N6-methyladenosine–mediated overexpression of long noncoding RNA ADAMTS9-AS2 triggers neuroblastoma differentiation via regulating LIN28B/let-7/MYCN signaling
Neuroblastomas have shed light on the differentiation disorder that is associated with spontaneous regression or differentiation in the same tumor at the same time. Long noncoding RNAs (lncRNAs) actively participate in a broad spectrum of biological processes. However, the detailed molecular mechani...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-11-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.165703 |
| _version_ | 1827767904890781696 |
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| author | Yun Liu Jun Zhang Fang Cao Xiaobao Dong Jie Li Yanna Cao Zhanglin Li Yan Guo Jie Yan Yuanyuan Liu Qiang Zhao |
| author_facet | Yun Liu Jun Zhang Fang Cao Xiaobao Dong Jie Li Yanna Cao Zhanglin Li Yan Guo Jie Yan Yuanyuan Liu Qiang Zhao |
| author_sort | Yun Liu |
| collection | DOAJ |
| description | Neuroblastomas have shed light on the differentiation disorder that is associated with spontaneous regression or differentiation in the same tumor at the same time. Long noncoding RNAs (lncRNAs) actively participate in a broad spectrum of biological processes. However, the detailed molecular mechanisms underlying lncRNA regulation of differentiation in neuroblastomas remain largely unknown. Here, we sequenced clinical samples of ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. We compared transcription profiles of neuroblastoma cells, ganglion cells, and intermediate state cells; verified the profiles in a retinoic acid–induced cell differentiation model and clinical samples; and screened out the lncRNA ADAMTS9 antisense RNA 2 (ADAMTS9-AS2), which contributed to neuroblastoma differentiation. ADAMTS9-AS2 upregulation in neuroblastoma cell lines inhibited proliferation and metastatic potential. Additional mechanistic studies illustrated that the interactions between ADAMTS9-AS2 and LIN28B inhibited the association between LIN28B and primary let-7 (pri-let-7) miRNA, then released pri-let-7 into cytoplasm to form mature let-7, resulting in the inhibition of oncogene MYCN activity that subsequently affected cancer stemness and differentiation. Furthermore, we showed that the observed differential expression of ADAMTS9-AS2 in neuroblastoma cells was due to N6-methyladenosine methylation. Finally, ADAMTS9-AS2 upregulation inhibited proliferation and cancer stem-like capabilities in vivo. Taken together, these results show that ADAMTS9-AS2 loss leads to malignant neuroblastoma by increasing metastasis and causing dysfunctional differentiation. |
| first_indexed | 2024-03-11T12:06:01Z |
| format | Article |
| id | doaj.art-c663f87e024945c6a19dae68527d10ee |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:01Z |
| publishDate | 2023-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-c663f87e024945c6a19dae68527d10ee2023-11-07T16:26:27ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-11-01822N6-methyladenosine–mediated overexpression of long noncoding RNA ADAMTS9-AS2 triggers neuroblastoma differentiation via regulating LIN28B/let-7/MYCN signalingYun LiuJun ZhangFang CaoXiaobao DongJie LiYanna CaoZhanglin LiYan GuoJie YanYuanyuan LiuQiang ZhaoNeuroblastomas have shed light on the differentiation disorder that is associated with spontaneous regression or differentiation in the same tumor at the same time. Long noncoding RNAs (lncRNAs) actively participate in a broad spectrum of biological processes. However, the detailed molecular mechanisms underlying lncRNA regulation of differentiation in neuroblastomas remain largely unknown. Here, we sequenced clinical samples of ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. We compared transcription profiles of neuroblastoma cells, ganglion cells, and intermediate state cells; verified the profiles in a retinoic acid–induced cell differentiation model and clinical samples; and screened out the lncRNA ADAMTS9 antisense RNA 2 (ADAMTS9-AS2), which contributed to neuroblastoma differentiation. ADAMTS9-AS2 upregulation in neuroblastoma cell lines inhibited proliferation and metastatic potential. Additional mechanistic studies illustrated that the interactions between ADAMTS9-AS2 and LIN28B inhibited the association between LIN28B and primary let-7 (pri-let-7) miRNA, then released pri-let-7 into cytoplasm to form mature let-7, resulting in the inhibition of oncogene MYCN activity that subsequently affected cancer stemness and differentiation. Furthermore, we showed that the observed differential expression of ADAMTS9-AS2 in neuroblastoma cells was due to N6-methyladenosine methylation. Finally, ADAMTS9-AS2 upregulation inhibited proliferation and cancer stem-like capabilities in vivo. Taken together, these results show that ADAMTS9-AS2 loss leads to malignant neuroblastoma by increasing metastasis and causing dysfunctional differentiation.https://doi.org/10.1172/jci.insight.165703Oncology |
| spellingShingle | Yun Liu Jun Zhang Fang Cao Xiaobao Dong Jie Li Yanna Cao Zhanglin Li Yan Guo Jie Yan Yuanyuan Liu Qiang Zhao N6-methyladenosine–mediated overexpression of long noncoding RNA ADAMTS9-AS2 triggers neuroblastoma differentiation via regulating LIN28B/let-7/MYCN signaling JCI Insight Oncology |
| title | N6-methyladenosine–mediated overexpression of long noncoding RNA ADAMTS9-AS2 triggers neuroblastoma differentiation via regulating LIN28B/let-7/MYCN signaling |
| title_full | N6-methyladenosine–mediated overexpression of long noncoding RNA ADAMTS9-AS2 triggers neuroblastoma differentiation via regulating LIN28B/let-7/MYCN signaling |
| title_fullStr | N6-methyladenosine–mediated overexpression of long noncoding RNA ADAMTS9-AS2 triggers neuroblastoma differentiation via regulating LIN28B/let-7/MYCN signaling |
| title_full_unstemmed | N6-methyladenosine–mediated overexpression of long noncoding RNA ADAMTS9-AS2 triggers neuroblastoma differentiation via regulating LIN28B/let-7/MYCN signaling |
| title_short | N6-methyladenosine–mediated overexpression of long noncoding RNA ADAMTS9-AS2 triggers neuroblastoma differentiation via regulating LIN28B/let-7/MYCN signaling |
| title_sort | n6 methyladenosine mediated overexpression of long noncoding rna adamts9 as2 triggers neuroblastoma differentiation via regulating lin28b let 7 mycn signaling |
| topic | Oncology |
| url | https://doi.org/10.1172/jci.insight.165703 |
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