The Interaction Between Long Non-coding RNA HULC and MicroRNA-622 via Transfer by Extracellular Vesicles Regulates Cell Invasion and Migration in Human Pancreatic Cancer
Although non-coding RNAs (ncRNAs) are involved in disease pathogenesis, their contributions to pancreatic ductal adenocarcinoma (PDAC) remain unclear. Recently, the interrelationship between two classes of ncRNA, long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), has been reported to contribute...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2020.01013/full |
| _version_ | 1818521796774723584 |
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| author | Kenji Takahashi Kazuya Koyama Yu Ota Hidetaka Iwamoto Keisuke Yamakita Satoshi Fujii Yohei Kitano |
| author_facet | Kenji Takahashi Kazuya Koyama Yu Ota Hidetaka Iwamoto Keisuke Yamakita Satoshi Fujii Yohei Kitano |
| author_sort | Kenji Takahashi |
| collection | DOAJ |
| description | Although non-coding RNAs (ncRNAs) are involved in disease pathogenesis, their contributions to pancreatic ductal adenocarcinoma (PDAC) remain unclear. Recently, the interrelationship between two classes of ncRNA, long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), has been reported to contribute to the epigenetic regulation of gene expression in several diseases including cancers. Moreover, some ncRNAs can be transferred by extracellular vesicles (EVs) from their donor cells to recipient cells. We previously verified that lncRNA HULC is up-regulated in PDAC cells and the intercellular transfer of HULC by EVs can promote PDAC cell invasion and migration through the induction of epithelial–mesenchymal transition (EMT). Therefore, we identified the miRNA that could target HULC and investigated the functional contributions of the miRNA–HULC interaction and EV transfer of miRNA to the EMT pathway in PDAC. Microarray analysis revealed 187 miRNAs that were decreased to <0.87-fold in Panc-1 cells treated with TGF-β compared with the control. Of these, miR-622 was predicted to target HULC directly by bioinformatics analysis. Expression of miR-622 was significantly down-regulated by TGF-β in a panel of PDAC cells. miR-622 overexpression by a miRNA mimic significantly decreased HULC expression, increased E-cadherin expression, and decreased expression of Snail, N-cadherin, and vimentin. Moreover, overexpression of miR-622 significantly reduced cell invasion and migration whereas inhibition of miR-622 increased HULC expression and promoted EMT signaling, invasion, and migration of PDAC cells. Furthermore, incubation with miR-622-overexpressing EVs could transfer miR-622, which significantly elevated miR-622 expression and decreased cell invasion and migration via inhibition of the EMT pathway in recipient PDAC cells. These results provide mechanistic insights into the development of PDAC by demonstrating that miR-622, as a miRNA downregulated by TGF-β, could target HULC and suppress invasion and migration by inhibiting EMT signaling via EV transfer. These observations may identify EV-encapsulated miRNA as a novel therapeutic target for human PDAC. |
| first_indexed | 2024-12-11T01:56:07Z |
| format | Article |
| id | doaj.art-d484b448699b4077b4e166afedd1a030 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-11T01:56:07Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Oncology |
| spelling | doaj.art-d484b448699b4077b4e166afedd1a0302022-12-22T01:24:37ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2020-06-011010.3389/fonc.2020.01013543443The Interaction Between Long Non-coding RNA HULC and MicroRNA-622 via Transfer by Extracellular Vesicles Regulates Cell Invasion and Migration in Human Pancreatic CancerKenji Takahashi0Kazuya Koyama1Yu Ota2Hidetaka Iwamoto3Keisuke Yamakita4Satoshi Fujii5Yohei Kitano6Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, JapanDivision of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, JapanDivision of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, JapanDivision of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, JapanDivision of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, JapanDepartment of Laboratory Medicine, Asahikawa Medical University, Asahikawa, JapanDivision of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, JapanAlthough non-coding RNAs (ncRNAs) are involved in disease pathogenesis, their contributions to pancreatic ductal adenocarcinoma (PDAC) remain unclear. Recently, the interrelationship between two classes of ncRNA, long non-coding RNAs (lncRNAs), and microRNAs (miRNAs), has been reported to contribute to the epigenetic regulation of gene expression in several diseases including cancers. Moreover, some ncRNAs can be transferred by extracellular vesicles (EVs) from their donor cells to recipient cells. We previously verified that lncRNA HULC is up-regulated in PDAC cells and the intercellular transfer of HULC by EVs can promote PDAC cell invasion and migration through the induction of epithelial–mesenchymal transition (EMT). Therefore, we identified the miRNA that could target HULC and investigated the functional contributions of the miRNA–HULC interaction and EV transfer of miRNA to the EMT pathway in PDAC. Microarray analysis revealed 187 miRNAs that were decreased to <0.87-fold in Panc-1 cells treated with TGF-β compared with the control. Of these, miR-622 was predicted to target HULC directly by bioinformatics analysis. Expression of miR-622 was significantly down-regulated by TGF-β in a panel of PDAC cells. miR-622 overexpression by a miRNA mimic significantly decreased HULC expression, increased E-cadherin expression, and decreased expression of Snail, N-cadherin, and vimentin. Moreover, overexpression of miR-622 significantly reduced cell invasion and migration whereas inhibition of miR-622 increased HULC expression and promoted EMT signaling, invasion, and migration of PDAC cells. Furthermore, incubation with miR-622-overexpressing EVs could transfer miR-622, which significantly elevated miR-622 expression and decreased cell invasion and migration via inhibition of the EMT pathway in recipient PDAC cells. These results provide mechanistic insights into the development of PDAC by demonstrating that miR-622, as a miRNA downregulated by TGF-β, could target HULC and suppress invasion and migration by inhibiting EMT signaling via EV transfer. These observations may identify EV-encapsulated miRNA as a novel therapeutic target for human PDAC.https://www.frontiersin.org/article/10.3389/fonc.2020.01013/fulllong non-coding RNAmicroRNAepithelial-mesenchymal transitioninvasionmigrationpancreatic ductal adenocarcinoma |
| spellingShingle | Kenji Takahashi Kazuya Koyama Yu Ota Hidetaka Iwamoto Keisuke Yamakita Satoshi Fujii Yohei Kitano The Interaction Between Long Non-coding RNA HULC and MicroRNA-622 via Transfer by Extracellular Vesicles Regulates Cell Invasion and Migration in Human Pancreatic Cancer Frontiers in Oncology long non-coding RNA microRNA epithelial-mesenchymal transition invasion migration pancreatic ductal adenocarcinoma |
| title | The Interaction Between Long Non-coding RNA HULC and MicroRNA-622 via Transfer by Extracellular Vesicles Regulates Cell Invasion and Migration in Human Pancreatic Cancer |
| title_full | The Interaction Between Long Non-coding RNA HULC and MicroRNA-622 via Transfer by Extracellular Vesicles Regulates Cell Invasion and Migration in Human Pancreatic Cancer |
| title_fullStr | The Interaction Between Long Non-coding RNA HULC and MicroRNA-622 via Transfer by Extracellular Vesicles Regulates Cell Invasion and Migration in Human Pancreatic Cancer |
| title_full_unstemmed | The Interaction Between Long Non-coding RNA HULC and MicroRNA-622 via Transfer by Extracellular Vesicles Regulates Cell Invasion and Migration in Human Pancreatic Cancer |
| title_short | The Interaction Between Long Non-coding RNA HULC and MicroRNA-622 via Transfer by Extracellular Vesicles Regulates Cell Invasion and Migration in Human Pancreatic Cancer |
| title_sort | interaction between long non coding rna hulc and microrna 622 via transfer by extracellular vesicles regulates cell invasion and migration in human pancreatic cancer |
| topic | long non-coding RNA microRNA epithelial-mesenchymal transition invasion migration pancreatic ductal adenocarcinoma |
| url | https://www.frontiersin.org/article/10.3389/fonc.2020.01013/full |
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