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首页> 外文期刊>BMC Cancer >Deregulation of microRNAs Let-7a and miR-21 mediate aberrant STAT3 signaling during human papillomavirus-induced cervical carcinogenesis: role of E6 oncoprotein
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Deregulation of microRNAs Let-7a and miR-21 mediate aberrant STAT3 signaling during human papillomavirus-induced cervical carcinogenesis: role of E6 oncoprotein

机译：microRNAs Let-7a和miR-21的失调介导人乳头瘤病毒引起的宫颈癌变过程中的STAT3异常信号：E6癌蛋白的作用

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Background Aberrantly expressed and constitutively active STAT3 signaling plays a pivotal role in initiation and progression of human papillomavirus-induced cervical carcinogenesis. However, the underlying mechanism(s) responsible for pleiotropic effects of STAT3 signaling is poorly understood. In view of emerging regulatory role of microRNAs, Let-7a and miR-21 that may interact with STAT3 signaling and/or its downstream effectors, present study was designed in HPV16-positive cervical cancer cells to assess the functional contribution of these miRs in STAT3 signaling in cervical cancer. Methods Functional silencing of STAT3 signaling and HPV16 oncoprotein expression in SiHa cells was done by STAT3-specific and 16 E6 siRNAs. Pharmacological intervention of STAT3 was done using specific inhibitors like curcumin and stattic. Loss-of-function study of miR-21 using miR-21 inhibitor and gain-of-function study of let-7a was done using let-7a mimic in SiHa cells. Results Functional silencing of STAT3 signaling in SiHa cells by STAT3-specific siRNA resulted in a dose-dependent decrease in cellular miR-21 level. Pharmacological intervention of STAT3 using specific inhibitors like curcumin and Stattic that abrogated STAT3 activation resulted in loss of cellular miR-21 pool. Contrary to this, specific targeting of miR-21 using miR-21 inhibitor resulted in an increased level of PTEN, a negative regulator of STAT3, and reduced active pSTAT3 level. Besides miR-21, restoration of cellular Let-7a using chemically synthesized Let-7a mimic reduced overall STAT3 level. Abrogation of HPV oncoprotein E6 by specific siRNA resulted in increased Let-7a but loss of miR-21 and a correspondingly reduced pSTAT3/STAT3 and elevated the level of cellular PTEN. Conclusions Our results demonstrate existence of a functional loop involving Let-7a, STAT3 and miR-21 which were found potentially regulated by viral oncoprotein E6. Implications: miR-21 and Let-7a along with STAT3 may prove useful targets for pharmacological intervention for management of cervical cancer.
机译：背景技术异常表达且组成性活跃的STAT3信号转导在人乳头瘤病毒引起的宫颈癌发生过程中起着关键作用。然而，对引起STAT3信号的多效性作用的潜在机制了解得很少。鉴于可能与STAT3信号传导和/或其下游效应子相互作用的microRNA，Let-7a和miR-21的调控作用，本研究在HPV16阳性宫颈癌细胞中进行设计，以评估这些miR在STAT3中的功能性贡献。子宫颈癌中的信号传导。方法通过STAT3特异性和16个E6 siRNA对SiHa细胞中的STAT3信号转导和HPV16癌蛋白表达进行功能沉默。 STAT3的药理干预是使用特定的抑制剂（如姜黄素和Statstat）进行的。使用miR-21抑制剂对miR-21进行功能丧失研究，并使用Si-7细胞中的let-7a模拟物进行let-7a的功能获得研究。结果STAT3特异性siRNA导致SiHa细胞中STAT3信号转导功能沉默，导致细胞miR-21水平呈剂量依赖性降低。使用特定抑制剂如姜黄素和Stattic的STAT3药理干预，取消STAT3激活会导致细胞miR-21库丢失。与此相反，使用miR-21抑制剂特异性靶向miR-21导致PTEN水平升高，STAT3负调节剂和活性pSTAT3水平降低。除了miR-21，使用化学合成的Let-7a模拟物恢复细胞Let-7a可以降低总STAT3水平。特异性siRNA抑制HPV癌蛋白E6导致Let-7a增加，但miR-21丢失，相应地pSTAT3 / STAT3减少，细胞PTEN水平升高。结论我们的结果表明存在一个涉及Let-7a，STAT3和miR-21的功能环，这些环可能被病毒癌蛋白E6调节。含义：miR-21和Let-7a以及STAT3可能被证明是治疗宫颈癌的药物干预的有用靶标。

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