Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in Cancer
The RNA interference (RNAi) machinery is an essential component of the cell, regulating miRNA biogenesis and function. RNAi complexes were thought to localize either in the nucleus, such as the microprocessor, or in the cytoplasm, such as the RNA-induced silencing complex (RISC). We recently reveale...
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MDPI AG
2020-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/7/2559 |
| _version_ | 1797571273894658048 |
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| author | Joyce Nair-Menon Amanda C. Daulagala Dean M. Connor Lauren Rutledge Trevor Penix Mary Catherine Bridges Bridgette Wellslager Demetri D. Spyropoulos Cynthia D. Timmers Ann-Marie Broome Antonis Kourtidis |
| author_facet | Joyce Nair-Menon Amanda C. Daulagala Dean M. Connor Lauren Rutledge Trevor Penix Mary Catherine Bridges Bridgette Wellslager Demetri D. Spyropoulos Cynthia D. Timmers Ann-Marie Broome Antonis Kourtidis |
| author_sort | Joyce Nair-Menon |
| collection | DOAJ |
| description | The RNA interference (RNAi) machinery is an essential component of the cell, regulating miRNA biogenesis and function. RNAi complexes were thought to localize either in the nucleus, such as the microprocessor, or in the cytoplasm, such as the RNA-induced silencing complex (RISC). We recently revealed that the core microprocessor components DROSHA and DGCR8, as well as the main components of RISC, including Ago2, also associate with the apical adherens junctions of well-differentiated cultured epithelial cells. Here, we demonstrate that the localization of the core RNAi components is specific and predominant at apical areas of cell-cell contact of human normal colon epithelial tissues and normal primary colon epithelial cells. Importantly, the apical junctional localization of RNAi proteins is disrupted or lost in human colon tumors and in poorly differentiated colon cancer cell lines, correlating with the dysregulation of the adherens junction component PLEKHA7. We show that the restoration of PLEKHA7 expression at adherens junctions of aggressively tumorigenic colon cancer cells restores the junctional localization of RNAi components and suppresses cancer cell growth in vitro and in vivo. In summary, this work identifies the apical junctional localization of the RNAi machinery as a key feature of the differentiated colonic epithelium, with a putative tumor suppressing function. |
| first_indexed | 2024-03-10T20:37:59Z |
| format | Article |
| id | doaj.art-9c52641694754e7d8966314c81655611 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T20:37:59Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9c52641694754e7d8966314c816556112023-11-19T20:55:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-04-01217255910.3390/ijms21072559Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in CancerJoyce Nair-Menon0Amanda C. Daulagala1Dean M. Connor2Lauren Rutledge3Trevor Penix4Mary Catherine Bridges5Bridgette Wellslager6Demetri D. Spyropoulos7Cynthia D. Timmers8Ann-Marie Broome9Antonis Kourtidis10Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADepartment of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADepartment of Pathology and Laboratory Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADepartment of Medicine, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425, USADepartment of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USADepartment of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USAThe RNA interference (RNAi) machinery is an essential component of the cell, regulating miRNA biogenesis and function. RNAi complexes were thought to localize either in the nucleus, such as the microprocessor, or in the cytoplasm, such as the RNA-induced silencing complex (RISC). We recently revealed that the core microprocessor components DROSHA and DGCR8, as well as the main components of RISC, including Ago2, also associate with the apical adherens junctions of well-differentiated cultured epithelial cells. Here, we demonstrate that the localization of the core RNAi components is specific and predominant at apical areas of cell-cell contact of human normal colon epithelial tissues and normal primary colon epithelial cells. Importantly, the apical junctional localization of RNAi proteins is disrupted or lost in human colon tumors and in poorly differentiated colon cancer cell lines, correlating with the dysregulation of the adherens junction component PLEKHA7. We show that the restoration of PLEKHA7 expression at adherens junctions of aggressively tumorigenic colon cancer cells restores the junctional localization of RNAi components and suppresses cancer cell growth in vitro and in vivo. In summary, this work identifies the apical junctional localization of the RNAi machinery as a key feature of the differentiated colonic epithelium, with a putative tumor suppressing function.https://www.mdpi.com/1422-0067/21/7/2559E-cadherinp120 cateninPLEKHA7DROSHADGCR8Ago2 |
| spellingShingle | Joyce Nair-Menon Amanda C. Daulagala Dean M. Connor Lauren Rutledge Trevor Penix Mary Catherine Bridges Bridgette Wellslager Demetri D. Spyropoulos Cynthia D. Timmers Ann-Marie Broome Antonis Kourtidis Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in Cancer International Journal of Molecular Sciences E-cadherin p120 catenin PLEKHA7 DROSHA DGCR8 Ago2 |
| title | Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in Cancer |
| title_full | Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in Cancer |
| title_fullStr | Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in Cancer |
| title_full_unstemmed | Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in Cancer |
| title_short | Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in Cancer |
| title_sort | predominant distribution of the rnai machinery at apical adherens junctions in colonic epithelia is disrupted in cancer |
| topic | E-cadherin p120 catenin PLEKHA7 DROSHA DGCR8 Ago2 |
| url | https://www.mdpi.com/1422-0067/21/7/2559 |
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