Oral Cancer Research Center, Changhua Christian Hospital, Changhua 500, Taiwan, R.O.C.
Department of Otorhinolaryngology‑Head and Neck Surgery, Changhua Christian Hospital, Changhua 500, Taiwan, R.O.C.
Int J Oncol. 2019 Oct;55(4):949-959. doi: 10.3892/ijo.2019.4866. Epub 2019 Aug 30.
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer. Despite advances in surgery, radiotherapy and chemotherapy, the overall 5‑year survival rate of patients with OSCC has not significantly improved. In addition, the prognosis of patients with advanced‑stage OSCC remains poor. Therefore, it is necessary to develop novel therapeutic modalities. Vincristine (VCR), a naturally occurring vinca alkaloid, is a classical microtubule‑destabilizing agent and is widely used in the treatment of a number of cancers. Despite the proven antitumor benefits of VCR treatment, one of the major reasons for the failure of treatment is drug resistance. Changes in the tumor microenvironment are responsible for cross‑talk between cells, which may facilitate drug resistance in cancers; secreted proteins may promote communication between cancer cells to induce the development of resistance. To identify the secreted proteins involved in VCR resistance, conditioned media was obtained, and an antibody array was conducted to screen a comprehensive secretion profile between VCR‑resistant (SAS‑VCR) and parental (SAS) OSCC cell lines. The results showed that amphiregulin (AREG) was highly expressed and secreted in SAS‑VCR cells. Pretreatment with exogenous recombinant AREG markedly increased drug resistance against VCR in OSCC cells, as assessed by an MTT assay. Colony formation, MTT and western blot assays were performed to investigate the effects of AREG knockdown on VCR sensitivity. The results indicated that AREG expression can regulate VCR resistance in OSCC cells; overexpression of AREG increased VCR resistance in parental cells, whereas AREG knockdown decreased the VCR resistance of resistant cells. In addition, it was also demonstrated that the glycogen synthase kinase‑3β pathway may be involved in AREG‑induced VCR resistance. These findings may provide rationale to combine VCR with blockade of AREG‑related pathways for the effective treatment of OSCC.
口腔鳞状细胞癌（OSCC）是最常见的口腔癌类型。尽管手术、放疗和化疗方面取得了进展，但 OSCC 患者的总体 5 年生存率并未显著提高。此外，晚期 OSCC 患者的预后仍然较差。因此，有必要开发新的治疗方法。长春新碱（VCR）是一种天然的长春花生物碱，是一种经典的微管不稳定药物，广泛用于治疗多种癌症。尽管 VCR 治疗具有已证实的抗肿瘤益处，但治疗失败的主要原因之一是耐药性。肿瘤微环境的变化负责细胞间的串扰，这可能促进癌症中的耐药性；分泌的蛋白质可能促进癌细胞之间的通讯，从而诱导耐药性的发展。为了鉴定与 VCR 耐药相关的分泌蛋白，获得了条件培养基，并进行了抗体阵列筛选，以筛选 VCR 耐药（SAS-VCR）和亲本（SAS）OSCC 细胞系之间的综合分泌谱。结果表明，在 SAS-VCR 细胞中， Amphiregulin（AREG）高度表达并分泌。通过 MTT 测定评估，外源性重组 AREG 预处理可显著增加 OSCC 细胞对 VCR 的耐药性。进行集落形成、MTT 和 Western blot 测定以研究 AREG 敲低对 VCR 敏感性的影响。结果表明，AREG 表达可以调节 OSCC 细胞中的 VCR 耐药性；AREG 的过表达增加了亲本细胞对 VCR 的耐药性，而 AREG 敲低降低了耐药细胞对 VCR 的耐药性。此外，还表明糖原合酶激酶-3β通路可能参与 AREG 诱导的 VCR 耐药性。这些发现可能为将 VCR 与阻断 AREG 相关途径联合用于有效治疗 OSCC 提供依据。
