生物谷报道：来自北京大学肿瘤学院北京癌症研究院，安阳肿瘤医院（Anyang Cancer Hospital）等处的研究人员通过对140个宫颈癌和161个食道癌样品的分析，发现人乳头瘤病毒(humanpapillomavims，HPV)16的早期转录区E6可以通过Akt 激活p70 S6激酶下游途径的机制来修改S6激酶的激活。这对于进一步了解HPV16作用机制，以及相关的治疗手段的发展意义重大。这一研究成果公布在British Journal of Cancer杂志上。
文章的通讯作者是来自北京市肿瘤研究所细胞遗传室主任柯杨教授，她主要的 研究方向包括：胃癌相关基因的克隆和功能研究；胃癌、食道癌的生物因素和遗传易感基因研究和人乳头状瘤病毒（HPV）致癌分子机制研究。
人乳头瘤病毒(humanpapillomavims，HPV)是一种最小的DNA病毒，该病毒直径约为50-60nm，呈无包膜的20面体对称的核衣壳结构，表面有72个壳微粒，内含8000个碱基对(bp)，分子量为5×106D，其中88％是病毒蛋白。
HPV基因组是双链环状DNA，以共价闭合的超螺旋结构、开放的环状结构、线性分子3种形式存在。HPV基因组编码为9个开放读码框架，分为3个功能区即早期转录区、晚期转录区和非转录区(控制区)。早期转录区又称为E区，由4 500个碱基对组成，分别编码为E1、E2、E3、E4、E5、E6、E7、E8等8个早期蛋白，具有参与病毒DNA的复制、转录、翻译调控和细胞转化等功能。E1涉及病毒DNA复制，在病毒开始复制中起关键作用。E2是一种反式激活蛋白，涉及病毒DNA转录的反式激活。E3功能不清。E4与病毒成熟胞浆蛋白有关。E5与细胞转化有关。E6和E7主要与病毒细胞转化功能及致癌性有关。
其中E6和E7经研究发现可以分别诱导p53的泛素化降解和pRb的高磷酸化失活，与宫颈癌和食道癌的发生发展关系密切。在之前的研究中，研究小组证明HPV16 E6可以与肿瘤抑制因子蛋白TSC2相互作用，导致后者降解，从而引起p70 S6激酶的磷酸化。在此基础上，研究人员对宫颈癌和食道癌中S6激酶磷酸化与HPV16感染之间的关系进行了研究：对140个宫颈癌和161个食道癌样品中的磷酸化S6激酶(Thr 389)和磷酸化S6激酶(Ser235/236)进行了免疫组化实验（Immunohistochemistry）分析。
结果发现比对于对照组，HPV16感染的宫颈癌样品中pS6激酶和pS6的免疫染色多得多，但S6激酶的表达在对照组和实验组中却相处无几。同时研究人员也
对Akt的磷酸化——S6激酶的关键调控子进行了检测，分析结果表明Akt磷酸化并未受到HPV16感染的影响。这些说明HPV16可以通过Akt 激活S6激酶下游途径的机制来修改S6激酶的激活。
原始出处:
British Journal of Cancer (2007) 97, 218-222.
doi:10.1038/sj.bjc.6603838 www.bjcancer.com Published online 10 July 2007
Increased phosphorylation of p70 S6 kinase is associated with HPV16 infection in cervical cancer and esophageal cancer
Y Zhou1, Y Pan1, S Zhang2, X Shi2, T Ning1 and Y Ke1,3,4
1Beijing Institute for Cancer Research, School of Oncology, Peking University No. 52, Fucheng Rd, Hai Dian District, Beijing 100036, PR China
2Department of Surgery, Anyang Cancer Hospital, Anyang City, Henan Province 455000, PR China
3Department of Cell Biology, Health Science Center, Peking University No. 38, Xueyuan Rd, Hai Dian District, Beijing 100083, PR China
4Cancer Research Center, Health Science Center, Peking University No. 38, Xueyuan Rd, Hai Dian District, Beijing 100083, PR China
Correspondence to: Dr Y Ke, E-mails: keyang@bjmu.edu.cn and karazhou@163.com
Received 9 January 2007; revised 11 May 2007; accepted 14 May 2007; published online 10 July 2007
HPV16 E6 interacts with and degrades tumour suppressor protein TSC2 leading to the phosphorylation of p70 S6 kinase. We studied the association of S6 kinase phosphorylation and HPV16 infection in cervical cancer and esophageal cancer. Immunohistochemistry was used to assess phosphorylated S6 kinase (Thr 389) and phosphorylated S6 (Ser235/236) in 140 cervical cancer and 161 esophageal cancer specimens. Immunohistochemical staining for pS6 kinase and pS6 was significantly more frequent in the HPV16-infected cervical cancer specimens than the HPV16-negative specimens. In contrast, the expression of S6 kinase was similar in both HPV16-positive and -negative samples. The phosphorylation of Akt, the key regulator of S6 kinase, was also detected. Our analysis showed that Akt phosphorylation was unaffected by HPV16 infection. These results together with our previous study suggest that HPV16 modifies S6 kinase activation via mechanism, which activates S6 kinase downstream of Akt function.
Keywords: S6 kinase; HPV; Akt; cervical cancer; esophageal cancer
