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Long noncoding RNA CRCMSL suppresses tumor invasive and metastasis in colorectal carcinoma through nucleocytoplasmic shuttling of HMGB2

Oncogene volume 38, pages 3019–3032 (2019)Cite this article

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Abstract

Long noncoding RNAs (lncRNAs) are pervasive transcripts that play pivotal roles in regulating chromatin dynamics, gene and protein expression. Aberrant expression and mutations of lncRNAs represent a driving force behind tumor invasion and metastasis, making them attractive cancer targets. However, most of the lncRNAs are still being discovered and conclusive experimental evidence for their functional relevance is still lacking for most malignancies. In this study, a differentially expressed lncRNA, designated as lnc-CRCMSL, is identified by microarray-based screenings on non-metastatic and metastatic CRC specimens. Lnc-CRCMSL is verified as an anti-metastatic gene and negatively correlated with the poor prognosis of CRC patients. Lnc-CRCMSL overexpression restricts tumor growth and metastasis in vivo and in vitro. Instead, lnc-CRCMSL silencing accelerates CRC cell proliferation and migration. RNA-pulldown assay identifies high mobility group box 2 (HMGB2) as a downstream protein of lnc-CRCMSL. Mechanically, lnc-CRCMSL physically binds to HMGB2 and stabilizes the localization of HMGB2 in the cytoplasm. Notably, lnc-CRCMSL knockdown lead to the shift of HMGB2 into nuclear, in which it triggers epithelial to mesenchymal transition (EMT) programming. Importantly, lnc-CRCMSL controls the cytoplasmic retention of HMGB2 and attenuates the interaction between HMGB2 and OCT4 to suppress EMT. Treatment of leptomycin B (LMB), a potent and specific nuclear export inhibitor, counteracts lnc-CRCMSL-mediated suppression of aggressive phenotypes and EMT process by accumulating the nuclear HMGB2.

Conclusion

Our data highlight the anti-metastatic role of lnc-CRCMSL in stabilizing HMGB2 through lncRNA-protein interactions in the cytoplasm, and suggest that targeting lnc-CRCMSL may represent a therapeutic opportunity for managing metastatic CRC.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81572813, 81773082, 81573848, 81774172), Guangdong Natural Science Foundation (2015A030313274), Science and Technology Program of Guangzhou (1563000235) and Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation (pdjhb0105).

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Author notes

  1. These author contributed equally: Qinrui Han, Lijun Xu, Weihao Lin and Xueqing Yao

Authors and Affiliations

  1. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China

    Qinrui Han & Xuegang Sun

  2. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Lijun Xu & Liang Zhao

  3. Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Lijun Xu, Weihao Lin, Muhong Jiang, Rui Zhou & Liang Zhao

  4. Second School of Clinical Medicine, Southern Medical University, 510515, Guangzhou, China

    Weihao Lin

  5. Department of Gastrointestinal Surgery, Guangdong General Hospital, Guangzhou, 510120, China

    Xueqing Yao

  6. Guangdong Province Key Laboratory of Molecular Tumor Pathology, Southern Medical University, Guangzhou, 510515, China

    Muhong Jiang, Rui Zhou & Liang Zhao

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  1. Qinrui Han
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Correspondence to Xuegang Sun or Liang Zhao.

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Precis: Findings identify and report a CRC metastasis suppressor lnc-CRCMSL with potential therapeutic applications.

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Han, Q., Xu, L., Lin, W. et al. Long noncoding RNA CRCMSL suppresses tumor invasive and metastasis in colorectal carcinoma through nucleocytoplasmic shuttling of HMGB2. Oncogene 38, 3019–3032 (2019). https://doi.org/10.1038/s41388-018-0614-4

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