2. Academic Validation
  3. ZIP10 drives osteosarcoma proliferation and chemoresistance through ITGA10-mediated activation of the PI3K/AKT pathway

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

  • J Exp Clin Cancer Res. 2021 Oct 27;40(1):340. doi: 10.1186/s13046-021-02146-8.
Hongyu Li  # 1,  Xin Shen  # 1,  Mengjun Ma  # 1,  Wenzhou Liu 2,  Wen Yang 1,  Peng Wang 1,  Zhaopeng Cai 1,  Rujia Mi 3,  Yixuan Lu 3,  Jiahao Zhuang 1,  Yuhang Jiang 1,  Yihui Song 1,  Yanfeng Wu 4,  Huiyong Shen 5
Affiliations

Affiliations

  • 1 Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025 Shennan Zhong Road, Shenzhen, Guangdong, 518033, China.
  • 2 Department of Orthopedics, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510000, China.
  • 3 Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025 Shennan Zhong Road, Shenzhen, 518033, Guangdong, China.
  • 4 Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025 Shennan Zhong Road, Shenzhen, 518033, Guangdong, China. wuyf@mail.sysu.edu.cn.
  • 5 Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, No. 3025 Shennan Zhong Road, Shenzhen, Guangdong, 518033, China. shenhuiy1026@126.com.
  • # Contributed equally.
PMID: 34706747 DOI: 10.1186/s13046-021-02146-8
Abstract

Background: The 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.

Methods: We 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.

Results: The 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.

Conclusions: We 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.

Keywords

Chemoresistance; ITGA10; Osteosarcoma; PI3K/AKT pathway; ZIP10/SLC39A10.

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