Downregulation of miR-99b-5p and Upregulation of Nuclear mTOR Cooperatively Promotes the Tumor Aggressiveness and Drug Resistance in African American Prostate Cancer.
Downregulation of miR-99b-5p and Upregulation of Nuclear mTOR Cooperatively Promotes the Tumor Aggressiveness and Drug Resistance in African American Prostate Cancer.
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DOI：
10.3390/ijms23179643
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发表时间：
2022-08-25
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
哺乳动物雷帕霉素靶蛋白（mTOR）调节多种基本细胞事件，包括细胞增殖、蛋白质合成、代谢、凋亡和自噬。肿瘤抑制miR-99b-5p在多种类型的癌症中参与调节PI3K/AKT/mTOR信号传导。我们之前的研究表明，miR-99b-5p/MTOR（下调/上调）配对是参与前列腺癌（PCa）差异的关键microRNA-mRNA调控组分。在本研究中，我们进一步验证了mTOR和miR-99b-5p在PCa、结肠癌、乳腺癌和肺癌标本和细胞系中的表达谱。免疫组织化学（IHC）、免疫荧光、Western blot和RT-qPCR分析证实，在不同的患者队列和一组癌细胞系中，mTOR上调，miR-99b-5p下调。有趣的是，在非裔美国人前列腺癌和其他晚期癌症中观察到核mTOR表达升高。转染miR-99b-5p模拟物导致核mTOR和雄激素受体（AR）显著减少，而细胞质mTOR和AR在PCa和其他癌细胞中轻微/中度至不减少，表明miR-99b-5p抑制mTOR和AR的表达及其核易位。此外，过表达miR-99b-5p靶向/抑制AR-mTOR轴，随后启动细胞凋亡并使多西他赛诱导的各种癌症细胞毒性增敏。总之，我们的数据表明，与miR-99b-5p/ mTOR配对或单独mTOR相比，miR-99b-5p/ mTOR配对可能是侵袭性前列腺癌更精确的诊断/预后生物标志物。利用miR-99b-5p靶向AR-mTOR轴也被认为是一种诱导细胞凋亡和克服侵袭性前列腺癌化疗耐药的新治疗策略。
Mammalian target of rapamycin (mTOR) regulates various fundamental cellular events including cell proliferation, protein synthesis, metabolism, apoptosis, and autophagy. Tumor suppressive miR-99b-5p has been implicated in regulating PI3K/AKT/mTOR signaling in a variety of types of cancer. Our previous study suggested the reciprocal miR-99b-5p/MTOR (downregulated/upregulated) pairing as a key microRNA-mRNA regulatory component involved in the prostate cancer (PCa) disparities. In this study, we further validated the expression profiles of mTOR and miR-99b-5p in the PCa, colon, breast, and lung cancer specimens and cell lines. The immunohistochemistry (IHC), immunofluorescence, Western blot, and RT-qPCR assays have confirmed that mTOR is upregulated while miR-99b-5p is downregulated in different patient cohorts and a panel of cancer cell lines. Intriguingly, elevated nuclear mTOR expression was observed in African American PCa and other advanced cancers. Transfection of the miR-99b-5p mimic resulted in a significant reduction in nuclear mTOR and androgen receptor (AR), while a slight/moderate to no decrease in cytoplasmic mTOR and AR in PCa and other cancer cells, suggesting that miR-99b-5p inhibits mTOR and AR expression and their nuclear translocation. Moreover, overexpression of miR-99b-5p targets/inhibits AR-mTOR axis, subsequently initiating cell apoptosis and sensitizing docetaxel-induced cytotoxicity in various cancers. In conclusion, our data suggest that reciprocal miR-99b-5p/nuclear mTOR pairing may be a more precise diagnostic/prognostic biomarker for aggressive PCa, than miR-99b-5p/MTOR pairing or mTOR alone. Targeting the AR-mTOR axis using miR-99b-5p has also been suggested as a novel therapeutic strategy to induce apoptosis and overcome chemoresistance in aggressive PCa.
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影响因子：
5.6
作者：
Popova NV;Jücker M
通讯作者：
Jücker M
影响因子：
3.7
作者：
Jiang N;Zhu S;Chen J;Niu Y;Zhou L
通讯作者：
Zhou L
影响因子：
5.2
作者：
Audet-Walsh, Etienne;Vernier, Mathieu;Giguere, Vincent
通讯作者：
Giguere, Vincent
跨务基因组全基因组关联的前列腺癌荟萃分析确定了新的敏感性基因座并告知遗传风险预测。
影响因子：
30.8
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Conti DV;Darst BF;Moss LC;Saunders EJ;Sheng X;Chou A;Schumacher FR;Olama AAA;Benlloch S;Dadaev T;Brook MN;Sahimi A;Hoffmann TJ;Takahashi A;Matsuda K;Momozawa Y;Fujita M;Muir K;Lophatananon A;Wan P;Le Marchand L;Wilkens LR;Stevens VL;Gapstur SM;Carter BD;Schleutker J;Tammela TLJ;Sipeky C;Auvinen A;Giles GG;Southey MC;MacInnis RJ;Cybulski C;Wokołorczyk D;Lubiński J;Neal DE;Donovan JL;Hamdy FC;Martin RM;Nordestgaard BG;Nielsen SF;Weischer M;Bojesen SE;Røder MA;Iversen P;Batra J;Chambers S;Moya L;Horvath L;Clements JA;Tilley W;Risbridger GP;Gronberg H;Aly M;Szulkin R;Eklund M;Nordström T;Pashayan N;Dunning AM;Ghoussaini M;Travis RC;Key TJ;Riboli E;Park JY;Sellers TA;Lin HY;Albanes D;Weinstein SJ;Mucci LA;Giovannucci E;Lindstrom S;Kraft P;Hunter DJ;Penney KL;Turman C;Tangen CM;Goodman PJ;Thompson IM Jr;Hamilton RJ;Fleshner NE;Finelli A;Parent MÉ;Stanford JL;Ostrander EA;Geybels MS;Koutros S;Freeman LEB;Stampfer M;Wolk A;Håkansson N;Andriole GL;Hoover RN;Machiela MJ;Sørensen KD;Borre M;Blot WJ;Zheng W;Yeboah ED;Mensah JE;Lu YJ;Zhang HW;Feng N;Mao X;Wu Y;Zhao SC;Sun Z;Thibodeau SN;McDonnell SK;Schaid DJ;West CML;Burnet N;Barnett G;Maier C;Schnoeller T;Luedeke M;Kibel AS;Drake BF;Cussenot O;Cancel-Tassin G;Menegaux F;Truong T;Koudou YA;John EM;Grindedal EM;Maehle L;Khaw KT;Ingles SA;Stern MC;Vega A;Gómez-Caamaño A;Fachal L;Rosenstein BS;Kerns SL;Ostrer H;Teixeira MR;Paulo P;Brandão A;Watya S;Lubwama A;Bensen JT;Fontham ETH;Mohler J;Taylor JA;Kogevinas M;Llorca J;Castaño-Vinyals G;Cannon-Albright L;Teerlink CC;Huff CD;Strom SS;Multigner L;Blanchet P;Brureau L;Kaneva R;Slavov C;Mitev V;Leach RJ;Weaver B;Brenner H;Cuk K;Holleczek B;Saum KU;Klein EA;Hsing AW;Kittles RA;Murphy AB;Logothetis CJ;Kim J;Neuhausen SL;Steele L;Ding YC;Isaacs WB;Nemesure B;Hennis AJM;Carpten J;Pandha H;Michael A;De Ruyck K;De Meerleer G;Ost P;Xu J;Razack A;Lim J;Teo SH;Newcomb LF;Lin DW;Fowke JH;Neslund-Dudas C;Rybicki BA;Gamulin M;Lessel D;Kulis T;Usmani N;Singhal S;Parliament M;Claessens F;Joniau S;Van den Broeck T;Gago-Dominguez M;Castelao JE;Martinez ME;Larkin S;Townsend PA;Aukim-Hastie C;Bush WS;Aldrich MC;Crawford DC;Srivastava S;Cullen JC;Petrovics G;Casey G;Roobol MJ;Jenster G;van Schaik RHN;Hu JJ;Sanderson M;Varma R;McKean-Cowdin R;Torres M;Mancuso N;Berndt SI;Van Den Eeden SK;Easton DF;Chanock SJ;Cook MB;Wiklund F;Nakagawa H;Witte JS;Eeles RA;Kote-Jarai Z;Haiman CA
通讯作者：
Haiman CA
影响因子：
2.4
作者：
Fu，Ping;Bu，Chunying;Wu，Jifeng
通讯作者：
Wu，Jifeng