IL-22/IL-22RA1通路在口腔鳞状细胞癌恶性进展中的作用及其机制

目的：探讨IL-22/IL-22受体A1（IL-22RA1）通路在口腔鳞状细胞癌（OSCC）恶性进展中的作用及其机制。方法：利用GEO数据库和免疫组化法分析IL-22RA1在OSCC组织及配对癌旁组织中的表达水平，采用组织芯片免疫组化法检测并分析IL-22RA1表达水平与OSCC患者临床病理特征的关系，通过EBI ArrayExpress数据库分析IL-22RA1表达水平与患者预后的关系。采用免疫荧光法检测IL-22和IL-22RA1在OSCC组织中表达水平并分析两者间的相关性。用RNA干扰技术敲减OSCC细胞WSU-HN4和CAL27的IL-22RA1表达，用qPCR法验证敲减效率。采用克隆形成实验、Transwell小室法分别检测IL-22对阴性对照（siNC）组和IL-22RA1敲减（siIL-22RA1）组OSCC 细胞克隆形成及迁移能力的影响，WB法检测IL-22 对OSCC细胞IL-22RA1表达水平及STAT1、STAT3和ERK1/2磷酸化水平的影响。结果：OSCC组织中IL-22RA1 mRNA的表达水平显著高于癌旁组织（P<0.05）。IL-22RA1表达水平与OSCC患者的肿瘤大小（P<0.05）、淋巴结转移（P<0.01）及预后不良（P<0.05）有关联。OSCC组织中的IL-22和IL-22RA1表达水平无明显关联，IL-22对OSCC细胞IL-22RA1表达无影响（均P>0.05）。IL-22可显著增强OSCC细胞的克隆形成和迁移能力（均P<0.01），并可激活OSCC细胞的STAT1、STAT3及ERK1/2 信号分子；敲减OSCC 细胞的IL-22RA1后，IL-22则无法发挥上述作用。结论：IL-22/IL-22RA1可通过调控细胞增殖和迁移促进OSCC的生长和转移，其下游机制可能是激活ERK1/2-STAT1/3信号通路。

Role of IL-22/IL-22RA1 pathway in the malignant progression of oral squamous carcinoma and its mechanism

Objective: To investigate the role of IL-22/IL-22RA1 (IL-22 receptor A1) pathway in the malignant progression of oral squamous cell carcinoma (OSCC) and the underlying mechanisms. Methods: The expression levels of IL-22RA1 in OSCC tissues and paired para-cancerous tissues were analyzed using the GEO database and immunohistochemistry. The association between IL-22RA1 expression and the clinicopathological characteristics of OSCC patients was detected and analyzed by tissue microarray immunohistochemistry. The relationship between IL-22RA1 expression and the prognosis of OSCC patients was analyzed using the EBI ArrayExpress database. The expression of IL-22 and IL-22RA1 in OSCC tissues was examined by immunofluorescence, and their association was also analyzed. IL-22RA1 expression was knocked down in OSCC WSU-HN4 and CAL27 cells by RNA interference technology, and the efficiency was verified using qPCR. The effects of IL-22 on the colonogenesis and migration of OSCC cells in the negative control (siNC) group and IL-22RA1 knock-down (siIL-22RA1) group were determined by plate cloning and transwell assays, respectively. The effects of IL-22 on the expression of IL-22RA1 and the phosphorylation level of STAT1, STAT3 and ERK1/2 in OSCC cells were detected using the WB assay. Results: The mRNA expression of IL-22RA1 in OSCC tissues was significantly higher than that in para-cancerous tissues (P<0.05). The expression of IL-22RA1 was associated with tumor size (P<0.05), lymph node metastasis (P<0.01), and poor prognosis (P<0.05) of OSCC patients. There was no significant correlation between the expression levels of IL-22 and IL-22RA1 in OSCC tissues, and IL-22 did not affect on the expression level of IL-22RA1 in OSCC cells (all P>0.05). IL-22 significantly enhanced the colony formation and migration abilities (all P<0.01) of OSCC cells, and activated STAT1, STAT3 and ERK1/2 signals in OSCC cells. After knocking down IL-22RA1 in OSCC cells, IL-22 could not exert the above effects. Conclusion: IL-22/IL-22RA1 can promote the growth and metastasis of OSCC by regulating cell proliferation and migration, and the downstream mechanism may be the activation of ERK1/2-STAT1/3 signaling pathway.