Acquired resistance is a barrier to cetuximab efficacy in patients with head and neck squamous cell carcinoma (HNSCC). Secreted phosphoprotein 1 (SPP1) is involved in various biological processes, including immune responses, cancer progression, and prognosis in many cancers, while little is known in HNSCC. Bioinformatics methods were used to identify candidate genes and further in vivo and in vitro experiments were performed to examine and validate the function of SPP1. We found that SPP1 was upregulated and has been found to have an oncogenic role in HNSCC. We further confirmed that overexpression of SPP1 affected proliferation, migration, invasion, and survival, and inhibited apoptosis, whereas silencing of SPP1 yielded opposite results to those of SPP1 overexpression. In addition, activation of the KRAS/MEK pathway contributed to the SPP1‐induced malignant progression of HNSCC and resistance to cetuximab. Furthermore, SPP1 knockdown or an MEK inhibitor overcame this cetuximab‐resistance pattern. Taken together, our findings for the first time identify the role of SPP1 in tumor promotion, prognostic prediction, and potential therapeutic targeting, as well as resistance to cetuximab in HNSCC.

中文翻译：

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头颈癌中分泌的磷蛋白1的上调通过KRAS / MEK途径影响恶性进展，预后和对西妥昔单抗的耐药性。

获得性耐药是头颈部鳞状细胞癌（HNSCC）患者西妥昔单抗疗效的障碍。分泌的磷蛋白1（SPP1）参与多种生物学过程，包括免疫应答，癌症进展和许多癌症的预后，而HNSCC知之甚少。使用生物信息学方法鉴定候选基因，并进行进一步的体内和体外实验以检查和验证SPP1的功能。我们发现SPP1被上调，并且在HNSCC中具有致癌作用。我们进一步证实，SPP1的过表达影响增殖，迁移，侵袭和存活，并抑制细胞凋亡，而SPP1的沉默产生与SPP1的过表达相反的结果。此外，KRAS / MEK途径的激活促进了SPP1诱导的HNSCC恶性进展和对西妥昔单抗的耐药性。此外，SPP1抑制或MEK抑制剂克服了这种西妥昔单抗耐药模式。综上所述，我们的发现首次确定了SPP1在肿瘤促进，预后预测和潜在治疗靶点中的作用，以及对HNSCC中西妥昔单抗的耐药性。