Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression
Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis ha...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/1/252 |
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| author | James Drury Piotr G. Rychahou Courtney O. Kelson Mariah E. Geisen Yuanyuan Wu Daheng He Chi Wang Eun Y. Lee B. Mark Evers Yekaterina Y. Zaytseva |
| author_facet | James Drury Piotr G. Rychahou Courtney O. Kelson Mariah E. Geisen Yuanyuan Wu Daheng He Chi Wang Eun Y. Lee B. Mark Evers Yekaterina Y. Zaytseva |
| author_sort | James Drury |
| collection | DOAJ |
| description | Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation of MMP28, a novel member of the metallopeptidase family of proteins. Using shRNA-mediated knockdown and overexpression of CD36, we confirmed that CD36 regulates MMP28 expression in CRC cells. siRNA-mediated knockdown of MMP28 decreases invasion of CRC cells, suggesting that MMP28 regulates the metastatic properties of cells downstream of CD36. Importantly, high expression of MMP28 leads to a significant decrease in active E-cadherin and an increase in the products of E-cadherin cleavage, CTF1 and CTF2. In summary, upregulation of CD36 expression promotes the metastatic properties of CRC via upregulation of MMP28 and an increase in E-cadherin cleavage, suggesting that targeting the CD36–MMP28 axis may be an effective therapeutic strategy for CRC metastasis. |
| first_indexed | 2024-03-10T03:46:55Z |
| format | Article |
| id | doaj.art-fadd2aa59bde4aa38f45670b9ec034ff |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T03:46:55Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fadd2aa59bde4aa38f45670b9ec034ff2023-11-23T11:18:30ZengMDPI AGCancers2072-66942022-01-0114125210.3390/cancers14010252Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin ExpressionJames Drury0Piotr G. Rychahou1Courtney O. Kelson2Mariah E. Geisen3Yuanyuan Wu4Daheng He5Chi Wang6Eun Y. Lee7B. Mark Evers8Yekaterina Y. Zaytseva9Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USADepartment of Surgery and Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USADepartment of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USADepartment of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USABiostatistics and Bioinformatics Shared Resource Facility, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USABiostatistics and Bioinformatics Shared Resource Facility, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USABiostatistics and Bioinformatics Shared Resource Facility, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USADepartment of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536, USADepartment of Surgery and Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USADepartment of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USAAltered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation of MMP28, a novel member of the metallopeptidase family of proteins. Using shRNA-mediated knockdown and overexpression of CD36, we confirmed that CD36 regulates MMP28 expression in CRC cells. siRNA-mediated knockdown of MMP28 decreases invasion of CRC cells, suggesting that MMP28 regulates the metastatic properties of cells downstream of CD36. Importantly, high expression of MMP28 leads to a significant decrease in active E-cadherin and an increase in the products of E-cadherin cleavage, CTF1 and CTF2. In summary, upregulation of CD36 expression promotes the metastatic properties of CRC via upregulation of MMP28 and an increase in E-cadherin cleavage, suggesting that targeting the CD36–MMP28 axis may be an effective therapeutic strategy for CRC metastasis.https://www.mdpi.com/2072-6694/14/1/252colorectal cancermetastasisfatty-acid metabolismCD36MMP28E-cadherin |
| spellingShingle | James Drury Piotr G. Rychahou Courtney O. Kelson Mariah E. Geisen Yuanyuan Wu Daheng He Chi Wang Eun Y. Lee B. Mark Evers Yekaterina Y. Zaytseva Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression Cancers colorectal cancer metastasis fatty-acid metabolism CD36 MMP28 E-cadherin |
| title | Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression |
| title_full | Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression |
| title_fullStr | Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression |
| title_full_unstemmed | Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression |
| title_short | Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression |
| title_sort | upregulation of cd36 a fatty acid translocase promotes colorectal cancer metastasis by increasing mmp28 and decreasing e cadherin expression |
| topic | colorectal cancer metastasis fatty-acid metabolism CD36 MMP28 E-cadherin |
| url | https://www.mdpi.com/2072-6694/14/1/252 |
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