A+/+ tumor sections show decreased JAM-A and E-cadherin expression level at the invasive edge as compared to tumor nodules and mammary duct. Scale bar; 100 µm; B) In tissue sections, TUNEL positive tumor cells were concentrated at the invasive edge of the tumor. Scale bar; 100 µm; C) In the wound assay (see Fig. 3) cultured MMTV-PyVmT/JAM-A−/− cells show strong TUNEL staining both at the migrating front and in the distal areas while JAM-A+/+ cells presented TUNEL staining only at the leading edge. Quantification is reported at the right panel, data are means +/− SEM of 3 experiments performed in quadruplicates. **p<0.01 by unpaired Student-t test. Scale bar; 300 µm; D) Western blot analysis of JAM-A and ZO-1 expression in 4T1 cells in sparse, sub-confluent, and confluent conditions. Quantification is reported in the right panels. The results are representative of 3 independent experiments.
Mentions: These data were further supported by in vivo observations. In MMTV-PyVmT carcinomas (Fig. 4A) we found that JAM-A is strongly decreased at the tumor invasive edge as compared to tumor nodules (Fig. 4A, compare a and b). The decrease in JAM-A and ZO-1 could be seen also in sparse/subconfluent cell cultures as compared to confluent cells (Fig. 4D). Consistently, when cells invade the surrounding tissue and junctions are partially dismantled, JAM-A expression is significantly reduced.

Bottom Line: Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased.We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis.JAM-A may be considered a negative prognostic factor and a potential therapeutic target.

View Article: PubMed Central - PubMed

Affiliation: IFOM, Foundation FIRC Institute of Molecular Oncology, Milan, Italy.

ABSTRACT
Intercellular junctions promote homotypic cell to cell adhesion and transfer intracellular signals which control cell growth and apoptosis. Junctional adhesion molecule-A (JAM-A) is a transmembrane immunoglobulin located at tight junctions of normal epithelial cells of mammary ducts and glands. In the present paper we show that JAM-A acts as a survival factor for mammary carcinoma cells. JAM-A mice expressing Polyoma Middle T under MMTV promoter develop significantly smaller mammary tumors than JAM-A positive mice. Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased. Tumor cells isolated from JAM-A mice or 4T1 cells incubated with JAM-A blocking antibodies showed reduced growth and increased apoptosis which paralleled altered junctional architecture and adhesive function. In a breast cancer clinical data set, tissue microarray data show that JAM-A expression correlates with poor prognosis. Gene expression analysis of mouse tumor samples showed a correlation between genes enriched in human G3 tumors and genes over expressed in JAM-A +/+ mammary tumors. Conversely, genes enriched in G1 human tumors correlate with genes overexpressed in JAM-A-/- tumors. We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis. JAM-A may be considered a negative prognostic factor and a potential therapeutic target.

Show MeSH
Related in: MedlinePlus