Axin2-蜗牛轴通过激活口腔鳞状细胞癌中的癌相关成纤维细胞促进骨侵袭。
The Axin2-snail axis promotes bone invasion by activating cancer-associated fibroblasts in oral squamous cell carcinoma.
机构信息
Key laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, Republic of Korea.
出版信息
BMC Cancer. 2020 Oct 12;20(1):987. doi: 10.1186/s12885-020-07495-9.
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.
背景
在骨侵袭性口腔鳞状细胞癌（OSCC）中，癌症相关成纤维细胞（CAFs）在 OSCC 细胞之前浸润到骨组织中。在本研究中，我们旨在研究 Axin2-Snail 轴在 CAFs 的生物学行为和 OSCC 骨侵袭中的作用。
方法
通过对包含 217 例长期随访患者组织样本的 OSCC 队列进行免疫组织化学分析，研究了 Axin2 和 Snail 表达的临床病理意义。进一步在体外和体内研究了 Axin2-Snail 轴对 OSCC 细胞和 CAFs 生物学行为的影响。
结果
Axin2 表达与 Snail 表达、间质状态和 OSCC 患者的骨侵袭显著相关。在多变量分析中，淋巴结转移、间质、Axin2 表达和 Snail 表达是我们队列中独立的不良预后因素。与这些发现一致的是，在体外 Axin2 敲低后，OSCC 细胞表现出减弱的致癌活性以及 Snail 和各种细胞因子的表达降低。在相关细胞因子中，C-C 基序趋化因子配体 5（CCL5）和白细胞介素 8（IL8）在体外对 CAFs 的生物学行为表现出强烈影响。此外，在 BALB/c 无胸腺裸鼠异种移植模型中，通过 Axin2 敲低 OSCC 细胞后，体内的间质反应和颅骨溶骨性病变均明显减少。
结论
Axin2-Snail 轴的致癌活性不仅限于癌细胞本身，而是通过调节细胞因子介导的肿瘤-间质相互作用扩展到 CAFs，这进一步影响了骨侵袭以及 OSCC 的不良预后。
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