Menzies Health Institute Queensland, School of Dentistry and Oral Health, Griffith University, Southport, Queensland, Australia; Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia.
Menzies Health Institute Queensland, School of Medical Science, Griffith University, Southport, Queensland, Australia; Department of Clinical Laboratory, Kaifeng Central Hospital, Kaifeng City, China.
Oral Oncol. 2018 Nov;86:105-112. doi: 10.1016/j.oraloncology.2018.09.006. Epub 2018 Sep 19.
Human papilloma virus (HPV) is the main culprit in cancers of the cervix, penis, anus, skin, eye and head and neck. Current treatments for HPV cancers have not altered survival outcomes for 30 years and there is a significant lack of targeted therapeutic agents in the management of advanced HPV-related HNSCC. Here we show that survival and maintenance of HPV-positive HNC cells relies on the continuous expression of the major HPV oncogene, E7, and that Aurora kinases are critical for survival of high-risk HPV-positive HNC cells.
To assess the role of HPV E7 on HNC cell survival, RNA interference (RNAi) of the E7 gene was initially performed. Using an Aurora kinase inhibitor, Alisertib, the role of Aurora kinases in the carcinogenesis of HPV E7 positive HNC tumour lines was then investigated. An in vivo HNC xenograft model was also utilised to assess loss of tumour volume in response to RNAi E7 gene silencing and Alisertib treatment.
RNAi silencing of the HPV E7 gene inhibited the growth of HPV-positive HNC cells and in vivo tumour load. We show that HPV E7 oncogene expression confers sensitivity to Alisertib on HNC cells where Alisertib-mediated loss in in vitro cell viability and in vivo tumour load is dependent on E7 expression. Moreover, Aurora kinase inhibition induced degradation of MCL-1 in HPV E7-expressing HNC cells.
Overall, we show that Aurora kinases are a novel therapeutic target for HPV-positive HNCs. It might be feasible to combine Aurora kinase and MCL-1 inhibitors for future HNC therapies.
人乳头瘤病毒（HPV）是宫颈癌、阴茎癌、肛门癌、皮肤癌、眼癌和头颈部癌症的主要元凶。目前，针对 HPV 癌症的治疗方法 30 年来并未改变生存结果，在管理晚期 HPV 相关的头颈部鳞状细胞癌（HNSCC）方面，靶向治疗药物明显缺乏。在这里，我们表明 HPV 阳性 HNC 细胞的存活和维持依赖于主要 HPV 癌基因 E7 的持续表达，并且 Aurora 激酶对于高危 HPV 阳性 HNC 细胞的存活至关重要。
为了评估 HPV E7 对 HNC 细胞存活的作用，最初进行了 E7 基因的 RNA 干扰（RNAi）。然后，使用 Aurora 激酶抑制剂 Alisertib，研究了 Aurora 激酶在 HPV E7 阳性 HNC 肿瘤细胞系致癌作用中的作用。还利用体内 HNC 异种移植模型来评估 RNAi E7 基因沉默和 Alisertib 治疗对肿瘤体积减少的作用。
HPV E7 基因的 RNAi 沉默抑制了 HPV 阳性 HNC 细胞的生长和体内肿瘤负荷。我们表明，HPV E7 癌基因表达使 HNC 细胞对 Alisertib 敏感，其中 Alisertib 介导的体外细胞活力丧失和体内肿瘤负荷降低依赖于 E7 表达。此外，Aurora 激酶抑制诱导 HPV E7 表达的 HNC 细胞中 MCL-1 的降解。
总体而言，我们表明 Aurora 激酶是 HPV 阳性 HNC 的一种新的治疗靶点。联合 Aurora 激酶和 MCL-1 抑制剂进行未来的 HNC 治疗可能是可行的。
