华西口腔医学杂志 ›› 2018, Vol. 36 ›› Issue (5): 544-551.doi: 10.7518/hxkq.2018.05.015
收稿日期:
2018-04-20
修回日期:
2018-07-24
出版日期:
2018-10-01
发布日期:
2018-10-18
作者简介:
崔广学,主任医师,硕士,E-mail: 基金资助:
Guang-xue Cui1(),Xiaolei Gao2,Xinhua Liang2(
)
Received:
2018-04-20
Revised:
2018-07-24
Online:
2018-10-01
Published:
2018-10-18
Supported by:
摘要:
人乳头瘤病毒(HPV)是头颈部鳞状细胞癌(HNSCC)的主要致病因素之一,HPV感染与HNSCC的侵袭转移存在密切关系。本文对HPV相关性头颈部鳞状细胞癌基因变异、HPV致癌蛋白E6、E7通过众多复杂细胞元件相互作用的特异性致癌机制进行了阐述,并进一步讨论了HPV阳性HNSCC侵袭转移相关的分子机制,包括非编码RNAs、肿瘤细胞的能量代谢紊乱、肿瘤细胞微环境、肿瘤干细胞、肿瘤血管生成及淋巴管生成的研究进展。
中图分类号:
崔广学,高晓磊,梁新华. 人乳头瘤病毒相关头颈部鳞状细胞癌侵袭转移的分子机制[J]. 华西口腔医学杂志, 2018, 36(5): 544-551.
Guang-xue Cui,Xiaolei Gao,Xinhua Liang. Invasion and metastasis mechanism of human papillomavirus in head and neck squamous cell carcinomas[J]. West China Journal of Stomatology, 2018, 36(5): 544-551.
表 1
HPV相关体细胞基因突变率
基因名称 | 突变发生率/% | |
---|---|---|
简称 | 全称 | |
pik3ca | 磷脂酰肌醇-3-激酶催化亚单位α基因(phosphatidylinosital-4,5-bisphosphate3-kinase, catalytic | 22~56 |
subunit alpha) | ||
traf3 | 肿瘤坏死因子受体相关因子3(tumor necrosis factor receptor-associated factor 3) | 22 |
tp63 | 肿瘤蛋白63(tumor protein p63) | 28 |
fgfr3 | 成纤维细胞生长因子受体3(fibroblast growth factor receptor 3) | 11~14 |
mll3 | 赖氨酸特异性甲基转移酶2C[lysine(K)-specific methyltransferase 2C] | 10 |
mll2 | 赖氨酸特异性甲基转移酶2B[lysine(K)-specific methyltransferase 2B] | 10 |
flg | 丝聚合蛋白(filaggrin) | 12 |
notch1 | notch 1 | 8~17 |
ddx3x | dead-box RNA解旋酶[DEAD (Asp-Glu-Ala-Asp) box helicase 3, X-linked] | 8 |
k-ras | kirsten rat sarcoma viral oncogene homolog | 6 |
cyld | 肿瘤抑制因子[cylindromatosis(turban tumor syndrome)] | 6 |
egfr | 表皮生长因子受体(epidermal growth factor receptor) | 6 |
pten | 编码与张力蛋白和辅助蛋白同源的磷酸酶和抑癌基因(phosphatase and tensin homolog) | 6 |
ddr2 | 盘状结构域受体(discoidin domain receptor 2) | 2~6 |
表 2
与HPV E6致癌蛋白相互作用细胞元件及产生的生物学效应
E6相互作用元件 | 生物学效应 |
---|---|
具有PDZ结构域的蛋白 | 降解具有PDZ(PSD-95、DLG、ZO-1的3个蛋白质的缩写)结构域的蛋白,导致细胞结构和极性丧失 |
E6AP | 降解p53;激活人端粒酶催化亚单位(human telomerase reversetranscriptase,hTERT)转录,诱导细胞永生化 |
Bak、FADD、Procaspase 8 | 诱导经典蛋白质降解,抑制细胞凋亡 |
BRCA1 | 激活雌激素受体信号通路 |
Tyk2 | 抑制Tyk2活性,从而抑制干扰素(interferons,IFN)诱导的信号通路 |
CBP/p300 | 通过cAMP反应元件结合蛋白(CREB-binding protein,CBP)下调p53活性 |
NFX1-91 | 下调NFX1-91,激活hTERT |
c-Myc | 提高hTERT基因表达 |
Dvl2 | 稳定β-连环素(β-catenin)表达和Wnt信号通路的活性 |
表 3
与HPV E7致癌蛋白相互作用细胞元件及产生的生物学效应
E7相互作用元件 | 生物学效应 |
---|---|
pRb family proteins | 破坏pRb-E2F复合体,启动E2F介导的转录机制 |
AP1 | 转录活化AP1 family |
Cyclin A/CDK2 | 调控细胞周期 |
Cyclin E/CDK2 | 通过与p107结果调控细胞周期 |
p21 | 灭活p21,调控CDK和增殖细胞核抗原(proliferating cell nuclear antigen,PCNA)抑制剂的功能 |
MPP2 | 提高MPP2(MAGUK p55亚家族成员2)特异性转录活性 |
p600 | 有利于肿瘤细胞非贴壁依赖性生长及转变 |
Mi2 | 与组蛋白去乙酰化酶(histone deacetylase,HDAC)形成复合体,促进E2F介导的转录机制 |
IRF1 | 消除干扰素调节因子1(interferon regulation factor 1,IRF1)转录活性 |
p48 | 下调IFNα介导的信号转导 |
p27 | 阻碍p27抑制细胞周期功能,促进细胞侵袭性 |
PP2A | 抑制蛋白磷酸酶2A(protein phosphatase 2A,PP2A)催化活性 |
表 5
头颈部肿瘤中与肿瘤淋巴管生成、淋巴结转移及预后相关的生长因子
生长因子 | 家族成员或受体 | 与HNSCC及淋巴结转移相关性 |
---|---|---|
VEGF | VEGF-A | 与口腔癌、咽癌、喉癌T分期正相关 |
与口腔癌、咽癌淋巴结转移正相关 | ||
VEGF-C | 与口腔癌淋巴结转移正相关 | |
HNSCC细胞侵袭能力提高 | ||
VEGF-D | 与口腔癌淋巴结转移正相关 | |
血管生成素(angiopoietins,Ang) | Ang-1 | 诱导VEGF受体-3高表达,提高VEGF-C、VEGF-D诱导淋巴管 |
生成能力 | ||
与口腔癌淋巴结转移正相关 | ||
Ang-2 | 与口腔癌预后差有关 | |
胰岛素样生长因子(insulin-like growth factor,IGF) | IGF-1R | 原发口咽癌及鼻咽癌未分化癌中高表达,转移淋巴结中高表达 |
成纤维细胞生长因子(fibroblast growth factor,FGF) | FGF-2 | 诱导体外淋巴管生成,促进VEGF-C分泌 |
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