头颈部鳞状细胞癌(HNSCC)是一种通过手术和/或(化学)放射疗法治疗的异质性疾病,但高达50%的晚期疾病患者会出现局部复发.确定支持治疗抗性的机制可以识别新的治疗靶标并帮助治疗选择。C末端张力蛋白样(CTEN)是张力蛋白家族的成员,在几种癌症中上调,尽管其在HNSCC中的表达和功能尚不清楚。我们发现CTEN在HNSCC中通常上调,特别是HPV-ve肿瘤。体外CTEN在HPV-ve(n=5)和HPV+ve(n=2)HNSCC细胞系中上调。体内CTEN的稳定shRNA敲除显着降低了肿瘤生长(SCC-25),体外功能分析显示,CTEN促进肿瘤细胞侵袭,在3D培养中的菌落形成和生长(SCC-25,Detroit562)。CTENsiRNA敲低后SCC-25细胞的RNA测序鉴定出349个差异表达基因(logFC>1,p<0.05)。基因本体论分析强调了与细胞运动和凋亡相关的术语,与体外研究结果一致。基于膜的抗体阵列证实,CTEN调节多种凋亡相关蛋白,包括HSP60和裂解的caspase-3。值得注意的是,在HPV+ve和HPV-veHNSCC患者的混合队列中(n=259),我们发现了一个重要的,CTEN与预后的独立负相关,仅限于接受(化学)放射治疗的患者,不是手术,与人乳头瘤病毒(HPV)状态无关。这些数据表明,CTEN通常在HNSCC中上调并发挥多种功能作用。其在调节对治疗的凋亡反应中的潜在作用表明作为预测性生物标志物或放射增敏靶标的用途。
Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease treated with surgery and/or (chemo) radiotherapy, but up to 50% of patients with late-stage disease develop locoregional recurrence. Determining the mechanisms underpinning treatment resistance could identify new therapeutic targets and aid treatment selection. C-terminal
tensin-like (CTEN) is a member of the
tensin family, upregulated in several cancers, although its expression and function in HNSCC are unknown. We found that CTEN is commonly upregulated in HNSCC, particularly HPV-ve tumours. In vitro CTEN was upregulated in HPV-ve (n = 5) and HPV+ve (n = 2) HNSCC cell lines. Stable shRNA knockdown of CTEN in vivo significantly reduced tumour growth (SCC-25), and functional analyses in vitro showed that CTEN promoted tumour cell invasion, colony formation and growth in 3D-culture (SCC-25, Detroit 562). RNA sequencing of SCC-25 cells following CTEN siRNA knockdown identified 349 differentially expressed genes (logFC > 1, p < 0.05). Gene ontology analysis highlighted terms relating to cell locomotion and apoptosis, consistent with in vitro findings. A membrane-based antibody array confirmed that CTEN regulated multiple apoptosis-associated proteins, including HSP60 and cleaved caspase-3. Notably, in a mixed cohort of HPV+ve and HPV-ve HNSCC patients (n = 259), we found a significant, independent negative association of CTEN with prognosis, limited to those patients treated with (chemo)radiotherapy, not surgery, irrespective of human papillomavirus (HPV) status. These data show that CTEN is commonly upregulated in HNSCC and exerts several functional effects. Its potential role in modulating apoptotic response to therapy suggests utility as a predictive biomarker or radio-sensitising target.