目的:β2-肾上腺素受体(β2-AR)和环氧合酶-2(COX-2)在各种恶性肿瘤中过度表达,包括口腔鳞状细胞癌(OSCC)。这表明它们可能有助于OSCC的发展。本研究旨在探讨β2-AR阻断和COX-2抑制对OSCC发展的潜在协同作用。
方法:用创伤愈合试验和transwell侵袭试验检测阻断β2-AR和抑制COX-2对OSCC细胞迁移和侵袭的影响。采用Westernblot和酶联免疫吸附试验(ELISA)检测OSCC进展相关基因的表达。在体内,建立OSCC异种移植模型,评价联合治疗对存活时间的影响,肿瘤大小,颌下淋巴结转移。免疫组织化学,蛋白质印迹,ELISA法检测侵袭转移相关基因的表达。
结果:体外,阻断β2-AR或单独抑制COX-2可以抑制OSCC细胞的侵袭和转移,抑制与联合治疗更为显著。侵袭和转移相关基因的表达,包括EGFR,TGF-β1,IL-1β,MMP2和VEGFA,大幅下调,尤其是联合治疗组。在体内,联合治疗可显着延长荷瘤小鼠的生存时间并抑制肿瘤的生长。此外,联合治疗组颌下淋巴结转移较少,并且上述基因的表达也被下调。
结论:β2-AR阻断和COX-2抑制联合应用可通过下调EGFR显著抑制OSCC的发展,TGF-β1,IL-1β,MMP2和VEGFA。研究结果表明,β2-AR阻滞剂和COX-2抑制剂的联合使用可能是OSCC的有希望的辅助疗法。这两种药物都是常用的,它们的安全性和有效性是公认的。因此,应在临床实践中推广其在OSCC佐剂中的使用。
OBJECTIVE: β2-adrenergic receptor (β2-AR) and cyclooxygenase-2 (COX-2) are overexpressed in various malignant tumours including oral squamous cell carcinoma (OSCC), suggesting that they may contribute to the development of OSCC. This study aims to investigate the potential synergistic effect of β2-AR blockade and COX-2 inhibition on suppressing the development of OSCC.
METHODS: Effects of blocking β2-AR and inhibiting COX-2 on migration and invasion of OSCC cells were detected by wound-healing assay and transwell invasion assay. Western blot and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of genes related to the progression of OSCC. In vivo, OSCC xenograft models were established to evaluate the effect of combined treatment on survival time, tumour size, and submandibular lymph node metastasis. Immunohistochemistry, Western blot, and ELISA were used to detect the expression of invasion and metastasis relative genes.
RESULTS: In vitro, blocking β2-AR or inhibiting COX-2 alone could suppress invasion and metastasis of OSCC cells, and suppression with combined treatment was more significant. Expression of genes related to invasion and metastasis, including EGFR, TGF-β1, IL-1β, MMP2, and VEGFA, were downregulated significantly, especially in the combined treatment group. In vivo, the combined treatment could significantly prolong survival time in tumour-bearing mice and inhibit the growth of tumours. Furthermore, submandibular lymph node metastasis was less in the combined treatment group, and expression of the abovementioned genes was also downregulated.
CONCLUSIONS: The combination of β2-AR blockade and COX-2 inhibition can significantly suppress the development of OSCC via downregulating EGFR, TGF-β1, IL-1β, MMP2, and VEGFA. Findings suggest that the combined use of a β2-AR blocker and a COX-2 inhibitor could be a promising adjuvant therapy in OSCC. Both drugs are commonly prescribed, and their safety and efficacy are well established. Their use in adjuvants in OSCC should therefore be promoted in clinical practice.