探索EZH2通路用于口咽癌新的表观遗传治疗策略。
Investigation of EZH2 pathways for novel epigenetic treatment strategies in oropharyngeal cancer.
作者信息
Idris Sherif, Lindsay Cameron, Kostiuk Morris, Andrews Colin, Côté David W J, O'Connell Daniel A, Harris Jeffrey, Seikaly Hadi, Biron Vincent L
机构信息
Division of Otolaryngology-Head & Neck Surgery, Department of Surgery, University of Alberta, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.
Alberta Head & Neck Centre for Oncology and Reconstruction, 1E4 Walter Mackenzie Centre, 8440-112 Street NW, Edmonton, AB, Canada, T6G 2B7.
出版信息
J Otolaryngol Head Neck Surg. 2016 Oct 28;45(1):54. doi: 10.1186/s40463-016-0168-9.
BACKGROUND
In recent decades, the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rising worldwide as a result of increasing oncogenic human papillomavirus (HPV) infections in the oropharynx. EZH2 is an epigenetic regulatory protein associated with tumor aggressiveness and negative survival outcomes in several human cancers. We aimed to determine the role of EZH2 as a potential therapeutic epigenetic target in HPV-positive and negative OPSCC.
METHODS
The expression of EZH2 was measured by immunohistochemistry (IHC) and droplet digital PCR (ddPCR) in 2 HPV-positive and 2 HPV-negative cell lines. The cell lines were then cultured and treated with one of 3 EZH2 epigenetic inhibitors (3-deazaneplanocin A, GSK-343 and EPZ005687) or DMSO (control). Following 2, 4 and 7 days of treatment, cells were analyzed and compared by gene expression, cell survival and proliferation assays.
RESULTS
EZH2 targeting resulted in greater inhibition of growth and survival in HPV-positive compared to HPV-negative cells lines. The expression profile of genes important in OPSCC also differed according to HPV-positivity for Ki67, CCND1, MET and PTEN/PIK3CA, but remained unchanged for EGFR, CDKN2A and p53.
CONCLUSION
Inhibition of EZH2 has anti-tumorigenic effects on OPSCC cells in culture that is more pronounced in HPV-positive cell lines. EZH2 is a promising epigenetic target for the treatment of OPSCC.
背景
近几十年来，由于口咽中致癌性人乳头瘤病毒（HPV）感染增加，口咽鳞状细胞癌（OPSCC）的发病率在全球范围内呈上升趋势。EZH2是一种表观遗传调节蛋白，与几种人类癌症的肿瘤侵袭性和不良生存结果相关。我们旨在确定EZH2作为HPV阳性和阴性OPSCC潜在治疗性表观遗传靶点的作用。
方法
通过免疫组织化学（IHC）和液滴数字PCR（ddPCR）检测2种HPV阳性和2种HPV阴性细胞系中EZH2的表达。然后将细胞系培养并用3种EZH2表观遗传抑制剂（3-去氮杂胞苷A、GSK-343和EPZ005687）之一或二甲基亚砜（对照）处理。处理2、4和7天后，通过基因表达、细胞存活和增殖试验对细胞进行分析和比较。
结果
与HPV阴性细胞系相比，靶向EZH2对HPV阳性细胞系的生长和存活抑制作用更大。在OPSCC中重要的基因表达谱也因HPV状态而异，Ki67、CCND1、MET和PTEN/PIK3CA有所不同，但EGFR、CDKN2A和p53保持不变。
结论
抑制EZH2对培养的OPSCC细胞具有抗肿瘤作用，在HPV阳性细胞系中更为明显。EZH2是治疗OPSCC的一个有前景的表观遗传靶点。
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