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

BMC Cancer

Eunae Cho¹  Yin-Zhe An²  Junqi Ling³  Xianglan Zhang⁴ 

[1] Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea;BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, South Korea;Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea;Key laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;Key laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China;Department of Endodontics, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, 56 Lingyuanxi Road, 510055, Guangzhou, Guangdong, China;Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea;Department of Pathology, Yanbian University Hospital, 133000, Yanji City, Jilin Province, China;

关键词: Axin2;    Snail;    Cytokine;    Cancer-stroma crosstalk;    CAFs;    Bone invasion;    Prognosis;    OSCC;   

DOI  :  10.1186/s12885-020-07495-9

来源: Springer

【 摘 要 】

BackgroundIn 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.MethodsThe 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.ResultsAxin2 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.ConclusionsOncogenic 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.

【 授权许可】

CC BY