ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway

Hongyu Li,Rujia Mi,Zhaopeng Cai,Yihui Song,Yuhang Jiang,Peng Wang,Mengjun Ma,Xin Shen,Wenzhou Liu,Yixuan Lu,Huiyong Shen,Jiahao Zhuang,Wen Yang,Yanfeng Wu

doi:10.1186/s13046-021-02146-8

Abstract

BackgroundThe zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; however, their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear.MethodsWe collected 64 OS patient tissues with (n = 12) or without (n = 52) chemotherapy. The expression levels of ZIP10 were measured by immunohistochemistry and applied to prognostic analysis. ZIP10 was knocked down or overexpressed in OS cell lines to explore its effect on proliferation and chemoresistance. RNA sequencing, quantitative real-time PCR, and western blotting analysis were performed to explore ZIP10-regulated downstream target genes. A xenograft mouse model was established to evaluate the mechanisms by which ZIP10 modulates chemoresistance in OS cells.ResultsThe expression of ZIP10 was significantly induced by chemotherapy and highly associated with the clinical outcomes of OS. Knockdown of ZIP10 suppressed OS cell proliferation and chemoresistance. In addition, ZIP10 promoted Zn content-induced cAMP-response element binding protein (CREB) phosphorylation and activation, which are required for integrin α10 (ITGA10) transcription and ITGA10-mediated PI3K/AKT pathway activation. Importantly, ITGA10 stimulated PI3K/AKT signaling but not the classical FAK or SRC pathway. Moreover, overexpression of ZIP10 promoted ITGA10 expression and conferred chemoresistance. Treatment with the CREB inhibitor 666–15 or the PI3K/AKT inhibitor GSK690693 impaired tumor chemoresistance in ZIP10-overexpressing cells. Finally, a xenograft mouse model established by subcutaneous injection of 143B cells confirmed that ZIP10 mediates chemotherapy resistance in OS cells via the ZIP10-ITGA10-PI3K/AKT axis.ConclusionsWe demonstrate that ZIP10 drives OS proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway, which might serve as a target for OS treatment.

Highlights

The zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear
ZIP10 promotes proliferation and chemoresistance in osteosarcoma Because Zn transporters ZIP/SLC39 have been implicated in tumor progression, we explored their role in OS chemoresistance
The results showed that ZIP10 expression in cisplatin-treated OS cells was nearly 3-fold that in untreated cells (Fig. 1a)

Summary

Introduction

The zinc transporters Zrt- and Irt-related protein (ZIP/SLC39) are overexpressed in human tumors and correlate with poor prognosis; their contributions to carcinogenesis and chemoresistance in osteosarcoma (OS) remain unclear. Among the zinc (Zn) transporters located in the cytomembrane are members of the Znt/SLC30 and ZIP/ SLC39 families [5]. In recent years, increasing evidence has shown that the ZIP/SLC39 family is involved in regulating tumor progression [6]. A study involving the OS cell line Saos-2 showed that ZIP10 is upregulated under conditions of Zn deficiency [10], suggesting that ZIP10 may be an important transporter for OS cells to maintain intracellular Zn levels. As some evidence suggests chemoprotective properties for Zn in cancers, the relationship between ZIP10 and chemoresistance in OS cells warrants attention

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