CCR9 initiates epithelial\u2013mesenchymal transition by activating Wnt/\u03b2-catenin pathways to promote osteosarcoma metastasis

Haoran Kong,Haonan Li,Guiwen Ye,Zhuning Chen,Jiacong Hong,Yanfeng Wu,Keng Chen,Wenhui Yu,Zhongyu Xie,Huiyong Shen

doi:10.1186/s12935-021-02320-0

Abstract

BackgroundOsteosarcoma (OS) patients with lung metastasis have poor prognoses, and effective therapeutic strategies for delaying or inhibiting the spread of lung metastasis from the primary OS site are lacking. Hence, it is critical to elucidate the underlying mechanisms of OS metastasis and to identify additional new effective treatment strategies for patients.MethodsDifferential expression and functional analyses were performed to identify key genes and relevant signaling pathways associated with OS lung metastasis. The expression of CCR9 in OS cell lines and tissues was measured by RT-qPCR, western blotting and immunohistochemistry. Cell migration and invasion were assessed by wound healing and Transwell Matrigel invasion assays, respectively. The regulatory relationship between CCR9 and the Wnt/β-catenin signaling pathway was further evaluated by rescue experiments.ResultsThe expression of CCR9 was elevated in OS cell lines and patients with lung metastasis. CCR9 promoted MG63 and HOS cell migration and invasion by activating the Wnt/β-catenin signaling pathway. Furthermore, knockdown of CCR9 repressed epithelial–mesenchymal transition (EMT) by downregulating mesenchymal markers (N-cadherin and Vimentin) and EMT-associated transcription factors (twist and snail) and upregulating an epithelial marker (E-cadherin).ConclusionsOur findings suggest that CCR9 promotes EMT by activating Wnt/β-catenin pathways to promote OS metastasis. CCR9 may be a promising therapeutic target to inhibit lung metastasis and serve as a novel prognostic marker for OS.

Highlights

Osteosarcoma (OS) patients with lung metastasis have poor prognoses, and effective therapeutic strategies for delaying or inhibiting the spread of lung metastasis from the primary OS site are lacking
To explore the functional roles of the above differentially expressed genes (DEGs), we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. These DEGs were enriched in biological process (BP), molecular function (MF), and cellular component (CC) terms
The threshold for the X axis was Log2fc ≥ 1 and Log2fc ≤ -1, and the threshold for the Y axis was P-value < 0.05. b GO enrichment analysis of DEGs revealed enriched biological process terms. c GO enrichment analysis of DEGs revealed enriched cellular component terms. d GO enrichment analysis of DEGs revealed enriched molecular function terms. e Top 5 enriched terms in the BP, MF and CC categories. f The top ten KEGG signaling pathways (KEGG analysis) enriched with the DEGs category, these DEGs were enriched in the terms immune response, G-protein coupled receptor signaling pathway, heterophilic cell–cell adhesion via plasma membrane cell adhesion molecules, cell surface receptor signaling pathway and chemotaxis (Fig. 1b)

Summary

Introduction

Osteosarcoma (OS) patients with lung metastasis have poor prognoses, and effective therapeutic strategies for delaying or inhibiting the spread of lung metastasis from the primary OS site are lacking. The most commonly used chemotherapy drugs in OS treatment are doxorubicin, cisplatin and methotrexate [5]. These treatments have greatly increased the survival rate of OS patients without metastasis over the past forty years [6]. Lung metastasis is the primary challenge for OS therapy, but effective therapeutic strategies for delaying or inhibiting the spread of lung metastasis from the primary OS site are lacking. It is critical to elucidate the underlying mechanisms of OS metastasis and to identify additional new effective treatment strategies for patients

Methods

Results

Discussion

Conclusion