Abstract
Insulin-like growth factor-2 mRNA-binding protein 2 (IGF2BP2, also known as IMP2), a novel class III N6-methyladenosine (m6A) reader, has recently gained attention due to its critical functions in recognizing and stabilizing m6A modified oncogenic transcripts. However, whether and how long non-coding RNAs (lncRNAs) facilitate IMP2’s role as m6A “reader” remains elusive, particularly in colorectal cancer (CRC). Here, we demonstrated that oncogenic LINC021 specifically bound with the m6A “reader” IMP2 protein and enhanced the mRNA stability of MSX1 and JARID2 in an m6A regulatory manner during CRC tumorigenesis and pathogenesis. Specifically, a remarkable upregulation of LINC021 was confirmed in CRC cell lines and clinical tissues (n = 130). High level of LINC021acted as an independent prognostic predictor for CRC clinical outcomes. Functional assays demonstrated that LINC021 exerted its functions as an oncogene to aggravate CRC malignant phenotypes including enhanced cell proliferation, colony formation, migration capabilities, and reduced cell apoptosis. Mechanistically, LINC021 directly recognized IMP2 protein, the latter enhanced the mRNA stability of transcripts such as MSX1 and JARID2 by recognizing their m6A-modified element RGGAC. Thus, these findings uncovered an essential LINC021/IMP2/MSX1 and JARID2 signaling axis in CRC tumorigenesis, which provided profound insights into our understanding of m6A modification regulated by lncRNA in CRC initiation and progression and shed light on the targeting of this axis for CRC treatment.
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Data availability
The authors declare that all the data supporting the findings in this study are available in this study and its Supplementary materials, or are available from the corresponding author through reasonable request. The Raw data were download from the Gene Expression Omnibus (GEO) website, show as follows:
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Acknowledgements
We gratefully appreciate the efforts and contributions of doctors, nurses, and technical staff at the First Hospital of China Medical University, Cancer Hospital of China Medical University.
Funding
This work was supported by grants from the National Natural Science Foundation of China (81872905, 82073884), Science and Technology Innovative Foundation for Young and Middle-aged Scientists of Shenyang City (RC200382), Shenyang High Level Talent Innovation and Entrepreneurship Team (2019-SYRCCY-B-01), and Major Special S&T Projects in Liaoning Province [2019JH1/10300005].
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HW, MW, and XD conceived and designed the project. HW, XD, QC, TS, XH, HG, ML, ZG, WY, LZ, KL performed experiments and/or data acquisition and analyses; HW, XD, QC, TS, XH, HG, ML, KL contributed technical/reagents materials, analytic tools and/or grant support; HW, MW, KL, and XD prepared, wrote, and/or revision the manuscript. All authors discussed the results and commented on the manuscript.
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This study was approved by the Ethics Committee of China Medical University. The animal experiments (CMU2020184) performed in this study were approved by the Institutional Animal Care and Use Committee of China Medical University.
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Wu, H., Ding, X., Hu, X. et al. LINC01021 maintains tumorigenicity by enhancing N6-methyladenosine reader IMP2 dependent stabilization of MSX1 and JARID2: implication in colorectal cancer. Oncogene 41, 1959–1973 (2022). https://doi.org/10.1038/s41388-022-02189-x
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DOI: https://doi.org/10.1038/s41388-022-02189-x
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