MicroRNA調(diào)控膠質(zhì)瘤替莫唑胺化療耐藥的研究進(jìn)展

徐勇明 王宏勤

MicroRNA調(diào)控膠質(zhì)瘤替莫唑胺化療耐藥的研究進(jìn)展

徐勇明 王宏勤

microRNA是一類非編碼的內(nèi)源性小分子RNA，對(duì)基因表達(dá)進(jìn)行轉(zhuǎn)錄后水平的調(diào)控。國(guó)內(nèi)外學(xué)者對(duì)miRNA在膠質(zhì)瘤耐藥中的作用做了積極的探索和研究，發(fā)現(xiàn)miRNA在耐藥中起十分重要的作用。本文將闡述miRNA與膠質(zhì)瘤替莫唑胺化療耐藥基因的關(guān)系，促進(jìn)在膠質(zhì)瘤中針對(duì)特定通路的新靶向治療的進(jìn)一步發(fā)展。

microRNA；膠質(zhì)瘤；替莫唑胺

膠質(zhì)瘤是顱內(nèi)最常見的惡性腫瘤，具有復(fù)發(fā)率高、致死、致殘率高的特點(diǎn)，且發(fā)病率隨著年齡的增加而增加，65～75歲之間為高發(fā)年齡段，中位生存期整體為6.1個(gè)月[1]。根據(jù)世界衛(wèi)生組織WHO2016年的病理分級(jí)又可將神經(jīng)膠質(zhì)瘤分為Ⅰ級(jí)、Ⅱ級(jí)、Ⅲ級(jí)和Ⅳ級(jí)，其中將膠質(zhì)瘤母細(xì)胞瘤分為IDH突變型和野生型，加入了彌漫型中線膠質(zhì)瘤-H3K27M突變型（Ⅳ級(jí)），Ⅳ級(jí) 主要是多形性膠質(zhì)母細(xì)胞瘤（glioblastoma multiforme，GBM）。目前膠質(zhì)瘤的臨床治療有手術(shù)切除、放化療、疫苗療法和溶瘤病毒治療等綜合療法[2]，但由于神經(jīng)膠質(zhì)瘤具有生長(zhǎng)迅速，高度浸潤(rùn)性等臨床特點(diǎn)，腫瘤組織和正常腦組織之間無明顯界限[3]，因此手術(shù)很難徹底將癌灶切除，且術(shù)后極易復(fù)發(fā)。另外由于血腦屏障的存在，許多化療藥物難以進(jìn)入腦內(nèi)針對(duì)性消滅膠質(zhì)瘤細(xì)胞，因此，目前國(guó)內(nèi)外臨床上采用的術(shù)后加放化療的聯(lián)合方案，治療效果不理想，其中位生存期仍然只有14.25個(gè)月[4]。替莫唑胺（Temozolomide，TMZ）是目前國(guó)內(nèi)外臨床上治療膠質(zhì)瘤最安全的一線化療藥物[5]，主要通過在細(xì)胞周期的G1晚期、S早期干擾DNA復(fù)制及錯(cuò)配修復(fù)誘導(dǎo)腫瘤細(xì)胞凋亡，進(jìn)而發(fā)揮抗腫瘤效應(yīng)[6]。但是臨床治療一段時(shí)間后，膠質(zhì)瘤患者會(huì)對(duì)替莫唑胺產(chǎn)生耐藥，從而使療效大大降低。膠質(zhì)瘤化療耐藥的機(jī)制很復(fù)雜，包括人體內(nèi)環(huán)境紊亂、DNA甲基化、基因突變等。研究發(fā)現(xiàn)，特異性的microRNA表達(dá)異常也與腫瘤細(xì)胞對(duì)替莫唑胺產(chǎn)生耐藥性密切相關(guān)[7]，目前明確與膠質(zhì)瘤替莫唑胺化療耐藥相關(guān)的microRNA包 括 miR-9、miR-125b、miR-136、miR-181b以及miR-221/222等[8-12]。

一、microRNA

MicroRNA是一類長(zhǎng)約20～25個(gè)核苷酸序列的非編碼的內(nèi)源性單鏈RNA分子。Lee等[13]首先在線蟲胚胎中發(fā)現(xiàn)lin-4小分子RNA，并命名為MicroRNA。隨著定量的MicroRNA基因表達(dá)分析平臺(tái)（miRQC）及高通量芯片技術(shù)的發(fā)展，MicroRNA與腫瘤的相關(guān)性已成為研究熱點(diǎn)[14]。它通過與靶基因mRNA3’UTR區(qū)完全或者部分結(jié)合，使靶基因mRNA切割或翻譯抑制，從而影響細(xì)胞生長(zhǎng)、分化、凋亡等重要過程[15,16]，參與調(diào)節(jié)轉(zhuǎn)錄后水平基因功能的表達(dá)[17,18]。它們調(diào)節(jié)腫瘤新生血管的生成、發(fā)生、發(fā)展、轉(zhuǎn)移及耐藥等多種生物學(xué)過程，近代生物信息學(xué)數(shù)據(jù)表明，每個(gè)MicroRNA可以控制數(shù)百個(gè)靶基因，MicroRNA幾乎在每一個(gè)遺傳途徑都存在潛在影響。最近的證據(jù)表明MicroRNA的突變或錯(cuò)表達(dá)與各種人類癌癥關(guān)聯(lián)，表明MicroRNA類似于腫瘤的抑癌基因和癌基因。微RNA已顯示抑制的重要的癌癥相關(guān)基因的表達(dá)，并可能被證明在診斷和治療癌癥是有用的[19,20]。隨著第一個(gè)癌癥靶向小分子 RNA（MicroRNA）的藥物-MRX34，基于脂質(zhì)體的miR-34模擬物于2013年4月在Ⅰ期肝癌患者身上進(jìn)行臨床試驗(yàn)，標(biāo)志著MicroRNA和其他非編碼RNA已逐漸作為抗癌藥物開發(fā)的新目標(biāo)[21]。

二、microRNA與腫瘤耐藥

隨著國(guó)內(nèi)外研究的不斷深入，發(fā)現(xiàn)腫瘤化療耐藥機(jī)制十分復(fù)雜。目前已明確的化療耐藥機(jī)制包括：藥物吸收減少、藥物排泄增加、細(xì)胞解毒系統(tǒng)的活化、藥物靶點(diǎn)的改變、藥物的改變或失活、DNA損傷修復(fù)增強(qiáng)、藥物誘導(dǎo)細(xì)胞凋亡的減少、藥物代謝途徑改變以及藥物誘導(dǎo)的細(xì)胞核型改變等[22,23]。目前研究較多是與藥物排泄相關(guān)的能量依賴轉(zhuǎn)運(yùn)體[24]，如ABC轉(zhuǎn)運(yùn)體、DNA錯(cuò)配修復(fù)系統(tǒng)、細(xì)胞凋亡蛋白及谷胱甘肽S轉(zhuǎn)移酶等。這些重要基因發(fā)生的一系列改變是導(dǎo)致腫瘤細(xì)胞產(chǎn)生耐藥性的主要機(jī)制之一。這些基因的改變包括突變、缺失、擴(kuò)增、轉(zhuǎn)置、DNA的異常甲基化以及microRNA的轉(zhuǎn)錄后調(diào)節(jié)等多種方式。近期有研究表明microRNA與腫瘤細(xì)胞對(duì)化療藥物的敏感程度密切相關(guān)，microRNA的突變、異常表達(dá)和異常加工均會(huì)影響microRNA的正常功能，進(jìn)而影響其靶基因的表達(dá)水平。若此類靶基因與腫瘤細(xì)胞耐藥性相關(guān)，將改變腫瘤細(xì)胞的藥物敏感程度。因此microRNA已成為腫瘤耐藥研究領(lǐng)域一個(gè)熱點(diǎn)[25]。例如：miR-21靶向調(diào)控MMR導(dǎo)致MMR過表達(dá)，MMR通過減少突變失配來抑制大腸癌細(xì)胞G/ M期阻滯和細(xì)胞凋亡，從而增強(qiáng)大腸癌細(xì)胞對(duì)5-FU的耐藥性[26]。

三、microRNA與膠質(zhì)瘤替莫唑胺耐藥基因

1.MicroRNA-138與BIM

證據(jù)表明，在膠質(zhì)瘤細(xì)胞中，MicroRNA-138通過調(diào)節(jié)細(xì)胞凋亡和自噬介導(dǎo)膠質(zhì)瘤對(duì)替莫唑胺耐藥，使其生長(zhǎng)和存活[27]。Stojcheva等[28]研究結(jié)果表明，膠質(zhì)瘤細(xì)胞長(zhǎng)期暴露在替莫唑胺環(huán)境下，MicroRNA-138可以通過靶向抑制細(xì)胞凋亡蛋白BIM從而抑制自噬介導(dǎo)替莫唑胺化療耐藥，并且發(fā)現(xiàn)這種調(diào)節(jié)作用伴有抑制凋亡因子Bcl-2的參與。

2.MicroRNA-16與Bcl-2

高度保守的MicroRNA-16是第一個(gè)被實(shí)驗(yàn)驗(yàn)證的與人類惡性腫瘤密切相關(guān)的微小RNA[29]，它可以調(diào)節(jié)細(xì)胞周期、抑制細(xì)胞增殖、促進(jìn)細(xì)胞凋亡和抑制腫瘤發(fā)生[30]。MicroRNA-16在許多腫瘤中低表達(dá)，如慢性淋巴細(xì)胞白血病、前列腺癌、肺癌等[31-33]。Han等[34]通過實(shí)驗(yàn)發(fā)現(xiàn)，在U251MG細(xì)胞中上調(diào)MicroRNA-16將導(dǎo)致Bcl-2蛋白表達(dá)水平下降，增強(qiáng)膠質(zhì)瘤細(xì)胞對(duì)替莫唑胺的敏感性。相反，下調(diào)MicroRNA-16，Bcl-2蛋白表達(dá)水平上升，將增強(qiáng)膠質(zhì)瘤對(duì)替莫唑胺的耐藥性。

3.MicroRNA-125b與Bak1

MicroRNA-125b相當(dāng)于一個(gè)潛在的致癌基因，現(xiàn)已證明其在惡性膠質(zhì)瘤干細(xì)胞和干細(xì)胞分裂中是必需的[35]，它能影響人類神經(jīng)膠質(zhì)瘤細(xì)胞的凋亡和擴(kuò)散。此外，越來越多的研究發(fā)現(xiàn)，MicroRNA-125b在某些腫瘤細(xì)胞中可能還影響它們的遷移和入侵[36]。前期研究表明，MicroRNA-125b低表達(dá)可以抑制U251膠質(zhì)瘤細(xì)胞的增殖，類似癌基因作用[37]。替莫唑胺可以有效地抑制神經(jīng)膠質(zhì)瘤細(xì)胞生長(zhǎng)和誘導(dǎo)細(xì)胞凋亡[38]，然而100 umol的替莫唑胺不能誘導(dǎo)膠質(zhì)瘤干細(xì)胞生長(zhǎng)抑制，但MicroRNA-125b抑制劑可以增加GSC對(duì)替莫唑胺的敏感性，抑制GSC的大量增殖和誘導(dǎo)細(xì)胞凋亡。Chen等[39]發(fā)現(xiàn)下調(diào)MicroRNA-125b導(dǎo)致Bak1過表達(dá)，此外，MicroRNA-125b抑制劑同樣使Bak1表達(dá)水平升高，以致提高了惡性膠質(zhì)瘤干細(xì)胞對(duì)替莫唑胺的化學(xué)敏感性。因此，MicroRNA-125b不僅負(fù)調(diào)控P53[40]，還負(fù)向調(diào)節(jié)Bak1，Bak1是細(xì)胞凋亡的調(diào)節(jié)器，它作用于線粒體，加速壓敏電阻器陰離子通道的開放，導(dǎo)致膜電位的損失和細(xì)胞色素c的釋放。MicroRNA-125b就是通過靶向調(diào)控Bak1調(diào)節(jié)線粒體途徑賦予人類惡性膠質(zhì)瘤干細(xì)胞抗替莫唑胺能力的。

4.MicroRNA-203與E2F3

越來越多的證據(jù)表明，MicroRNA-203的表達(dá)水平與癌細(xì)胞增殖、侵襲和耐藥性相關(guān)[41,42]。Tang等[43]通過實(shí)驗(yàn)證明，MicroRNA-203在U87MG細(xì)胞中的表達(dá)明顯比A172低，異位表達(dá)的MicroRNA-203顯著抑制U87MG細(xì)胞的侵襲和增強(qiáng)其對(duì)替莫唑胺的敏感性。相反，miR-203抑制劑明顯促進(jìn)A172細(xì)胞的侵襲和衰減它們對(duì)替莫唑胺的敏感性，MicroRNA-203與腫瘤的生物侵襲性呈負(fù)相關(guān)。因此，在神經(jīng)膠質(zhì)瘤細(xì)胞中，MicroRNA-203通過靶向調(diào)控E2F3，提高膠質(zhì)瘤細(xì)胞對(duì)替莫唑胺的敏感性和抑制其生物侵襲性。

四、展望

隨著國(guó)內(nèi)外學(xué)者對(duì)MicroRNA的不斷深入研究，已取得重大進(jìn)展。特別是對(duì)MicroRNA的作用機(jī)制及其在腫瘤臨床治療中的應(yīng)用。MicroRNA參與人體多種生物學(xué)過程及腫瘤的發(fā)生、發(fā)展、耐藥，機(jī)制十分復(fù)雜，因此，要完全闡明MicroRNA的機(jī)制需很長(zhǎng)一段時(shí)間努力及更進(jìn)一步的研究。

現(xiàn)階段，手術(shù)切除加化療是治療膠質(zhì)瘤的主要手段，而化療常用藥物是替莫唑胺，多個(gè)實(shí)驗(yàn)已證實(shí)，MicroRNA在對(duì)抗膠質(zhì)瘤化療藥物替莫唑胺的敏感性及耐受性中發(fā)揮重要作用。但是MicroRNA在膠質(zhì)瘤耐藥性中的研究尚處于萌芽階段，到目前為止，只發(fā)現(xiàn)少數(shù)耐藥基因，且功能及機(jī)制尚不清楚，匱乏的理論基礎(chǔ)不足于表明其能在臨床中發(fā)揮重要作用。

因此，從分子細(xì)胞生物學(xué)方面著手，找到影響膠質(zhì)瘤對(duì)替莫唑胺敏感程度的關(guān)鍵MicroRNA，這不僅有利于膠質(zhì)瘤細(xì)胞對(duì)替莫唑胺耐藥機(jī)理的的深入分析，更有利于尋找新的藥物作用靶標(biāo)及避免對(duì)藥物產(chǎn)生耐藥的關(guān)鍵點(diǎn)，更好地服務(wù)于臨床治療。相信隨著膠質(zhì)瘤耐藥機(jī)制的不斷深入研究，惡性膠質(zhì)瘤耐藥問題將逐步得到解決，膠質(zhì)瘤治愈將成為可能。

[1]Brodbelt A,Greenberg D,Winters T,et al.Glioblastoma in England:2007-2011[J].Eur J Cancer,2015,51(4):533-542.

[2]Desjardins A,Vlahovic G,Friedman HS.Vaccine Therapy, Oncolytic Viruses,and Gliomas[J].Oncology(Williston Park),2016, 30(3):211-218.

[3]Zhou X,Ren Y,Moore L,et al.Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status[J].Lab Invest, 2010,90(2):144-155.

[4]Miglierini P,Bouchekoua M,Rousseau B,et al.Impact of the per-operatory application of GLIADEL wafers(BCNU,carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme:efficacy and toxicity[J].Clin Neurol Neurosurg,2012,114(9):1222-1225.

[5]Plowman J,Waud WR,Koutsoukos AD,et al.Preclinical antitumor activity of temozolomide in mice:efficacy against human brain tumor xenografts and synergism with 1,3-bis(2-chloroethyl)-1-nitrosourea[J].Cancer Res,1994,54(14):3793-3799.

[6]McFaline-Figueroa JL,Braun CJ,Stanciu M,et al.Minor Changes in Expression of the Mismatch Repair Protein MSH2 Exert a Major Impact on Glioblastoma Response to Temozolomide [J].Cancer Res,2015,75(15):3127-3138.

[7]Feng R,Dong L.Knockdown of micro RNA-127 reverses adriamycin resistance via cell cycle arrest and apoptosis sensitization in adriamycin-resistant human glioma cells[J].Int J Clin Exp Pathol,2015,8(6):6107-6116.

[8]Munoz JL, Rodriguez-Cruz V,Ramkissoon SH,et al. Temozolomide resistance in glioblastoma occurs by miRNA-9-targeted PTCH1,independent of sonic hedgehog level[J]. Oncotarget,2015,6(2):1190-1201.

[9]Shi L,Zhang S,Feng K,et al.MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis[J].Int J Oncol,2012,40(1): 119-129.

[10]Wu H,Liu Q,Cai T,et al.MiR-136 modulates glioma cell sensitivity to temozolomide by targeting astrocyte elevated gene-1 [J].Diagn Pathol,2014,9:173.

[11]Li P,Lu X,Wang Y,et al.MiR-181b suppresses proliferation of and reduces chemoresistance to temozolomide in U87 glioma stem cells[J].J Biomed Res,2010,24(6):436-443.

[12]Quintavalle C,Mangani D,Roscigno G,et al.MiR-221/222 target the DNA methyltransferase MGMT in glioma cells[J].PLoS One, 2013,8(9):e74466.

[13]Lee RC,Feinbaum RL,Ambros V.The C.elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14[J].Cell,1993,75(5):843-854.

[14]Mestdagh P,Hartmann N,Baeriswyl L,et al.Evaluation of quantitative miRNA expression platforms in the microRNA quality control(miRQC)study[J].Nat Methods,2014,11(8):809-815.

[15]Stahlhut Espinosa CE,Slack FJ.The role of microRNAs in cancer[J].Yale J Biol Med,2006,79(3-4):131-140.

[16]Shen J,Hung MC.Signaling-mediated regulation of MicroRNA processing[J].Cancer Res,2015,75(5):783-791.

[17]Khorkova O,Myers AJ,Hsiao J,et al.Natural antisense transcripts[J].Hum Mol Genet,2014,23(R1):R54-R63.

[18]Garajova I,Le Large TY,Giovannetti E,et al.The Role of MicroRNAs in Resistance to Current Pancreatic Cancer Treatment:Translational Studies and Basic Protocols for Extraction and PCR Analysis[J].Methods Mol Biol,2016,1395: 163-187.

[19]Esquela-Kerscher A,Slack FJ.Oncomirs-microRNAs with a role in cancer[J].Nat Rev Cancer,2006,6(4):259-269.

[20]Weber F,Teresi RE,Broelsch CE,et al.A limited set of human MicroRNA is deregulated in follicular thyroid carcinoma[J].J Clin Endocrinol Metab,2006,91(9):3584-3591.

[21]Ling H,Fabbri M,Calin GA.MicroRNAs and other non-coding RNAs as targets for anticancer drug development[J].Nat Rev Drug Discov,2013,12(11):847-865.

[22]Gottesman MM.Mechanisms of cancer drug resistance[J].Annu Rev Med,2002,53:615-627.

[23]Khamisipour G,Jadidi-Niaragh F,Jahromi AS,et al.Mechanisms of tumor cell resistance to the current targeted-therapy agents[J]. Tumour Biol,2016.

[24]Rigalli JP,Ciriaci N,Mottino AD,et al.Modulation of expression and activity of ABC transporters by the phytoestrogen genistein. Impact on drug disposition[J].Curr Med Chem,2016,23(13): 1370-13789.

[25]Berman M,Mattheolabakis G,Suresh M,et al.Reversing epigenetic mechanisms of drug resistance in solid tumors using targeted microRNA delivery[J].Expert Opin Drug Deliv,2016,13 (7):987-998.

[26]Tomimaru Y,Eguchi H,Nagano H,et al.MicroRNA-21 induces resistance to the anti-tumour effect of interferon-alpha/5-fluorouracil in hepatocellular carcinoma cells[J].Br J Cancer, 2010,103(10):1617-1626.

[27]Chan XH,Nama S,Gopal F,et al.Targeting glioma stem cells by functional inhibition of a prosurvival oncomiR-138 in malignant gliomas[J].Cell Rep,2012,2(3):591-602.

[28]Stojcheva N,Schechtmann G,Sass S,et al.MicroRNA-138 promotes acquired alkylator resistance in glioblastoma by targeting the Bcl-2-interacting mediator BIM[J].Oncotarget,2016,7(11): 12937-12950.

[29]Calin GA,Dumitru CD,Shimizu M,et al.Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia[J].Proc Natl Acad Sci USA,2002,99(24):15524-15529.

[30]Aqeilan RI,Calin GA,Croce CM.miR-15a and miR-16-1 in cancer:discovery,function and future perspectives[J].Cell Death Differ,2010,17(2):215-220.

[31]Kasar S,Underbayev C,Hassan M,et al.Alterations in the mir-15a/16-1 Loci Impairs Its Processing and Augments B-1 Expansion in De Novo Mouse Model of Chronic Lymphocytic Leukemia(CLL)[J].PLoS One,2016,11(3):e149331.

[32]Porkka KP,Ogg EL,Saramaki OR,et al.The miR-15a-miR-16-1 locus is homozygously deleted in a subset of prostate cancers[J]. Genes Chromosomes Cancer,2011,50(7):499-509.

[33]Lan F,Yue X,Ren G,et al.miR-15a/16 enhances radiation sensitivity of non-small cell lung cancer cells by targeting the TLR1/NF-kappaB signaling pathway[J].Int J Radiat Oncol Biol Phys,2015,91(1):73-81.

[34]Han J,Chen Q.MiR-16 modulate temozolomide resistance by regulating BCL-2 in human glioma cells[J].Int J Clin Exp Pathol,2015,8(10):12698-12707.

[35]Shi L,Zhang S,Feng K,et al.MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis[J].Int J Oncol,2012,40(1): 119-129.

[36]Cairo S,Wang Y,de Reynies A,et al.Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer[J].Proc Natl Acad Sci USA,2010,107(47):20471-20476.

[37]Shi L,Zhang J,Pan T,et al.MiR-125b is critical for the suppression of human U251 glioma stem cell proliferation[J]. Brain Res,2010,1312:120-126.

[38]Kim JT,Kim JS,Ko KW,et al.Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas[J].Oncol Rep,2006,16(1):33-39.

[39]Chen J,Fu X,Wan Y,et al.miR-125b inhibitor enhance the chemosensitivity of glioblastoma stem cells to temozolomide by targeting Bak1[J].Tumour Biol,2014,35(7):6293-6302.

[40]Le MT,Teh C,Shyh-Chang N,et al.MicroRNA-125b is a novel negative regulator of p53[J].Genes Dev,2009,23(7):862-876.

[41]Zhang Z,Zhang B,Li W,et al.Epigenetic Silencing of miR-203 Upregulates SNAI2 and Contributes to the Invasiveness of Malignant Breast Cancer Cells[J].Genes Cancer,2011,2(8):782-791.

[42]Li Y,Yuan Y,Tao K,et al.Inhibition of BCR/ABL protein expression by miR-203 sensitizes for imatinib mesylate[J].PLoS One,2013,8(4):e61858.

[43]Tang G,Wu J,Xiao G,et al.MiR-203 sensitizes glioma cells to temozolomide and inhibits glioma cell invasion by targeting E2F3 [J].Mol Med Rep,2015,11(4):2838-2844.

Advances in Glioma Temozolomide-Resistance Regulated by MicroRNA

Xu Yongming,Wang Hongqin.Department of Neurosurgery,First Hospital of Shanxi Medical University,Taiyuan 030001, China

Wang Hongqin,Email:whq1968hq@163.com

MicroRNAs(miRNA)are small non-coding RNAs of endogenous small molecules, which are important to regulate the post-transcription of gene expression.MiRNAs in glioma drug resistance has been explored and researched,found that the miRNA plays an important role in drug resistance.Currently,we made a systematic review of the miRNA and Glioma for Temozolomide(TMZ) chemotherapy drug resistance gene for promoting specific pathways in Glioma of new targeted therapy of the further development.

MicroRNA;Glioma;Temozolomide

2016-03-18）

（本文編輯：張麗）

10.3877/cma.j.issn.2095-9141.2016.04.012

國(guó)家自然科學(xué)基金(NO：81470115)

030001太原，山西醫(yī)科大學(xué)第一臨床醫(yī)學(xué)院神經(jīng)外科

王宏勤，Email：whq1968hq@163.com

徐勇明,王宏勤.MicroRNA調(diào)控膠質(zhì)瘤替莫唑胺化療耐藥的研究進(jìn)展[J/CD].中華神經(jīng)創(chuàng)傷外科電子雜志,2016,2(4):241-244.