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The Axin2-snail axis promotes bone invasion by activating cancer-associated fibroblasts in oral squamous cell carcinoma

 Yin-Zhe An  ;  Eunae Cho  ;  Junqi Ling  ;  Xianglan Zhang 
 BMC CANCER, Vol.20(1) : 987, 2020-10 
Journal Title
Issue Date
Axin2 ; Bone invasion ; CAFs ; Cancer-stroma crosstalk ; Cytokine ; OSCC ; Prognosis ; Snail
Background: In bone-invasive oral squamous cell carcinoma (OSCC), cancer-associated fibroblasts (CAFs) infiltrate into bony tissue ahead of OSCC cells. In the present study, we aimed to investigate the role of the Axin2-Snail axis in the biological behaviour of CAFs and bone invasion in OSCC. Methods: The clinicopathological significance of Axin2 and Snail expression was investigated by immunohistochemistry in an OSCC cohort containing 217 tissue samples from patients with long-term follow-up. The influence of the Axin2-Snail axis on the biological behaviour of OSCC cells and CAFs was further investigated both in vitro and in vivo. Results: Axin2 expression was significantly associated with Snail expression, the desmoplasia status, and bone invasion in patients with OSCC. In multivariate analysis, lymph node metastasis, desmoplasia, Axin2 expression, and Snail expression were independent poor prognostic factors in our cohort. Consistent with these findings, OSCC cells demonstrated attenuated oncogenic activity as well as decreased expression of Snail and various cytokines after Axin2 knockdown in vitro. Among the related cytokines, C-C motif chemokine ligand 5 (CCL5) and interleukin 8 (IL8) demonstrated a strong influence on the biological behaviour of CAFs in vitro. Moreover, both the desmoplastic reaction and osteolytic lesions in the calvaria were predominantly decreased after Axin2 knockdown in OSCC cells in vivo using a BALB/c athymic nude mouse xenograft model. Conclusions: Oncogenic activities of the Axin2-Snail axis are not limited to the cancer cells themselves but rather extend to CAFs via regulation of the cytokine-mediated cancer-stromal interaction, with further implications for bone invasion as well as a poor prognosis in OSCC.
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2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Research Institute (부설연구소) > 1. Journal Papers
Yonsei Authors
Zhang, Xiang Lan(장향란)
Cho, Eunae(조은애산드라) ORCID logo https://orcid.org/0000-0002-0820-3019
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