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Association between Gαi2 and ELMO1/Dock180 connects chemokine signalling with Rac activation and metastasis.

Li H, Yang L, Fu H, Yan J, Wang Y, Guo H, Hao X, Xu X, Jin T, Zhang N - Nat Commun (2013)

Bottom Line: Binding of CXCL12 to CXCR4 triggers activation of heterotrimeric Gi proteins that regulate actin polymerization and migration.CXCL12 triggers a Gαi2-dependent membrane translocation of ELMO1, which associates with Dock180 to activate small G-proteins Rac1 and Rac2.In vivo, ELMO1 expression is associated with lymph node and distant metastasis, and knocking down ELMO1 impairs metastasis to the lung.

View Article: PubMed Central - PubMed

Affiliation: Tianjin Medical University Cancer Institute and Hospital and Research Center of Basic Medical Sciences, He Xi District, Tianjin 300060, China.

ABSTRACT
The chemokine CXCL12 and its G-protein-coupled receptor CXCR4 control the migration, invasiveness and metastasis of breast cancer cells. Binding of CXCL12 to CXCR4 triggers activation of heterotrimeric Gi proteins that regulate actin polymerization and migration. However, the pathways linking chemokine G-protein-coupled receptor/Gi signalling to actin polymerization and cancer cell migration are not known. Here we show that CXCL12 stimulation promotes interaction between Gαi2 and ELMO1. Gi signalling and ELMO1 are both required for CXCL12-mediated actin polymerization, migration and invasion of breast cancer cells. CXCL12 triggers a Gαi2-dependent membrane translocation of ELMO1, which associates with Dock180 to activate small G-proteins Rac1 and Rac2. In vivo, ELMO1 expression is associated with lymph node and distant metastasis, and knocking down ELMO1 impairs metastasis to the lung. Our findings indicate that a chemokine-controlled pathway, consisting of Gαi2, ELMO1/Dock180, Rac1 and Rac2, regulates the actin cytoskeleton during breast cancer metastasis.

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ELMO1 has a role in breast cancer metastasis in vivo.(a) Immunohistochemical analysis of ELMO1 expression in invasive ductal breast carcinoma tissues and normal breast tissues. The entire sample (81 invasive ductal breast carcinoma tissues and 7 normal breast tissues) was blocked for 1 h. The antibodies and the dilution factors were as follows: ELMO1 (1:100), Polink-2 plus Polymer HRP Detection System for Goat Primary Antibody. (b) Immunohistochemical analysis of ELMO2 expression in invasive ductal carcinoma tissues and normal breast tissues. The entire sample (81 invasive ductal breast carcinoma tissues and 7 normal breast tissues) was blocked for 1 h. The antibodies and the dilution factors were as follows: ELMO2 (1:50), Polink-2 plus Polymer HRP Detection System for Goat Primary Antibody. (c) Western blotting analysis for four stable siELMO1 clones and comparison of tumour size in SCID mice. (d) Comparison of spontaneous lung metastasis and images of representative lung metastasis. (e) Human tumour foci on mouse lungs were visualized by haematoxylin and eosin staining. (f) The number of lung metastases was counted and plotted (n=10). (g) A model for ELMO1 regulated the migration and chemotaxis of breast cancer cells by associating with Dock180, Gαi2, Rac1 and Rac2.
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f5: ELMO1 has a role in breast cancer metastasis in vivo.(a) Immunohistochemical analysis of ELMO1 expression in invasive ductal breast carcinoma tissues and normal breast tissues. The entire sample (81 invasive ductal breast carcinoma tissues and 7 normal breast tissues) was blocked for 1 h. The antibodies and the dilution factors were as follows: ELMO1 (1:100), Polink-2 plus Polymer HRP Detection System for Goat Primary Antibody. (b) Immunohistochemical analysis of ELMO2 expression in invasive ductal carcinoma tissues and normal breast tissues. The entire sample (81 invasive ductal breast carcinoma tissues and 7 normal breast tissues) was blocked for 1 h. The antibodies and the dilution factors were as follows: ELMO2 (1:50), Polink-2 plus Polymer HRP Detection System for Goat Primary Antibody. (c) Western blotting analysis for four stable siELMO1 clones and comparison of tumour size in SCID mice. (d) Comparison of spontaneous lung metastasis and images of representative lung metastasis. (e) Human tumour foci on mouse lungs were visualized by haematoxylin and eosin staining. (f) The number of lung metastases was counted and plotted (n=10). (g) A model for ELMO1 regulated the migration and chemotaxis of breast cancer cells by associating with Dock180, Gαi2, Rac1 and Rac2.

Mentions: To evaluate any potential contribution of ELMO proteins to the metastasis of breast cancer in vivo, we first examined the expression of ELMO1 and ELMO2 in tissue specimens from 81 patients with human invasive ductal carcinoma, which accounts for the majority of breast cancer cases, and 7 healthy controls using an immunohistochemical analysis. Positive ELMO1 staining was detected in 57 patient samples but only in 1 healthy control (Fig. 5a, Table 2 and Supplementary Fig. S7A). The expression of ELMO2 was also found to be higher in tumour tissues than in the normal breast tissues from healthy individuals (Fig. 5b, Table 2 and Supplementary Fig. S7B), suggesting that expression of ELMO1 and/or ELMO2 was elevated during tumorigenesis of breast cancer. Furthermore, analyses of lymph nodes from breast cancer patients revealed that 45 out of 51 lymph nodes with metastases stained positive for ELMO1, whereas only 12 out of 30 lymph nodes without metastases stained positive (P=0.0001, χ2-statistics, Table 3). Moreover, ELMO1 expression was detected in 23 out of 26 distant metastasis cases (lung and liver with cancer cells), and in 34 out of 55 non-distance metastasis cases (lung and liver with no detectable cancer cells; Table 3). These results suggested that expressions of ELMO1 and/or ELMO2 were closely correlated with metastasis of breast cancers, either as a cause or as a consequence.


Association between Gαi2 and ELMO1/Dock180 connects chemokine signalling with Rac activation and metastasis.

Li H, Yang L, Fu H, Yan J, Wang Y, Guo H, Hao X, Xu X, Jin T, Zhang N - Nat Commun (2013)

ELMO1 has a role in breast cancer metastasis in vivo.(a) Immunohistochemical analysis of ELMO1 expression in invasive ductal breast carcinoma tissues and normal breast tissues. The entire sample (81 invasive ductal breast carcinoma tissues and 7 normal breast tissues) was blocked for 1 h. The antibodies and the dilution factors were as follows: ELMO1 (1:100), Polink-2 plus Polymer HRP Detection System for Goat Primary Antibody. (b) Immunohistochemical analysis of ELMO2 expression in invasive ductal carcinoma tissues and normal breast tissues. The entire sample (81 invasive ductal breast carcinoma tissues and 7 normal breast tissues) was blocked for 1 h. The antibodies and the dilution factors were as follows: ELMO2 (1:50), Polink-2 plus Polymer HRP Detection System for Goat Primary Antibody. (c) Western blotting analysis for four stable siELMO1 clones and comparison of tumour size in SCID mice. (d) Comparison of spontaneous lung metastasis and images of representative lung metastasis. (e) Human tumour foci on mouse lungs were visualized by haematoxylin and eosin staining. (f) The number of lung metastases was counted and plotted (n=10). (g) A model for ELMO1 regulated the migration and chemotaxis of breast cancer cells by associating with Dock180, Gαi2, Rac1 and Rac2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f5: ELMO1 has a role in breast cancer metastasis in vivo.(a) Immunohistochemical analysis of ELMO1 expression in invasive ductal breast carcinoma tissues and normal breast tissues. The entire sample (81 invasive ductal breast carcinoma tissues and 7 normal breast tissues) was blocked for 1 h. The antibodies and the dilution factors were as follows: ELMO1 (1:100), Polink-2 plus Polymer HRP Detection System for Goat Primary Antibody. (b) Immunohistochemical analysis of ELMO2 expression in invasive ductal carcinoma tissues and normal breast tissues. The entire sample (81 invasive ductal breast carcinoma tissues and 7 normal breast tissues) was blocked for 1 h. The antibodies and the dilution factors were as follows: ELMO2 (1:50), Polink-2 plus Polymer HRP Detection System for Goat Primary Antibody. (c) Western blotting analysis for four stable siELMO1 clones and comparison of tumour size in SCID mice. (d) Comparison of spontaneous lung metastasis and images of representative lung metastasis. (e) Human tumour foci on mouse lungs were visualized by haematoxylin and eosin staining. (f) The number of lung metastases was counted and plotted (n=10). (g) A model for ELMO1 regulated the migration and chemotaxis of breast cancer cells by associating with Dock180, Gαi2, Rac1 and Rac2.
Mentions: To evaluate any potential contribution of ELMO proteins to the metastasis of breast cancer in vivo, we first examined the expression of ELMO1 and ELMO2 in tissue specimens from 81 patients with human invasive ductal carcinoma, which accounts for the majority of breast cancer cases, and 7 healthy controls using an immunohistochemical analysis. Positive ELMO1 staining was detected in 57 patient samples but only in 1 healthy control (Fig. 5a, Table 2 and Supplementary Fig. S7A). The expression of ELMO2 was also found to be higher in tumour tissues than in the normal breast tissues from healthy individuals (Fig. 5b, Table 2 and Supplementary Fig. S7B), suggesting that expression of ELMO1 and/or ELMO2 was elevated during tumorigenesis of breast cancer. Furthermore, analyses of lymph nodes from breast cancer patients revealed that 45 out of 51 lymph nodes with metastases stained positive for ELMO1, whereas only 12 out of 30 lymph nodes without metastases stained positive (P=0.0001, χ2-statistics, Table 3). Moreover, ELMO1 expression was detected in 23 out of 26 distant metastasis cases (lung and liver with cancer cells), and in 34 out of 55 non-distance metastasis cases (lung and liver with no detectable cancer cells; Table 3). These results suggested that expressions of ELMO1 and/or ELMO2 were closely correlated with metastasis of breast cancers, either as a cause or as a consequence.

Bottom Line: Binding of CXCL12 to CXCR4 triggers activation of heterotrimeric Gi proteins that regulate actin polymerization and migration.CXCL12 triggers a Gαi2-dependent membrane translocation of ELMO1, which associates with Dock180 to activate small G-proteins Rac1 and Rac2.In vivo, ELMO1 expression is associated with lymph node and distant metastasis, and knocking down ELMO1 impairs metastasis to the lung.

View Article: PubMed Central - PubMed

Affiliation: Tianjin Medical University Cancer Institute and Hospital and Research Center of Basic Medical Sciences, He Xi District, Tianjin 300060, China.

ABSTRACT
The chemokine CXCL12 and its G-protein-coupled receptor CXCR4 control the migration, invasiveness and metastasis of breast cancer cells. Binding of CXCL12 to CXCR4 triggers activation of heterotrimeric Gi proteins that regulate actin polymerization and migration. However, the pathways linking chemokine G-protein-coupled receptor/Gi signalling to actin polymerization and cancer cell migration are not known. Here we show that CXCL12 stimulation promotes interaction between Gαi2 and ELMO1. Gi signalling and ELMO1 are both required for CXCL12-mediated actin polymerization, migration and invasion of breast cancer cells. CXCL12 triggers a Gαi2-dependent membrane translocation of ELMO1, which associates with Dock180 to activate small G-proteins Rac1 and Rac2. In vivo, ELMO1 expression is associated with lymph node and distant metastasis, and knocking down ELMO1 impairs metastasis to the lung. Our findings indicate that a chemokine-controlled pathway, consisting of Gαi2, ELMO1/Dock180, Rac1 and Rac2, regulates the actin cytoskeleton during breast cancer metastasis.

Show MeSH
Related in: MedlinePlus