CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer.
CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer.
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CTEN诱导肿瘤细胞侵袭、存活及放疗后头颈癌预后。
DOI：
10.3390/cancers12102963
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发表时间：
2020-10-13
期刊：
影响因子：
5.2
通讯作者：
Thomas GJ
中科院分区：
文献类型：
--
作者：
Fleming JC;Woo J;Moutasim K;Hanley CJ;Frampton SJ;Wood O;Ward M;Woelk CH;Ottensmeier CH;Hafizi S;Kim D;Thomas GJ
C-末端张力蛋白样（CTEN）是一种在头颈癌（HNSCC）中高度表达的细胞骨架蛋白。我们使用基因敲低研究了CTEN功能，发现CTEN以几种方式促进HNSCC进展，促进肿瘤细胞侵袭和细胞存活。值得注意的是，CTEN表达保护肿瘤细胞免受辐射诱导的细胞凋亡，并且与此一致，我们发现CTEN表达预测用放射疗法（而不是手术）治疗的患者的存活，这表明CTEN可能具有作为放射疗法抗性的预测标志物的效用。头颈部鳞状细胞癌（HNSCC）是一种通过手术和/或（化疗）放疗治疗的异质性疾病，但高达50%的晚期疾病患者会发生局部复发。确定治疗耐药的机制可以确定新的治疗靶点并有助于治疗选择。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通常在HNSCC中上调，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。体内稳定的CTEN的shRNA敲低显著降低了肿瘤生长（SCC-25），体外功能分析表明CTEN促进了肿瘤细胞侵袭、集落形成和3D培养中的生长（SCC-25，Detroit 562）。CTEN siRNA敲低后SCC-25细胞的RNA测序鉴定出349个差异表达的基因（logFC > 1，p < 0.05）。基因本体分析突出了与细胞运动和凋亡相关的术语，与体外研究结果一致。一种基于膜的抗体阵列证实，CTEN调节多种乳腺癌相关蛋白，包括HSP 60和裂解的caspase-3。值得注意的是，在HPV+ve和HPV−ve HNSCC患者（n = 259）的混合队列中，我们发现CTEN与预后存在显著的独立负相关性，仅限于接受（化疗）放疗而非手术治疗的患者，无论人乳头瘤病毒（HPV）状态如何。这些数据表明，CTEN通常在HNSCC中上调，并发挥几种功能作用。其在调节对治疗的凋亡反应中的潜在作用表明其作为预测性生物标志物或放射增敏靶点的效用。
C-terminal tensin-like, or CTEN, is a cytoskeletal protein that is expressed highly in head and neck cancer (HNSCC). We studied CTEN function using gene knockdown and found that CTEN contributes to HNSCC progression in several ways, promoting tumour cell invasion and also cell survival. Notably, CTEN expression protects tumour cells from radiation-induced apoptosis and consistent with this, we found that CTEN expression predicts for survival in patients treated with radiotherapy (but not surgery), suggesting that CTEN may have utility as a predictive marker of radiotherapy resistance. 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.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
6.2
作者：
Cracchiolo JR;Baxi SS;Morris LG;Ganly I;Patel SG;Cohen MA;Roman BR
通讯作者：
Roman BR
影响因子：
5.7
作者：
Blanchard, Pierre;Baujat, Bertrand;Pignon, Jean-Pierre
通讯作者：
Pignon, Jean-Pierre
影响因子：
3.7
作者：
Chan, Lo-Kong;Ko, Frankie Chi Fat;Yam, Judy Wai Ping
通讯作者：
Yam, Judy Wai Ping
影响因子：
14.9
作者：
Chen J;Bardes EE;Aronow BJ;Jegga AG
通讯作者：
Jegga AG