The Axin2-snail axis promotes bone invasion by activating cancer-associated fibroblasts in oral squamous cell carcinoma
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RESEARCH ARTICLE
Open Access
The Axin2-snail axis promotes bone invasion by activating cancer-associated fibroblasts in oral squamous cell carcinoma Yin-Zhe An1†, Eunae Cho2,3,4†, Junqi Ling1,5* and Xianglan Zhang4,6*
Abstract 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. Keywords: Axin2, Snail, Cytokine, Cancer-stroma crosstalk, CAFs, Bone invasion, Prognosis, OSCC
Background Oral squamous cell carcinoma (OSCC) is the most common histological type of oral cancer. OSCC cells often penetrate underlying bone, and 12–56% of patients with * Correspondence: [email protected]; [email protected] † Yin-Zhe An and Eunae Cho contributed equally to this work. 1 Key laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China 4 Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Republic of Korea Full list of author information is available at the end of the article
OSCC present with bone invasion [1]. According to the American Joint Committee on Cancer (AJCC) classification, the presence of bone invasion can upstage this type of cancer regardless of tumour size because bone invasion is a major poor prognostic indicator of OSCC [2–4]. However, the molecular mechanism underlying the invasion of adj
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