MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular Carcinoma
Recent studies report that the polarity gene myelin and lymphocyte protein 2 (MAL2), is overexpressed in multiple human carcinomas largely at the transcript level. Because chromosome 8q24 amplification (where MAL2 resides) is associated with hepatocellular- and cholangio-carcinomas, we examined MAL2...
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| Language: | English |
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MDPI AG
2020-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/2/422 |
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| author | Alfonso López-Coral Gianna-Jade del Vecchio Joeffrey J. Chahine Bhaskar V. Kallakury Pamela L. Tuma |
| author_facet | Alfonso López-Coral Gianna-Jade del Vecchio Joeffrey J. Chahine Bhaskar V. Kallakury Pamela L. Tuma |
| author_sort | Alfonso López-Coral |
| collection | DOAJ |
| description | Recent studies report that the polarity gene myelin and lymphocyte protein 2 (MAL2), is overexpressed in multiple human carcinomas largely at the transcript level. Because chromosome 8q24 amplification (where MAL2 resides) is associated with hepatocellular- and cholangio-carcinomas, we examined MAL2 protein expression in these human carcinoma lesions and adjacent benign tissue using immunohistochemistry. For comparison, we analyzed renal cell carcinomas that are not associated with chromosome 8q24 amplification. Surprisingly, we found that MAL2 protein levels were decreased in the malignant tissues compared to benign in all three carcinomas, suggesting MAL2 expression may be anti-oncogenic. Consistent with this conclusion, we determined that endogenously overexpressed MAL2 in HCC-derived Hep3B cells or exogenously expressed MAL2 in hepatoma-derived Clone 9 cells (that lack endogenous MAL2) promoted actin-based protrusion formation with a reciprocal decrease in invadopodia. MAL2 overexpression also led to decreased cell migration, invasion and proliferation (to a more modest extent) while loss of MAL2 expression reversed the phenotypes. Mutational analysis revealed that a putative Ena/VASP homology 1 recognition site confers the MAL2-phenotype suggesting its role in tumor suppression involves actin remodeling. To reconcile decreased MAL2 protein expression in human carcinomas and its anti-oncogenic phenotypes with increased transcript levels, we propose a transcriptional regulatory model for MAL2 transient overexpression. |
| first_indexed | 2024-03-12T09:22:42Z |
| format | Article |
| id | doaj.art-ea40302a3ad6437aaa8a314a24b0eb7d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T09:22:42Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ea40302a3ad6437aaa8a314a24b0eb7d2023-09-02T14:26:20ZengMDPI AGCancers2072-66942020-02-0112242210.3390/cancers12020422cancers12020422MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular CarcinomaAlfonso López-Coral0Gianna-Jade del Vecchio1Joeffrey J. Chahine2Bhaskar V. Kallakury3Pamela L. Tuma4Department of Biology, The Catholic University of America, Washington, DC 20064, USADepartment of Biology, The Catholic University of America, Washington, DC 20064, USADepartment of Biology, The Catholic University of America, Washington, DC 20064, USADepartment of Pathology, MedStar Georgetown University Hospital, Washington, DC 20007, USADepartment of Biology, The Catholic University of America, Washington, DC 20064, USARecent studies report that the polarity gene myelin and lymphocyte protein 2 (MAL2), is overexpressed in multiple human carcinomas largely at the transcript level. Because chromosome 8q24 amplification (where MAL2 resides) is associated with hepatocellular- and cholangio-carcinomas, we examined MAL2 protein expression in these human carcinoma lesions and adjacent benign tissue using immunohistochemistry. For comparison, we analyzed renal cell carcinomas that are not associated with chromosome 8q24 amplification. Surprisingly, we found that MAL2 protein levels were decreased in the malignant tissues compared to benign in all three carcinomas, suggesting MAL2 expression may be anti-oncogenic. Consistent with this conclusion, we determined that endogenously overexpressed MAL2 in HCC-derived Hep3B cells or exogenously expressed MAL2 in hepatoma-derived Clone 9 cells (that lack endogenous MAL2) promoted actin-based protrusion formation with a reciprocal decrease in invadopodia. MAL2 overexpression also led to decreased cell migration, invasion and proliferation (to a more modest extent) while loss of MAL2 expression reversed the phenotypes. Mutational analysis revealed that a putative Ena/VASP homology 1 recognition site confers the MAL2-phenotype suggesting its role in tumor suppression involves actin remodeling. To reconcile decreased MAL2 protein expression in human carcinomas and its anti-oncogenic phenotypes with increased transcript levels, we propose a transcriptional regulatory model for MAL2 transient overexpression.https://www.mdpi.com/2072-6694/12/2/422hepatocellular carcinomacholangiocarcinomatumor suppressormal2actin |
| spellingShingle | Alfonso López-Coral Gianna-Jade del Vecchio Joeffrey J. Chahine Bhaskar V. Kallakury Pamela L. Tuma MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular Carcinoma Cancers hepatocellular carcinoma cholangiocarcinoma tumor suppressor mal2 actin |
| title | MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular Carcinoma |
| title_full | MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular Carcinoma |
| title_fullStr | MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular Carcinoma |
| title_full_unstemmed | MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular Carcinoma |
| title_short | MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular Carcinoma |
| title_sort | mal2 induced actin based protrusion formation is anti oncogenic in hepatocellular carcinoma |
| topic | hepatocellular carcinoma cholangiocarcinoma tumor suppressor mal2 actin |
| url | https://www.mdpi.com/2072-6694/12/2/422 |
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