生物谷報(bào)道：來(lái)自北京大學(xué)腫瘤學(xué)院北京癌癥研究院,，安陽(yáng)腫瘤醫(yī)院（Anyang Cancer Hospital）等處的研究人員通過(guò)對(duì)140個(gè)宮頸癌和161個(gè)食道癌樣品的分析,，發(fā)現(xiàn)人乳頭瘤病毒(humanpapillomavims，HPV)16的早期轉(zhuǎn)錄區(qū)E6可以通過(guò)Akt 激活p70 S6激酶下游途徑的機(jī)制來(lái)修改S6激酶的激活,。這對(duì)于進(jìn)一步了解HPV16作用機(jī)制,，以及相關(guān)的治療手段的發(fā)展意義重大。這一研究成果公布在British Journal of Cancer雜志上,。
文章的通訊作者是來(lái)自北京市腫瘤研究所細(xì)胞遺傳室主任柯楊教授,，她主要的 研究方向包括：胃癌相關(guān)基因的克隆和功能研究,；胃癌、食道癌的生物因素和遺傳易感基因研究和人乳頭狀瘤病毒（HPV）致癌分子機(jī)制研究,。
人乳頭瘤病毒(humanpapillomavims,，HPV)是一種最小的DNA病毒，該病毒直徑約為50-60nm,，呈無(wú)包膜的20面體對(duì)稱的核衣殼結(jié)構(gòu),，表面有72個(gè)殼微粒，內(nèi)含8000個(gè)堿基對(duì)(bp),，分子量為5×106D,，其中88％是病毒蛋白。
HPV基因組是雙鏈環(huán)狀DNA,，以共價(jià)閉合的超螺旋結(jié)構(gòu),、開(kāi)放的環(huán)狀結(jié)構(gòu)、線性分子3種形式存在,。HPV基因組編碼為9個(gè)開(kāi)放讀碼框架,，分為3個(gè)功能區(qū)即早期轉(zhuǎn)錄區(qū)、晚期轉(zhuǎn)錄區(qū)和非轉(zhuǎn)錄區(qū)(控制區(qū)),。早期轉(zhuǎn)錄區(qū)又稱為E區(qū),，由4 500個(gè)堿基對(duì)組成，分別編碼為E1,、E2,、E3、E4,、E5,、E6、E7,、E8等8個(gè)早期蛋白,，具有參與病毒DNA的復(fù)制、轉(zhuǎn)錄,、翻譯調(diào)控和細(xì)胞轉(zhuǎn)化等功能,。E1涉及病毒DNA復(fù)制，在病毒開(kāi)始復(fù)制中起關(guān)鍵作用,。E2是一種反式激活蛋白,，涉及病毒DNA轉(zhuǎn)錄的反式激活。E3功能不清,。E4與病毒成熟胞漿蛋白有關(guān),。E5與細(xì)胞轉(zhuǎn)化有關(guān)。E6和E7主要與病毒細(xì)胞轉(zhuǎn)化功能及致癌性有關(guān),。
其中E6和E7經(jīng)研究發(fā)現(xiàn)可以分別誘導(dǎo)p53的泛素化降解和pRb的高磷酸化失活,，與宮頸癌和食道癌的發(fā)生發(fā)展關(guān)系密切,。在之前的研究中，研究小組證明HPV16 E6可以與腫瘤抑制因子蛋白TSC2相互作用,，導(dǎo)致后者降解,，從而引起p70 S6激酶的磷酸化。在此基礎(chǔ)上,，研究人員對(duì)宮頸癌和食道癌中S6激酶磷酸化與HPV16感染之間的關(guān)系進(jìn)行了研究：對(duì)140個(gè)宮頸癌和161個(gè)食道癌樣品中的磷酸化S6激酶(Thr 389)和磷酸化S6激酶(Ser235/236)進(jìn)行了免疫組化實(shí)驗(yàn)（Immunohistochemistry）分析,。
結(jié)果發(fā)現(xiàn)比對(duì)于對(duì)照組，HPV16感染的宮頸癌樣品中pS6激酶和pS6的免疫染色多得多,，但S6激酶的表達(dá)在對(duì)照組和實(shí)驗(yàn)組中卻相處無(wú)幾,。同時(shí)研究人員也
對(duì)Akt的磷酸化——S6激酶的關(guān)鍵調(diào)控子進(jìn)行了檢測(cè)，分析結(jié)果表明Akt磷酸化并未受到HPV16感染的影響,。這些說(shuō)明HPV16可以通過(guò)Akt 激活S6激酶下游途徑的機(jī)制來(lái)修改S6激酶的激活,。
原始出處:
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: [email protected] and [email protected]
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
