LncRNA miR663AHG represses the development of colon cancer in a miR663a-dependent manner
Abstract The MIR663AHG gene encodes both miR663AHG and miR663a. While miR663a contributes to the defense of host cells against inflammation and inhibits colon cancer development, the biological function of lncRNA miR663AHG has not been previously reported. In this study, the subcellular localization...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-07-01
|
| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01510-1 |
| _version_ | 1797784755173851136 |
|---|---|
| author | Hongfan Yuan Qianwen Ren Yantao Du Yuwan Ma Liankun Gu Jing Zhou Wei Tian Dajun Deng |
| author_facet | Hongfan Yuan Qianwen Ren Yantao Du Yuwan Ma Liankun Gu Jing Zhou Wei Tian Dajun Deng |
| author_sort | Hongfan Yuan |
| collection | DOAJ |
| description | Abstract The MIR663AHG gene encodes both miR663AHG and miR663a. While miR663a contributes to the defense of host cells against inflammation and inhibits colon cancer development, the biological function of lncRNA miR663AHG has not been previously reported. In this study, the subcellular localization of lncRNA miR663AHG was determined by RNA-FISH. miR663AHG and miR663a were measured by qRT-PCR. The effects of miR663AHG on the growth and metastasis of colon cancer cells were investigated in vitro and in vivo. CRISPR/Cas9, RNA pulldown, and other biological assays were used to explore the underlying mechanism of miR663AHG. We found that miR663AHG was mainly distributed in the nucleus of Caco2 and HCT116 cells and the cytoplasm of SW480 cells. The expression level of miR663AHG was positively correlated with the level of miR663a (r = 0.179, P = 0.015) and significantly downregulated in colon cancer tissues relative to paired normal tissues from 119 patients (P < 0.008). Colon cancers with low miR663AHG expression were associated with advanced pTNM stage (P = 0.021), lymph metastasis (P = 0.041), and shorter overall survival (hazard ratio = 2.026; P = 0.021). Experimentally, miR663AHG inhibited colon cancer cell proliferation, migration, and invasion. The growth of xenografts from RKO cells overexpressing miR663AHG was slower than that of xenografts from vector control cells in BALB/c nude mice (P = 0.007). Interestingly, either RNA-interfering or resveratrol-inducing expression changes of miR663AHG or miR663a can trigger negative feedback regulation of transcription of the MIR663AHG gene. Mechanistically, miR663AHG could bind to miR663a and its precursor pre-miR663a, and prevent the degradation of miR663a target mRNAs. Disruption of the negative feedback by knockout of the MIR663AHG promoter, exon-1, and pri-miR663A-coding sequence entirely blocked these effects of miR663AHG, which was restored in cells transfected with miR663a expression vector in rescue experiment. In conclusion, miR663AHG functions as a tumor suppressor that inhibits the development of colon cancer through its cis-binding to miR663a/pre-miR663a. The cross talk between miR663AHG and miR663a expression may play dominant roles in maintaining the functions of miR663AHG in colon cancer development. |
| first_indexed | 2024-03-13T00:44:25Z |
| format | Article |
| id | doaj.art-4d43099914aa4909b76e04875f41225f |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-13T00:44:25Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-4d43099914aa4909b76e04875f41225f2023-07-09T11:06:12ZengNature Publishing GroupCell Death Discovery2058-77162023-07-019111210.1038/s41420-023-01510-1LncRNA miR663AHG represses the development of colon cancer in a miR663a-dependent mannerHongfan Yuan0Qianwen Ren1Yantao Du2Yuwan Ma3Liankun Gu4Jing Zhou5Wei Tian6Dajun Deng7Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Cancer Etiology, Peking University Cancer Hospital and InstituteKey Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Cancer Etiology, Peking University Cancer Hospital and InstituteThe First Affiliated Hospital of Ningbo UniversityKey Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Cancer Etiology, Peking University Cancer Hospital and InstituteKey Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Cancer Etiology, Peking University Cancer Hospital and InstituteKey Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Cancer Etiology, Peking University Cancer Hospital and InstituteKey Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Cancer Etiology, Peking University Cancer Hospital and InstituteKey Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Cancer Etiology, Peking University Cancer Hospital and InstituteAbstract The MIR663AHG gene encodes both miR663AHG and miR663a. While miR663a contributes to the defense of host cells against inflammation and inhibits colon cancer development, the biological function of lncRNA miR663AHG has not been previously reported. In this study, the subcellular localization of lncRNA miR663AHG was determined by RNA-FISH. miR663AHG and miR663a were measured by qRT-PCR. The effects of miR663AHG on the growth and metastasis of colon cancer cells were investigated in vitro and in vivo. CRISPR/Cas9, RNA pulldown, and other biological assays were used to explore the underlying mechanism of miR663AHG. We found that miR663AHG was mainly distributed in the nucleus of Caco2 and HCT116 cells and the cytoplasm of SW480 cells. The expression level of miR663AHG was positively correlated with the level of miR663a (r = 0.179, P = 0.015) and significantly downregulated in colon cancer tissues relative to paired normal tissues from 119 patients (P < 0.008). Colon cancers with low miR663AHG expression were associated with advanced pTNM stage (P = 0.021), lymph metastasis (P = 0.041), and shorter overall survival (hazard ratio = 2.026; P = 0.021). Experimentally, miR663AHG inhibited colon cancer cell proliferation, migration, and invasion. The growth of xenografts from RKO cells overexpressing miR663AHG was slower than that of xenografts from vector control cells in BALB/c nude mice (P = 0.007). Interestingly, either RNA-interfering or resveratrol-inducing expression changes of miR663AHG or miR663a can trigger negative feedback regulation of transcription of the MIR663AHG gene. Mechanistically, miR663AHG could bind to miR663a and its precursor pre-miR663a, and prevent the degradation of miR663a target mRNAs. Disruption of the negative feedback by knockout of the MIR663AHG promoter, exon-1, and pri-miR663A-coding sequence entirely blocked these effects of miR663AHG, which was restored in cells transfected with miR663a expression vector in rescue experiment. In conclusion, miR663AHG functions as a tumor suppressor that inhibits the development of colon cancer through its cis-binding to miR663a/pre-miR663a. The cross talk between miR663AHG and miR663a expression may play dominant roles in maintaining the functions of miR663AHG in colon cancer development.https://doi.org/10.1038/s41420-023-01510-1 |
| spellingShingle | Hongfan Yuan Qianwen Ren Yantao Du Yuwan Ma Liankun Gu Jing Zhou Wei Tian Dajun Deng LncRNA miR663AHG represses the development of colon cancer in a miR663a-dependent manner Cell Death Discovery |
| title | LncRNA miR663AHG represses the development of colon cancer in a miR663a-dependent manner |
| title_full | LncRNA miR663AHG represses the development of colon cancer in a miR663a-dependent manner |
| title_fullStr | LncRNA miR663AHG represses the development of colon cancer in a miR663a-dependent manner |
| title_full_unstemmed | LncRNA miR663AHG represses the development of colon cancer in a miR663a-dependent manner |
| title_short | LncRNA miR663AHG represses the development of colon cancer in a miR663a-dependent manner |
| title_sort | lncrna mir663ahg represses the development of colon cancer in a mir663a dependent manner |
| url | https://doi.org/10.1038/s41420-023-01510-1 |
| work_keys_str_mv | AT hongfanyuan lncrnamir663ahgrepressesthedevelopmentofcoloncancerinamir663adependentmanner AT qianwenren lncrnamir663ahgrepressesthedevelopmentofcoloncancerinamir663adependentmanner AT yantaodu lncrnamir663ahgrepressesthedevelopmentofcoloncancerinamir663adependentmanner AT yuwanma lncrnamir663ahgrepressesthedevelopmentofcoloncancerinamir663adependentmanner AT liankungu lncrnamir663ahgrepressesthedevelopmentofcoloncancerinamir663adependentmanner AT jingzhou lncrnamir663ahgrepressesthedevelopmentofcoloncancerinamir663adependentmanner AT weitian lncrnamir663ahgrepressesthedevelopmentofcoloncancerinamir663adependentmanner AT dajundeng lncrnamir663ahgrepressesthedevelopmentofcoloncancerinamir663adependentmanner |