Background/Objectives:During the repair of a wounded epithelium, keratinocytes become invasive via the epithelial-to-mesenchymal transition (EMT) process. Usually temporary and controlled, EMT persists in a chronically inflamed epithelium and is exacerbated in epithelial dysplasia and dysregulated in invasive carcinomas. Here we investigated the effects that IL-1 beta, IL-6, and IL-8, inflammatory cytokines expressed in specimens from OPMDs and OSCCs, have on NOKs and OSCC cells. Methods: AKT activation and EMT induction were assessed along with cellular invasiveness.Results:IL-1 beta, IL-6, and IL-8 induced EMT in NOKs, ex novo conferring them invasive capacity. The same cytokines exacerbated the constitutive EMT and invasiveness of OSCC cells. Since these phenomena were accompanied by AKT activation, we tested whether they could be influenced by RTV, a long-used anti-HIV drug that was previously found to block the activation of human AKT and exert antitumor effects. We observed that therapeutic amounts of RTV counteract all the above-mentioned tumorigenic activities of ILs. Finally, consistent with the key role that AKT and EMT play in OSCC radio-resistance, RTV increased OSCC cells’ sensitivity to therapeutic doses of ionizing radiation.Conclusions:These preliminary in vitro findings encourage the use of RTV to prevent the malignant evolution of OPMDs, reduce the risk of OSCC metastasis, and improve the outcomes of anti-OSCC radiotherapy.
背景/目的：在受损上皮修复过程中，角质形成细胞通过上皮-间质转化（EMT）过程获得侵袭性。EMT通常具有暂时性和可控性，但在慢性炎症上皮中持续存在，在上皮异型增生中加剧，并在侵袭性癌中失调。本研究探讨了在口腔潜在恶性病变（OPMDs）和口腔鳞状细胞癌（OSCCs）标本中表达的炎症因子IL-1β、IL-6和IL-8对正常口腔角质形成细胞（NOKs）及OSCC细胞的影响。方法：通过评估AKT活化、EMT诱导及细胞侵袭性进行分析。结果：IL-1β、IL-6和IL-8可诱导NOKs发生EMT，并使其获得侵袭能力。相同细胞因子能加剧OSCC细胞固有的EMT表型及侵袭性。由于这些现象均伴随AKT活化，我们测试了抗HIV药物利托那韦（RTV）的干预效果——该药物既往研究显示可阻断人AKT活化并发挥抗肿瘤作用。实验观察到治疗浓度的RTV能拮抗上述所有ILs介导的致瘤活性。最后，基于AKT和EMT在OSCC放射抵抗中的关键作用，RTV可增强OSCC细胞对治疗剂量电离辐射的敏感性。结论：这些初步体外研究结果支持将RTV用于预防OPMDs恶性进展、降低OSCC转移风险，并提升抗OSCC放疗疗效。
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