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Abstract：
Oral squamous cell carcinoma (OSCC) is a cancer associated with high mortality (accounting for 3.1/100,000 deaths per year in Brazil in 2013) and a high frequency of amplification in the expression of the epidermal growth factor receptor (EGFR). Treatment with the EGFR inhibitor cetuximab leads to drug resistance in patients with OSCC due to unknown mechanisms. Galectin‑3 (Gal‑3) is a β‑galactoside binding lectin that regulates multiple signaling pathways in cells. The present study aimed to investigate the effect of Gal‑3 in cetuximab‑resistant (cet‑R) OSCC. The OSCC HSC3 cell line was selected to establish a mouse xenograft model, which was treated with cetuximab to induce resistance. Subsequently, a Gal‑3 inhibitor was used to treat cet‑R tumors, and the tumor volume was monitored. The expression of Gal‑3, phosphorylated (p)‑ERK1/2 and p‑Akt was assessed using immunohistochemistry. The combined effect of cetuximab and the Gal‑3 inhibitor on HSC3 tumor xenografts was also investigated. HSC3 cells were cultured in vitro to investigate the regulatory effects of Gal‑3 on ERK1/2 and Akt via western blotting. In addition, the effects of the Gal‑3 inhibitor on the proliferation, colony formation, invasion and apoptosis of HSC3 cells were investigated by performing Cell Counting Kit‑8, colony formation, Transwell and apoptosis assays, respectively. In cet‑R OSCC tumors, increased expression of Gal‑3, p‑ERK1/2 and p‑Akt was observed. Further research demonstrated that Gal‑3 regulated the expression of both ERK1/2 and Akt in HSC3 cells by promoting phosphorylation. Moreover, the Gal‑3 inhibitor decreased the proliferation and invasion, but increased the apoptosis of cet‑R HSC3 cells. In addition, the Gal‑3 inhibitor suppressed the growth of cet‑R tumors. Collectively, the results indicated that the Gal‑3 inhibitor and cetuximab displayed a synergistic inhibitory effect on OSCC tumors. In summary, the present study demonstrated that Gal‑3 may serve an important role in cet‑R OSCC. The combination of cetuximab and the Gal‑3 inhibitor may display a synergistic antitumor effect, thereby inhibiting the development of cetuximab resistance in OSCC.
摘要：
口腔鳞状细胞癌（OSCC）是一种与高死亡率（2013年巴西每年死亡3.1/100,000）和表皮生长因子受体（EGFR）表达扩增频率高的癌症。EGFR抑制剂西妥昔单抗治疗由于未知的机制导致OSCC患者的耐药性。半乳糖凝集素-3（Gal-3）是一种β-半乳糖苷结合凝集素，可调节细胞中的多种信号通路。本研究旨在研究Gal‑3在西妥昔单抗耐药（cet‑R）OSCC中的作用。选择OSCCHSC3细胞系建立小鼠异种移植模型,用西妥昔单抗治疗以诱导耐药性。随后，Gal‑3抑制剂用于治疗cet‑R肿瘤，并监测肿瘤体积。使用免疫组织化学评估Gal‑3，磷酸化（p）‑ERK1/2和p‑Akt的表达。还研究了西妥昔单抗和Gal‑3抑制剂对HSC3肿瘤异种移植物的联合作用。体外培养HSC3细胞，通过蛋白质印迹法研究Gal‑3对ERK1/2和Akt的调节作用。此外,Gal‑3抑制剂对增殖的影响，菌落形成,HSC3细胞的侵袭和凋亡通过进行细胞计数试剂盒-8，集落形成，Transwell和细胞凋亡测定，分别。在cet‑ROSCC肿瘤中，观察到Gal‑3、p‑ERK1/2和p‑Akt的表达增加。进一步的研究表明，Gal‑3通过促进磷酸化调节HSC3细胞中ERK1/2和Akt的表达。此外，Gal‑3抑制剂降低了增殖和侵袭，但增加了cet‑RHSC3细胞的凋亡。此外,Gal‑3抑制剂抑制cet‑R肿瘤的生长。总的来说，结果表明,Gal‑3抑制剂和西妥昔单抗对OSCC肿瘤具有协同抑制作用.总之,本研究表明，Gal-3可能在cet-ROSCC中起重要作用。西妥昔单抗和Gal‑3抑制剂的组合可能显示出协同抗肿瘤作用，从而抑制OSCC中西妥昔单抗耐药性的发展。
