Baicalein mediates the anti-tumor activity in Osteosarcoma through lncRNA-NEF driven Wnt/β-catenin signaling regulatory axis

Feng-Wei Zhang; Li-Yang Peng; Chuan-Jian Shi; Jian-Chi Li; Feng-Xiang Pang; Wei-Ming Fu; Xiao-Hua Pan; Jin-Fang Zhang

doi:10.1016/j.jot.2021.12.001

Baicalein mediates the anti-tumor activity in Osteosarcoma through lncRNA-NEF driven Wnt/β-catenin signaling regulatory axis

J Orthop Translat. 2022 Mar 11:33:132-141. doi: 10.1016/j.jot.2021.12.001. eCollection 2022 Mar.

Authors

Feng-Wei Zhang^{1

2}, Li-Yang Peng^{1

2}, Chuan-Jian Shi^{3

4}, Jian-Chi Li⁵, Feng-Xiang Pang^{1

2}, Wei-Ming Fu^{3

4}, Xiao-Hua Pan⁶, Jin-Fang Zhang^{1

2}

Affiliations

¹ Key Laboratory of Orthopaedics and Traumatology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, PR China.
² Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, PR China.
³ School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 511458, PR China.
⁴ Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, PR China.
⁵ Department of Orthopaedics and Traumatology, Shenzhen Tenth People's Hospital Affiliated to Jinan University, University of Chinese Academy of Sciences Shenzhen Hospital (Guangming), Shenzhen, Guangdong, 518106, PR China.
⁶ Department of Orthopaedics, The Second School of Clinical Medicine, Southern Medical University, The Second Affiliated Hospital of Shenzhen University, The Clinical Medical College of Guangdong Medical University, People's Hospital of Shenzhen Baoan District, Shenzhen, PR China.

Abstract

Background: Osteosarcoma (OS) is a common type of malignant bone tumor in adolescents with high risk of metastasis. However, the clinical management still remains unsatisfactory. Traditional Chinese medicine (TCM) has been widely considered as an alternative treatment, and their extracts have proved to possess great potential for drug discovery. Baicalein (BA), the active pharmaceutical ingredient of rhizoma coptidis, was proved to have anti-tumor properties in OS, but the mechanism remains poorly understood.

Methods: The potential anti-cancer effects on cell growth, cell cycle, apoptosis and migration were examined in OS cells. Moreover, the lncRNA-Neighboring Enhancer of FOXA2 (lncRNA-NEF) and Wnt/β-catenin signaling were detected by qPCR and Western blotting assays. The in vivo effect of GA on tumor growth was investigated using a xenograft mice model.

Results: In the present study, BA was found to significantly suppress tumor growth in vitro and in vivo. And it was also found to inhibit the invasion and metastasis as well. As for the mechanism investigation, lncRNA-NEF was obviously upregulated by BA in OS cells, and thus induced the inactivation of Wnt/β-catenin signaling. Moreover, lncRNA-NEF knockdown partially reversed the BA-induced anti-cancer activities; and successfully compensated the suppressive effect on Wnt/β-catenin signaling. We therefore suggested that BA induced the inactivation of Wnt/β-catenin signaling through promoting lncRNA-NEF expression.

Conclusions: In conclude, our results demonstrated that BA suppressed tumor growth and metastasis in vitro and in vivo through an lncRNA-NEF driven Wnt/β-catenin regulatory axis, in which lncRNA-NEF was upregulated by BA, and thus induced the inactivation of Wnt/β-catenin signaling.

The translational potential of this article: The findings derived from this study validates the anti-cancer activity of BA in OS and provides a novel underlying mechanism, which suggest that BA may be a potential candidate to develop the effective drug for OS patients.

Keywords: Baicalein; Metastasis; Osteosarcoma; Wnt/β-catenin signaling; lncRNA-Neighboring Enhancer of FOXA2(lncRNA-NEF).