Oncogenic human papillomaviruses activate the tumor-associated lens epithelial-derived growth factor (LEDGF) gene.
Oncogenic human papillomaviruses activate the tumor-associated lens epithelial-derived growth factor (LEDGF) gene.
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DOI：
10.1371/journal.ppat.1003957
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发表时间：
2014-03
期刊：
影响因子：
6.7
通讯作者：
Hoppe-Seyler F
中科院分区：
文献类型：
--
作者：
Leitz J;Reuschenbach M;Lohrey C;Honegger A;Accardi R;Tommasino M;Llano M;von Knebel Doeberitz M;Hoppe-Seyler K;Hoppe-Seyler F
人乳头瘤病毒（HPV）E6/E7癌基因的表达是HPV诱导的恶性细胞转化的关键。识别HPV癌基因攻击的细胞靶点对于我们理解HPV相关致癌的分子机制至关重要，并可能开辟新的治疗机会。在这里，我们确定透镜上皮衍生生长因子（LEDGF）基因作为一种新的细胞靶基因的HPV癌基因。LEDGF表达升高最近与人类致癌有关，并且可以保护肿瘤细胞免受不同形式的细胞应激。我们发现，HPV阳性癌细胞内LEDGF mRNA和蛋白水平严重依赖于病毒癌基因表达的维持。异位E6/E7表达至少部分通过激活LEDGF启动子刺激原代角质形成细胞中的LEDGF转录。通过RNA干扰抑制内源性LEDGF表达导致HPV阳性癌细胞对遗传毒性剂的敏感性增加。宫颈组织标本的免疫组化分析显示，与组织学正常的宫颈上皮相比，HPV阳性病变中LEDGF蛋白水平显著升高。总之，这些结果表明，E6/E7依赖性维持细胞内LEDGF表达对于保护HPV阳性癌细胞免受各种形式的细胞应激，包括DNA损伤至关重要。这可以支持肿瘤细胞存活，并有助于宫颈癌对临床中的遗传毒性治疗策略的治疗抗性。特定类型的人乳头瘤病毒（HPV）与恶性肿瘤（如宫颈癌）的发展密切相关。几乎所有的宫颈癌都含有HPV DNA，宫颈癌细胞的致瘤生长行为取决于两种病毒癌基因E6和E7的活性。研究HPV癌基因支持肿瘤细胞生长的活性具有重要意义。这将使新的见解病毒诱导的致癌作用的分子机制，也可能是有用的，为癌症治疗的新方法的开发。我们在此表明HPV癌基因刺激并维持HPV阳性癌细胞中细胞LEDGF基因的表达。宫颈的一致性、癌前病变和恶性病变表现出显著增加的LEDGF蛋白水平。LEDGF对于保护肿瘤细胞免受各种形式的细胞应激（包括DNA损伤）至关重要。病毒致癌基因对LEDGF的刺激可能是HPV支持宫颈癌细胞生长的关键生存机制，并在临床上提供对化疗和放疗的抗性。
The expression of the human papillomavirus (HPV) E6/E7 oncogenes is crucial for HPV-induced malignant cell transformation. The identification of cellular targets attacked by the HPV oncogenes is critical for our understanding of the molecular mechanisms of HPV-associated carcinogenesis and may open novel therapeutic opportunities. Here, we identify the Lens Epithelial-Derived Growth Factor (LEDGF) gene as a novel cellular target gene for the HPV oncogenes. Elevated LEDGF expression has been recently linked to human carcinogenesis and can protect tumor cells towards different forms of cellular stress. We show that intracellular LEDGF mRNA and protein levels in HPV-positive cancer cells are critically dependent on the maintenance of viral oncogene expression. Ectopic E6/E7 expression stimulates LEDGF transcription in primary keratinocytes, at least in part via activation of the LEDGF promoter. Repression of endogenous LEDGF expression by RNA interference results in an increased sensitivity of HPV-positive cancer cells towards genotoxic agents. Immunohistochemical analyses of cervical tissue specimens reveal a highly significant increase of LEDGF protein levels in HPV-positive lesions compared to histologically normal cervical epithelium. Taken together, these results indicate that the E6/E7-dependent maintenance of intracellular LEDGF expression is critical for protecting HPV-positive cancer cells against various forms of cellular stress, including DNA damage. This could support tumor cell survival and contribute to the therapeutic resistance of cervical cancers towards genotoxic treatment strategies in the clinic. Specific types of human papillomaviruses (HPVs) are closely linked to the development of malignant tumors, such as cervical cancer. Virtually all cervical cancers contain HPV DNA and the tumorigenic growth behavior of cervical cancer cells is dependent on the activity of two viral oncogenes, called E6 and E7. It is important to study the activities by which the HPV oncogenes can support the growth of tumor cells. This should allow new insights into the molecular mechanisms of virus-induced carcinogenesis and could also be useful for developing novel approaches for cancer therapy. We here show that the HPV oncogenes stimulate and maintain expression of the cellular LEDGF gene in HPV-positive cancer cells. Consistently, pre-malignant and malignant lesions of the cervix exhibit significantly increased LEDGF protein levels. LEDGF is crucial for the protection of tumor cells against various forms of cellular stress, including DNA damage. LEDGF stimulation by the viral oncogenes could be a critical survival mechanism by which HPVs support the growth of cervical cancer cells and provide resistance towards chemo- and radiotherapy in the clinic.
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影响因子：
4.8
作者：
Cherepanov, P;Maertens, G;Debyser, Z
通讯作者：
Debyser, Z
影响因子：
9
作者：
Bhargavan B;Fatma N;Chhunchha B;Singh V;Kubo E;Singh DP
通讯作者：
Singh DP
影响因子：
3.7
作者：
Basu A;Rojas H;Banerjee H;Cabrera IB;Perez KY;De León M;Casiano CA
通讯作者：
Casiano CA
DOI：
10.1007/978-1-61779-182-6_1
发表时间：
2011-01-01
期刊：
CELL CYCLE SYNCHRONIZATION: METHODS AND PROTOCOLS
影响因子：
--
作者：
Banfalvi, Gaspar
通讯作者：
Banfalvi, Gaspar
影响因子：
5.4
作者：
Caldeira, S;Zehbe, I;Tommasino, M
通讯作者：
Tommasino, M