Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels
Abstract Background Grb2-associated binder 2 (Gab2) is a scaffolding protein that serves as a critical signaling amplifier downstream of tyrosine kinase receptors. Our previous study has shown that Gab2 induces epithelial-to-mesenchymal transition (EMT) and promotes metastasis in colorectal cancer (...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-017-0524-2 |
| _version_ | 1828401121905868800 |
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| author | Chenbo Ding Junmin Luo Xiaobo Fan Longmei Li Shanshan Li Kunming Wen Jihong Feng Guoqiu Wu |
| author_facet | Chenbo Ding Junmin Luo Xiaobo Fan Longmei Li Shanshan Li Kunming Wen Jihong Feng Guoqiu Wu |
| author_sort | Chenbo Ding |
| collection | DOAJ |
| description | Abstract Background Grb2-associated binder 2 (Gab2) is a scaffolding protein that serves as a critical signaling amplifier downstream of tyrosine kinase receptors. Our previous study has shown that Gab2 induces epithelial-to-mesenchymal transition (EMT) and promotes metastasis in colorectal cancer (CRC). However, the role of Gab2 in CRC growth and angiogenesis remains unclear. Methods The expression of vascular endothelial growth factor (VEGF) in different colorectal tissues was detected by immunohistochemistry and qRT-PCR to evaluate its correlation with Gab2. Lentiviral vectors bearing Gab2 gene and its small interfering RNAs were constructed and transfected into CRC cell lines. The effects of Gab2 on the cell proliferation in vitro and tumorigenesis in vivo, were examined via CCK‑8 assay, colony formation assay as well as tumorigenicity assay respectively. Moreover, to assess its potential role in tumor growth and angiogenesis, the expression of Ki67, CD34 and vascular endothelial growth factor receptor-2 (VEGFR2) were detected by immunohistochemistry in CRC cells tumors. Finally, we evaluated the impact of Gab2 on the expression of c-Myc and VEGF, and the probable effect of mechanistic targeted extracellular signal-regulated kinase (ERK) pathway in suppressing tumor growth and angiogenesis. Results Up-regulation of Gab2 expression was found to be positively correlated with VEGF in CRC tissues. Exogenous expression of Gab2 obviously promoted, whereas silencing of Gab2 inhibited, proliferation and clone formation of human CRC cells in vitro. Of note, Gab2 enhanced tumorigenesis and tumor growth in mouse xenografts with high Ki67 expression, and led to an increased vessel density with strong CD34 and VEGFR2 activity. In addition, elevated Gab2 expression obviously up-regulated the expression of VEGF, and stimulated the activation of its downstream genes, ERK1/2 and c-Myc in CRC cells. Instead, down-regulated Gab2 expression significantly reduced the levels of VEGF, and inhibited the transduction of ERK/c-Myc pathway. Finally, we revealed that mechanistic target of mitogen-activated protein kinase (MEK) could attenuate Gab2-induced tumor growth and angiogenesis via altering VEGF and c-Myc levels. Conclusions The results from our study suggest that Gab2 promotes intestinal tumor growth and angiogenesis through upregulation of VEGF expression mediated by the MEK/ERK/c-Myc pathway. |
| first_indexed | 2024-12-10T09:41:46Z |
| format | Article |
| id | doaj.art-e941e1934561469c8c90c4653edf0677 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-10T09:41:46Z |
| publishDate | 2017-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-e941e1934561469c8c90c4653edf06772022-12-22T01:53:58ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662017-04-0136111110.1186/s13046-017-0524-2Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levelsChenbo Ding0Junmin Luo1Xiaobo Fan2Longmei Li3Shanshan Li4Kunming Wen5Jihong Feng6Guoqiu Wu7Medical School of Southeast UniversityDepartment of Immunology, Zunyi Medical CollegeMedical School of Southeast UniversityDepartment of Immunology, Zunyi Medical CollegeDepartment of Immunology, Zunyi Medical CollegeDepartment of Gastrointestinal Surgery, the Affiliated Hospital of Zunyi Medical CollegeDepartment of Oncology, the Affiliated Hospital of Zunyi Medical CollegeMedical School of Southeast UniversityAbstract Background Grb2-associated binder 2 (Gab2) is a scaffolding protein that serves as a critical signaling amplifier downstream of tyrosine kinase receptors. Our previous study has shown that Gab2 induces epithelial-to-mesenchymal transition (EMT) and promotes metastasis in colorectal cancer (CRC). However, the role of Gab2 in CRC growth and angiogenesis remains unclear. Methods The expression of vascular endothelial growth factor (VEGF) in different colorectal tissues was detected by immunohistochemistry and qRT-PCR to evaluate its correlation with Gab2. Lentiviral vectors bearing Gab2 gene and its small interfering RNAs were constructed and transfected into CRC cell lines. The effects of Gab2 on the cell proliferation in vitro and tumorigenesis in vivo, were examined via CCK‑8 assay, colony formation assay as well as tumorigenicity assay respectively. Moreover, to assess its potential role in tumor growth and angiogenesis, the expression of Ki67, CD34 and vascular endothelial growth factor receptor-2 (VEGFR2) were detected by immunohistochemistry in CRC cells tumors. Finally, we evaluated the impact of Gab2 on the expression of c-Myc and VEGF, and the probable effect of mechanistic targeted extracellular signal-regulated kinase (ERK) pathway in suppressing tumor growth and angiogenesis. Results Up-regulation of Gab2 expression was found to be positively correlated with VEGF in CRC tissues. Exogenous expression of Gab2 obviously promoted, whereas silencing of Gab2 inhibited, proliferation and clone formation of human CRC cells in vitro. Of note, Gab2 enhanced tumorigenesis and tumor growth in mouse xenografts with high Ki67 expression, and led to an increased vessel density with strong CD34 and VEGFR2 activity. In addition, elevated Gab2 expression obviously up-regulated the expression of VEGF, and stimulated the activation of its downstream genes, ERK1/2 and c-Myc in CRC cells. Instead, down-regulated Gab2 expression significantly reduced the levels of VEGF, and inhibited the transduction of ERK/c-Myc pathway. Finally, we revealed that mechanistic target of mitogen-activated protein kinase (MEK) could attenuate Gab2-induced tumor growth and angiogenesis via altering VEGF and c-Myc levels. Conclusions The results from our study suggest that Gab2 promotes intestinal tumor growth and angiogenesis through upregulation of VEGF expression mediated by the MEK/ERK/c-Myc pathway.http://link.springer.com/article/10.1186/s13046-017-0524-2Gab2Colorectal cancerAngiogenesisVEGF |
| spellingShingle | Chenbo Ding Junmin Luo Xiaobo Fan Longmei Li Shanshan Li Kunming Wen Jihong Feng Guoqiu Wu Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels Journal of Experimental & Clinical Cancer Research Gab2 Colorectal cancer Angiogenesis VEGF |
| title | Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels |
| title_full | Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels |
| title_fullStr | Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels |
| title_full_unstemmed | Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels |
| title_short | Elevated Gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating VEGF levels |
| title_sort | elevated gab2 induces tumor growth and angiogenesis in colorectal cancer through upregulating vegf levels |
| topic | Gab2 Colorectal cancer Angiogenesis VEGF |
| url | http://link.springer.com/article/10.1186/s13046-017-0524-2 |
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