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

doi:10.7518/hxkq.2018.05.015

摘要/Abstract

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。

关键词: 人乳头瘤病毒, 头颈部鳞状细胞癌, 侵袭转移

Abstract:

Human papillomavirus (HPV) is a major causative agent of head and neck squamous cell carcinomas (HNSCC). Over the past several decades, an increasing number of studies established the strong association of HPV with the invasion and metastasis of HNSCC. In the present study, we reviewed the gene mutations in HPV-associated HNSCC and the unique mechanism of E6- and E7-mediated carcinogenesis via interactions with an array of cellular elements. We further discussed the progress in the mechanisms of invasion and metastasis; these mechanisms include non-coding RNAs, deregulating cellular energetics, tumor microenvironment, cancer stem cells, angiogenesis, and lymphangiogenesis.

Key words: human papillomavirus, head and neck squamous cell carcinomas, invasion and metastasis

中图分类号:

R789.5

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.

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基因名称		突变发生率/%
简称	全称	突变发生率/%
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

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

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

HPV致癌蛋白		miRNAs
E6蛋白	上调	miR-33、miR-34a、miR-363、miR-497
	下调	miR-125a、miR-126、miR-127-3p、miR-142-5p、miR-145、miR-155、miR-181a/b、miR-20b、miR-218、
		miR-221、miR-222、miR-24a、miR-29a、miR-379
E7蛋白	上调	miR-15a、miR-20b、miR-224
	下调	miR-145、miR-21、miR-127-3p

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