2. Academic Validation
  3. Troxerutin suppresses the stemness of osteosarcoma via the CD155/SRC/β-catenin signaling axis

Troxerutin suppresses the stemness of osteosarcoma via the CD155/SRC/β-catenin signaling axis

  • Cell Mol Biol Lett. 2025 Apr 11;30(1):45. doi: 10.1186/s11658-025-00724-8.
Junkai Chen # 1 2,  Hongbo Li # 1 2,  Qinglin Jin # 3,  Xiaoguang Li 4,  Yiwen Zhang 5,  Jingnan Shen 1 2,  Gang Huang 1 2,  Junqiang Yin 1 2,  Changye Zou 1 2,  Xinyu Li 6,  Xin He 7,  Xianbiao Xie 8 9,  Tiao Lin 10 11
Affiliations

Affiliations

  • 1 Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Musculoskeletal Oncology, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 4 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 5 Institute of Human Virology, Department of Pathogen Biology and Biosecurity, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
  • 6 Department of Urology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
  • 7 Institute of Human Virology, Department of Pathogen Biology and Biosecurity, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China. hexin59@mail.sysu.edu.cn.
  • 8 Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. xiexbiao@mail.sysu.edu.cn.
  • 9 Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. xiexbiao@mail.sysu.edu.cn.
  • 10 Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. lindiao@mail.sysu.edu.cn.
  • 11 Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. lindiao@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 40217455 DOI: 10.1186/s11658-025-00724-8
Abstract

Background: Osteosarcoma is the most prevalent primary malignant bone tumor affecting pediatric and adolescent individuals. However, despite the passage of three decades, there has been no notable enhancement in the overall survival rate of patients with osteosarcoma. In recent years, CD155 has been reported to exhibit abnormal amplification in a range of tumors, yet the precise underlying mechanism remains elusive. The objective of this study is to investigate the role of CD155 in osteosarcoma, and to identify drugs that specifically target this molecule, thereby offering a novel direction for the treatment of osteosarcoma.

Methods: The prognosis of patients with osteosarcoma with high and low expression of CD155 was verified by immunohistochemistry. CCK-8 and colony formation assays were used to detect cell proliferation and drug resistance. Transwell experiments were used to detect cell migration and invasion. The sphere formation experiment was used to evaluate the stemness of tumor cells. Additionally, in vivo animal models were utilized to assess the functional role of CD155 in a biological context. RNA-seq and co-immunoprecipitation methods were used to search for downstream target molecules and signaling pathways of CD155. Finally, virtual screening was used to find drugs targeting CD155.

Results: In this study, we have established the significant amplification of CD155 in osteosarcoma. Utilizing a comprehensive array of experimental methods, including CCK-8 assay, colony formation assay, Transwell assay, and in vivo animal models, we unequivocally demonstrate that CD155 significantly potentiates the malignancy of osteosarcoma both in vitro and in vivo. Additionally, our findings reveal that CD155 promotes osteosarcoma stemness by modulating the Wnt/β-catenin signaling pathway. Advanced molecular techniques, such as RNA Sequencing and co-immunoprecipitation, have been instrumental in elucidating the mechanism of CD155 in activating the Wnt/β-catenin pathway via the Src/Akt/GSK3β signaling axis, thereby enhancing the stem-cell-like properties of osteosarcoma cells. To explore targeted therapeutic options, we conducted virtual screening and identified troxerutin as a promising CD155 inhibitor.

Conclusions: Our findings reveal that troxerutin effectively inhibits CD155, attenuates the Src/Akt/GSK3β signaling cascade, diminishes the nuclear localization of β-catenin, and consequently mitigates osteosarcoma stemness. These discoveries position troxerutin as a promising candidate for targeted osteosarcoma therapy.

Keywords

CD155; Osteosarcoma; Stemness; Troxerutin; β-catenin.

Figures
Products