Research Paper Volume 13, Issue 6 pp 8380—8395

Extracellular HMGB1 promotes CD44 expression in hepatocellular carcinoma via regulating miR-21

Jun Li1, *, , Haozhen Ren1, *, , Jinglin Wang1, , Pengfei Zhang1, , Xiaolei Shi1, ,

  • 1 Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
* Equal contribution

Received: September 24, 2019       Accepted: October 12, 2020       Published: March 4, 2021
How to Cite

Copyright: © 2021 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


As a member of damage-associated molecular patterns (DAMPs), extracellular high-mobility group box 1 (HMGB1) plays a critical role in hepatocellular carcinoma (HCC) progression. Cluster differentiation 44 (CD44) has been demonstrated to participate in HCC progression. However, the relationship between extracellular HMGB1 and CD44 remains unclear. In this study, our results indicated that extracellular HMGB1 promoted the invasion, sphere formation and EMT process of HCC by increasing CD44 expression, which was dependent on miR-21. Moreover, miR-21 upregulated CD44 expression via activating OCT4/TGF-β1 signaling. Finally, we demonstrated the activation of Rage/JNK signaling caused by extracellular HMGB1 was responsible for miR-21 overexpression. Together, these findings reveal an important role of extracellular HMGB1 in HCC progression through upregulating miR-21/CD44.


Rage: the receptor for advanced glycation end products; HMGB1: high-mobility group box 1; DAMPs: damage-associated molecular patterns; HA: hyaluronan acid.