The lncRNA Malat1 functions as a ceRNA to contribute to berberine-mediated inhibition of HMGB1 by sponging miR-181c-5p in poststroke inflammation

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Abstract

Long non-coding RNAs (lncRNAs) have been identified as essential mediators in neurological dysfunction. Our previous study shows that berberine (BBR) hampers the nuclear-to-cytosolic translocation of high-mobility group box 1 (HMGB1) in the process of poststroke inflammation. In this study, we explored the role of lncRNA metastasis‐associated lung adenocarcinoma transcript 1 (Malat1) in the process of BBR-induced inhibition of HMGB1 in ischemic brain. Before the 60-min MCAO surgery, the mice were pretreated with BBR (50 mg· kg−1 per day, ig) for 14 days or ICV injected with specific lentiviral vector or shRNA. We showed that MCAO caused marked increase in the expression Malat1 and HMGB1 in the ipsilateral cortex, which was significantly attenuated by pretreatment with BBR. Knockdown of Malat1 attenuated the inflammatory injury after brain ischemia, whereas overexpression of Malat1 exacerbated ischemic brain inflammation. Overexpression of Malat1 also reversed BBR-induced reduction of HMGB1 and proinflammatory cytokines. The above results suggested a potential correlation between Malat1 and stroke inflammation. Based on informatics analysis we predicted that HMGB1 was a direct downstream target of miR-181c-5p, whereas Malat1 acted as a competitive endogenous RNA (ceRNA) for miR-181c-5p targeted the 3′-UTR of HMGB1 to promote inflammation after ischemic stroke. Knockdown of Malat1 significantly decreased HMGB1 level, which could be abrogated by transfection with miR-181c-5p inhibitors. Taken together, our results demonstrate for the first time that Malat1/miR-181c-5p/HMGB1 axis may be a key pathway of BBR-induced antiinflammation effects in stroke, and they may provide a novel avenue for targeted therapy.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant No. 81773987), the Program of Nanjing Health and Family Planning Commission (YKK188107) and the Hospital Pharmaceutical Research Program of Nanjing Pharmaceutical Commission (2017YX001).

Author information

JRZ and JGS conceived and designed the study. DWC, MML and RD performed the experiments. MML, RD and LN analyzed the data. DWC and WRF wrote the paper. JRZ, LN and JGS reviewed and edited the manuscript. All authors read and approved the manuscript.

Correspondence to Jun-rong Zhu or Li Niu or Jian-guo Sun.

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The authors declare that they have no conflict of interest.

Additional information

These authors are co-first authors: Ding-wen Cao, Man-man Liu, Rui Duan

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Keywords

  • Malat1
  • miR-181c-5p
  • HMGB1
  • stroke
  • inflammation
  • berberine