Oncogenic role of MIR516A in human bladder cancer was mediated by its attenuating PHLPP2 expression and BECN1-dependent autophagy.
Oncogenic role of MIR516A in human bladder cancer was mediated by its attenuating PHLPP2 expression and BECN1-dependent autophagy.
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MIR516A 在人膀胱癌中的致癌作用是通过其减弱的 PHLPP2 表达和 BECN1 依赖性自噬介导的
DOI：
10.1080/15548627.2020.1733262
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发表时间：
2021-04
期刊：
影响因子：
13.3
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Jin H;Ma J;Xu J;Li H;Chang Y;Zang N;Tian Z;Wang X;Zhao N;Liu L;Chen C;Xie Q;Lu Y;Fang Z;Huang X;Huang C;Huang H
摘要尽管已有报道MIR516A在多种癌症中表达下调并发挥肿瘤抑制作用，但它的表达及其在人类膀胱癌中的潜在作用尚不清楚。出乎意料的是，我们发现MIR516A在人BC组织和细胞系中显著上调，而抑制MIR516A的表达则减弱了BC细胞在体外的单层生长和体内移植瘤的生长，并伴随着PHLPP2的表达增加。进一步的研究表明，MIR516A能够直接与PHLPP2基因的3‘非翻译区结合，这是其抑制PHLPP2表达所必需的。在MIR516A抑制的细胞中，PHLPP2的表达下调可以逆转BC细胞的生长，提示PHLPP2是MIR516A的下游调节因子，参与了MIR516A的致癌作用。PHLPP2能够间接介导BECN1/Beclin1的稳定，从而促进BECN1依赖的巨噬/自噬，抑制BC肿瘤细胞的生长。此外，我们的结果表明，通过减弱MIR516A而增加的自噬导致了体内异种移植瘤形成的显著抑制。综上所述，我们的结果揭示了MIR516A在BC生长中具有新的致癌功能，其机制是直接与PHLPP2 3‘-UTR结合并抑制PHLPP2的表达，进而至少部分促进CUL4A介导的BECN1蛋白的降解，从而减弱自噬并促进BC生长，这是MIR516A在其他癌症中发现的一个独特功能。缩写：ATG3：自噬相关3；ATG5：自噬相关5；ATG7：自噬相关7；ATG12：自噬相关12；BAF：巴菲尔霉素A1；BC：膀胱癌；CHX：环己亚胺；Co-IP：免疫共沉淀；CUL3：cullin 3；CUL4A：cullin 4A；CUL4B：cullin 4B；IF：免疫荧光：IHC-p：免疫组织化学-石蜡；MIR516A：microRNA 516a(microRNA 516a1和microRNA 516a2)；MS：MS；PHLP2：结构域和富含亮氨酸的重复蛋白磷酸酶。
ABSTRACT Although MIR516A has been reported to be downregulated and act as a tumor suppressor in multiple cancers, its expression and potential contribution to human bladder cancer (BC) remain unexplored. Unexpectedly, we showed here that MIR516A was markedly upregulated in human BC tissues and cell lines, while inhibition of MIR516A expression attenuated BC cell monolayer growth in vitro and xenograft tumor growth in vivo, accompanied with increased expression of PHLPP2. Further studies showed that MIR516A was able to directly bind to the 3′-untranslated region of PHLPP2 mRNA, which was essential for its attenuating PHLPP2 expression. The knockdown of PHLPP2 expression in MIR516A-inhibited cells could reverse BC cell growth, suggesting that PHLPP2 is a MIR516A downstream mediator responsible for MIR516A oncogenic effect. PHLPP2 was able to mediate BECN1/Beclin1 stabilization indirectly, therefore promoting BECN1-dependent macroautophagy/autophagy, and inhibiting BC tumor cell growth. In addition, our results indicated that the increased autophagy by attenuating MIR516A resulted in a dramatic inhibition of xenograft tumor formation in vivo. Collectively, our results reveal that MIR516A has a novel oncogenic function in BC growth by directing binding to PHLPP2 3′-UTR and inhibiting PHLPP2 expression, in turn at least partly promoting CUL4A-mediated BECN1 protein degradation, thereby attenuating autophagy and promoting BC growth, which is a distinct function of MIR516A identified in other cancers. Abbreviation: ATG3: autophagy related 3; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; BAF: bafilomycin A1; BC: bladder cancer; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CUL3: cullin 3; CUL4A: cullin 4A; CUL4B: cullin 4B; IF: immunofluorescence: IHC-p: immunohistochemistry-paraffin; MIR516A: microRNA 516a (microRNA 516a1 and microRNA 516a2); MS: mass spectrometry; PHLPP2: PH domain and leucine rich repeat protein phosphatase.
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SQSTM1/p62的上调有助于镍诱导的人支气管上皮细胞的恶性转化
影响因子：
13.3
作者：
Huang H;Zhu J;Li Y;Zhang L;Gu J;Xie Q;Jin H;Che X;Li J;Huang C;Chen LC;Lyu J;Gao J;Huang C
通讯作者：
Huang C
影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
--
作者：
Jin H;Yu Y;Hu Y;Lu C;Li J;Gu J;Zhang L;Huang H;Zhang D;Wu XR;Gao J;Huang C
通讯作者：
Huang C
贯穿历史：PHLPP磷酸酶生命的十年。
影响因子：
3.9
作者：
Grzechnik AT;Newton AC
通讯作者：
Newton AC
DOI：
10.1158/1078-0432.ccr-13-0341
发表时间：
2013-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kabbout M;Garcia MM;Fujimoto J;Liu DD;Woods D;Chow CW;Mendoza G;Momin AA;James BP;Solis L;Behrens C;Lee JJ;Wistuba II;Kadara H
通讯作者：
Kadara H