Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis
Abstract Background Epithelial cell adhesion molecule (EpCAM) is known to highly expression and promotes cancer progression in many cancer types, including colorectal cancer. While metastasis is one of the main causes of cancer treatment failure, the involvement of EpCAM signaling in metastatic proc...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-08-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-04390-2 |
| _version_ | 1797355577119080448 |
|---|---|
| author | Chi-Chiu Lee Chia-Jui Yu Sushree Shankar Panda Kai-Chi Chen Kang-Hao Liang Wan-Chen Huang Yu-Shiuan Wang Pei-Chin Ho Han-Chung Wu |
| author_facet | Chi-Chiu Lee Chia-Jui Yu Sushree Shankar Panda Kai-Chi Chen Kang-Hao Liang Wan-Chen Huang Yu-Shiuan Wang Pei-Chin Ho Han-Chung Wu |
| author_sort | Chi-Chiu Lee |
| collection | DOAJ |
| description | Abstract Background Epithelial cell adhesion molecule (EpCAM) is known to highly expression and promotes cancer progression in many cancer types, including colorectal cancer. While metastasis is one of the main causes of cancer treatment failure, the involvement of EpCAM signaling in metastatic processes is unclear. We propose the potential crosstalk of EpCAM signaling with the HGFR signaling in order to govern metastatic activity in colorectal cancer. Methods Immunoprecipitation (IP), enzyme-linked immunosorbent assay (ELISA), and fluorescence resonance energy transfer (FRET) was conducted to explore the extracellular domain of EpCAM (EpEX) and HGFR interaction. Western blotting was taken to determine the expression of proteins in colorectal cancer (CRC) cell lines. The functions of EpEX in CRC were investigated by proliferation, migration, and invasion analysis. The combined therapy was validated via a tail vein injection method for the metastasis and orthotopic colon cancer models. Results This study demonstrates that the EpEX binds to HGFR and induces downstream signaling in colon cancer cells. Moreover, EpEX and HGF cooperatively mediate HGFR signaling. Furthermore, EpEX enhances the epithelial-to-mesenchymal transition and metastatic potential of colon cancer cells by activating ERK and FAK-AKT signaling pathways, and it further stabilizes active β-catenin and Snail proteins by decreasing GSK3β activity. Finally, we show that the combined treatment of an anti-EpCAM neutralizing antibody (EpAb2-6) and an HGFR inhibitor (crizotinib) significantly inhibits tumor progression and prolongs survival in metastatic and orthotopic animal models of colon cancer. Conclusion Our findings illuminate the molecular mechanisms underlying EpCAM signaling promotion of colon cancer metastasis, further suggesting that the combination of EpAb2-6 and crizotinib may be an effective strategy for treating cancer patients with high EpCAM expression. |
| first_indexed | 2024-03-08T14:13:09Z |
| format | Article |
| id | doaj.art-6494a8b5d11346ee9f7c2cd26962d028 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-03-08T14:13:09Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-6494a8b5d11346ee9f7c2cd26962d0282024-01-14T12:34:26ZengBMCJournal of Translational Medicine1479-58762023-08-0121112210.1186/s12967-023-04390-2Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasisChi-Chiu Lee0Chia-Jui Yu1Sushree Shankar Panda2Kai-Chi Chen3Kang-Hao Liang4Wan-Chen Huang5Yu-Shiuan Wang6Pei-Chin Ho7Han-Chung Wu8Institute of Cellular and Organismic Biology, Academia SinicaInstitute of Cellular and Organismic Biology, Academia SinicaInstitute of Cellular and Organismic Biology, Academia SinicaInstitute of Cellular and Organismic Biology, Academia SinicaInstitute of Cellular and Organismic Biology, Academia SinicaInstitute of Cellular and Organismic Biology, Academia SinicaInstitute of Cellular and Organismic Biology, Academia SinicaBiomedical Translation Research Center (BioTReC), Academia SinicaInstitute of Cellular and Organismic Biology, Academia SinicaAbstract Background Epithelial cell adhesion molecule (EpCAM) is known to highly expression and promotes cancer progression in many cancer types, including colorectal cancer. While metastasis is one of the main causes of cancer treatment failure, the involvement of EpCAM signaling in metastatic processes is unclear. We propose the potential crosstalk of EpCAM signaling with the HGFR signaling in order to govern metastatic activity in colorectal cancer. Methods Immunoprecipitation (IP), enzyme-linked immunosorbent assay (ELISA), and fluorescence resonance energy transfer (FRET) was conducted to explore the extracellular domain of EpCAM (EpEX) and HGFR interaction. Western blotting was taken to determine the expression of proteins in colorectal cancer (CRC) cell lines. The functions of EpEX in CRC were investigated by proliferation, migration, and invasion analysis. The combined therapy was validated via a tail vein injection method for the metastasis and orthotopic colon cancer models. Results This study demonstrates that the EpEX binds to HGFR and induces downstream signaling in colon cancer cells. Moreover, EpEX and HGF cooperatively mediate HGFR signaling. Furthermore, EpEX enhances the epithelial-to-mesenchymal transition and metastatic potential of colon cancer cells by activating ERK and FAK-AKT signaling pathways, and it further stabilizes active β-catenin and Snail proteins by decreasing GSK3β activity. Finally, we show that the combined treatment of an anti-EpCAM neutralizing antibody (EpAb2-6) and an HGFR inhibitor (crizotinib) significantly inhibits tumor progression and prolongs survival in metastatic and orthotopic animal models of colon cancer. Conclusion Our findings illuminate the molecular mechanisms underlying EpCAM signaling promotion of colon cancer metastasis, further suggesting that the combination of EpAb2-6 and crizotinib may be an effective strategy for treating cancer patients with high EpCAM expression.https://doi.org/10.1186/s12967-023-04390-2EpCAMEpEXHGFRCancer progressionEpithelial-to-mesenchymal transitionInvasion |
| spellingShingle | Chi-Chiu Lee Chia-Jui Yu Sushree Shankar Panda Kai-Chi Chen Kang-Hao Liang Wan-Chen Huang Yu-Shiuan Wang Pei-Chin Ho Han-Chung Wu Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis Journal of Translational Medicine EpCAM EpEX HGFR Cancer progression Epithelial-to-mesenchymal transition Invasion |
| title | Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis |
| title_full | Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis |
| title_fullStr | Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis |
| title_full_unstemmed | Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis |
| title_short | Epithelial cell adhesion molecule (EpCAM) regulates HGFR signaling to promote colon cancer progression and metastasis |
| title_sort | epithelial cell adhesion molecule epcam regulates hgfr signaling to promote colon cancer progression and metastasis |
| topic | EpCAM EpEX HGFR Cancer progression Epithelial-to-mesenchymal transition Invasion |
| url | https://doi.org/10.1186/s12967-023-04390-2 |
| work_keys_str_mv | AT chichiulee epithelialcelladhesionmoleculeepcamregulateshgfrsignalingtopromotecoloncancerprogressionandmetastasis AT chiajuiyu epithelialcelladhesionmoleculeepcamregulateshgfrsignalingtopromotecoloncancerprogressionandmetastasis AT sushreeshankarpanda epithelialcelladhesionmoleculeepcamregulateshgfrsignalingtopromotecoloncancerprogressionandmetastasis AT kaichichen epithelialcelladhesionmoleculeepcamregulateshgfrsignalingtopromotecoloncancerprogressionandmetastasis AT kanghaoliang epithelialcelladhesionmoleculeepcamregulateshgfrsignalingtopromotecoloncancerprogressionandmetastasis AT wanchenhuang epithelialcelladhesionmoleculeepcamregulateshgfrsignalingtopromotecoloncancerprogressionandmetastasis AT yushiuanwang epithelialcelladhesionmoleculeepcamregulateshgfrsignalingtopromotecoloncancerprogressionandmetastasis AT peichinho epithelialcelladhesionmoleculeepcamregulateshgfrsignalingtopromotecoloncancerprogressionandmetastasis AT hanchungwu epithelialcelladhesionmoleculeepcamregulateshgfrsignalingtopromotecoloncancerprogressionandmetastasis |