TRAIP modulates the IGFBP3/AKT pathway to enhance the invasion and proliferation of osteosarcoma by promoting KANK1 degradation

Mi Li,Wei Wu,Xin Jin,Zengwu Shao,Sisi Deng

doi:10.1038/s41419-021-04057-0

Abstract

Osteosarcoma is one of the most common primary malignancies in bones and is characterized by high metastatic rates. Circulating tumor cells (CTCs) derived from solid tumors can give rise to metastatic lesions, increasing the risk of death in patients with cancer. Here, we used bioinformatics tools to compare the gene expression between CTCs and metastatic lesions in osteosarcoma to identify novel molecular mechanisms underlying osteosarcoma metastasis. We identified TRAIP as a key differentially expressed gene with prognostic significance in osteosarcoma. We demonstrated that TRAIP regulated the proliferation and invasion of osteosarcoma cells. In addition, we found that TRAIP promoted KANK1 polyubiquitination and subsequent degradation, downregulating IGFBP3 and activating the AKT pathway in osteosarcoma cells. These results support the critical role of the TRAIP/KANK1/IGFBP3/AKT signaling axis in osteosarcoma progression and suggest that TRAIP may represent a promising therapeutic target for osteosarcoma.

Highlights

Mesenchymal stem cell-derived osteosarcoma is one of the most common primary malignancies in bones [1], and it is common in children and adolescents
TRAIP enhances osteosarcoma cell proliferation by promoting KANK1 degradation To explore the role of KANK1 in osteosarcoma, we evaluated its expression levels in osteosarcoma tissues
We found that TRAIP regulated IGFBP3 expression through KANK1 in osteosarcoma cells (Fig. 7k)

Summary

Introduction

Mesenchymal stem cell-derived osteosarcoma is one of the most common primary malignancies in bones [1], and it is common in children and adolescents. With the recent progress in surgical oncology and neoadjuvant chemotherapies, the 5-year survival rate of patients with osteosarcoma has increased from approximately 20–70% [2]. Circulating tumor cells (CTC) are cancer cells from solid tumors or metastatic lesions that circulate in the body through the peripheral blood [5]. Most CTCs undergo apoptosis or phagocytosis, some survive and give rise to metastatic lesions, increasing the risk of death in patients with cancer [6]. Recent developments in bioinformatics tools have played an important role in elucidating the molecular mechanisms underlying cancer development and progression. The use of in silico tools to better understand CTCs remains limited

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Conclusion