miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3ζ.
miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3ζ.
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DOI：
10.1186/1476-4598-13-80
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发表时间：
2014-04-08
期刊：
影响因子：
37.3
通讯作者：
Chan EK
中科院分区：
文献类型：
--
作者：
Jung HM;Phillips BL;Chan EK
虽然在许多生物过程中，microrna （mirna）在转录后调控基因表达方面得到了广泛的研究，但细胞mirna介导的病毒基因调控尚不清楚。特别是，人乳头瘤病毒（HPV）基因和mirna之间的相互作用以及这些相互作用如何导致HPV相关癌症仍然是难以捉摸的。短暂转染miR-375 mimic用于补偿hpv阳性癌症中miR-375的功能缺失。采用qRT-PCR、western blot、双荧光素酶测定、间接免疫荧光分析等方法研究miR-375在hpv阳性肿瘤中对致癌分子及其下游分子的调控作用。所有实验至少进行三次，以达到学生t检验确定的统计学显著性。在这项研究中，我们证明了miR-375如何负调控HPV16和18转录本。我们还发现了一种由miR-375直接调控的细胞蛋白e6相关蛋白（E6AP）。mir -375介导的HPV转录物和E6AP的抑制升高了主要的肿瘤抑制因子p53、p21和视网膜母细胞瘤蛋白1 （RB）。miR-375靶点的协同调控与肿瘤抑制因子的增加导致端粒酶逆转录酶（TERT）转录降低~60%，端粒酶活性降低~35%。此外，mir -375介导的14-3-3ζ调节有助于通过改变TERT的核易位来降低端粒酶活性。综上所述，mir -375介导的对hpv相关癌变中多种致癌成分的抑制产生了累积的生物学反应，以挽救关键的肿瘤抑制因子并降低端粒酶活性，从而导致细胞周期阻滞和细胞增殖抑制。
While microRNAs (miRNAs) are extensively studied in post-transcriptional regulation of gene expressions in many biological processes, cellular miRNA-mediated regulation of viral genes remains unclear. In particular, the interplay between human papillomavirus (HPV) genes and miRNAs and how these interactions contribute to HPV-associated cancers remain elusive. Transient transfection of miR-375-mimic was used to compensate the loss-of-function of miR-375 in HPV-positive cancer. Regulation of oncogenic molecules and their downstream molecules via miR-375 in HPV-positive cancer was investigated using qRT-PCR, western blot, dual luciferase assay, indirect immunofluorescence analysis. All experiments were conducted at least three times to achieve statistical significance determined by Student t-test. In this study, we demonstrated how miR-375 negatively regulates HPV16 and 18 transcripts. We also found a cellular protein, E6-associated protein (E6AP), directly regulated by miR-375. miR-375-mediated repression of HPV transcripts and E6AP elevated major tumor suppressors p53, p21, and retinoblastoma protein 1 (RB). Cooperative regulation of miR-375 targets along with the increase of tumor suppressors led to ~60% reduction of telomerase reverse transcriptase (TERT) transcription followed by ~35% decrease of telomerase activity. Furthermore, miR-375-mediated regulation of 14-3-3ζ contributes to decrease telomerase activity by altering nuclear translocation of TERT. Taken together, miR-375-mediated suppression of multiple oncogenic components in HPV-associated carcinogenesis generates a cumulative biological response to rescue key tumor suppressors and diminish telomerase activity, which results in cell cycle arrest and cell proliferation inhibition.
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DOI：
10.1158/1078-0432.ccr-08-3131
发表时间：
2009-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Avissar M;Christensen BC;Kelsey KT;Marsit CJ
通讯作者：
Marsit CJ
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
2.7
作者：
del Moral-Hernandez, Oscar;Lopez-Urrutia, Eduardo;Villegas-Sepulveda, Nicolas
通讯作者：
Villegas-Sepulveda, Nicolas
影响因子：
8
作者：
Ceballos, E;Delgado, MD;León, J
通讯作者：
León, J
影响因子：
64.5
作者：
Hemann, MT;Strong, MA;Greider, CW
通讯作者：
Greider, CW