司鑫鑫, 孫玉潔

江蘇省人類功能基因組學(xué)重點(diǎn)實驗室, 南京醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院細(xì)胞生物學(xué)系, 南京210029

DNA甲基化異常與腫瘤耐藥

司鑫鑫, 孫玉潔

江蘇省人類功能基因組學(xué)重點(diǎn)實驗室, 南京醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院細(xì)胞生物學(xué)系, 南京210029

腫瘤耐藥是導(dǎo)致腫瘤化療失敗的主要原因, 其產(chǎn)生機(jī)制復(fù)雜多樣, 是多種因素共同作用的結(jié)果。近年來,表觀遺傳改變在腫瘤耐藥中的作用日益受到關(guān)注。DNA甲基化是一種重要的表觀遺傳修飾, 在調(diào)節(jié)基因表達(dá)和維持基因組穩(wěn)定性中扮演著重要角色。原發(fā)性或獲得性耐藥的腫瘤細(xì)胞大多伴隨 DNA異常甲基化, 越來越多的證據(jù)顯示, DNA甲基化異常是腫瘤細(xì)胞耐藥表型產(chǎn)生的重要機(jī)制。文章就DNA甲基化異常與腫瘤細(xì)胞耐藥的關(guān)系及相關(guān)作用機(jī)制進(jìn)行了綜述。

腫瘤耐藥; DNA甲基化; 基因組穩(wěn)定性; 基因表達(dá)

惡性腫瘤是危害人類健康的重大疾病, 化療是治療惡性腫瘤的重要手段之一。盡管隨著新藥的問世和醫(yī)療水平的提高, 腫瘤治療水平得到極大提高,但腫瘤耐藥依然是臨床腫瘤治療的主要障礙之一,其機(jī)制復(fù)雜多樣, 是多種因素共同參與的結(jié)果[1,2],如細(xì)胞抗凋亡能力增強(qiáng)、DNA損傷修復(fù)能力異常、ATP依賴性藥物轉(zhuǎn)運(yùn)泵表達(dá)上調(diào)、藥物代謝改變等,這其中涉及一系列基因表達(dá)調(diào)控的異常。越來越多的證據(jù)顯示, DNA甲基化異常是腫瘤細(xì)胞耐藥表型產(chǎn)生的重要機(jī)制。認(rèn)識DNA甲基化改變在腫瘤耐藥性形成過程中的作用, 對于更好地認(rèn)識腫瘤耐藥的產(chǎn)生機(jī)制, 進(jìn)而有效預(yù)防和逆轉(zhuǎn)耐藥表型具有重要的意義。

1 特定基因的甲基化異常與腫瘤耐藥

化療藥物通過引起DNA損傷、抑制增殖、促進(jìn)細(xì)胞凋亡等多種途徑殺死腫瘤細(xì)胞, 如：鉑類藥物可引起DNA鏈間或鏈內(nèi)交聯(lián), 造成DNA斷裂, 抑制DNA和RNA合成, 抑制細(xì)胞有絲分裂; 喜樹堿類化療藥物可抑制拓?fù)洚悩?gòu)酶Ⅰ, 阻止 DNA解旋,造成DNA損傷, 誘導(dǎo)細(xì)胞凋亡; 植物類藥物如長春新堿、紫杉醇等, 可與微管結(jié)合影響其穩(wěn)定性, 使有絲分裂停滯。腫瘤細(xì)胞內(nèi)上述相關(guān)通路中的基因啟動子甲基化水平異常所致表達(dá)改變均可能影響腫瘤細(xì)胞對化療藥物的敏感性。

1.1 DNA損傷修復(fù)基因的異常甲基化與腫瘤耐藥

烷化劑、鉑類等多種化療藥物能破壞DNA結(jié)構(gòu)引起DNA損傷, 帶有DNA損傷的細(xì)胞必須在細(xì)胞周期中暫停, 以便得到及時修復(fù)。DNA損傷修復(fù)是恢復(fù) DNA正常序列結(jié)構(gòu)和維持遺傳信息相對穩(wěn)定的細(xì)胞反應(yīng), 包括錯配修復(fù)、切除修復(fù)、雙鏈斷裂修復(fù)等。DNA損傷修復(fù)能力的改變是多種化療藥物耐藥的重要分子基礎(chǔ)。

DNA錯配修復(fù)系統(tǒng)在腫瘤細(xì)胞中常表現(xiàn)為功能異常。錯配修復(fù)系統(tǒng)的失活, 除了在多種腫瘤的發(fā)生過程中發(fā)揮重要作用, 也是導(dǎo)致惡性腫瘤耐藥的一個重要因素。錯配修復(fù)系統(tǒng)失活使細(xì)胞監(jiān)測DNA損傷的能力下降, 因而不能激活凋亡反應(yīng); 基因突變率升高, 基因組不穩(wěn)定性增加, 直接或間接地促進(jìn)腫瘤耐藥表型的形成[3,4]。DNA甲基化升高可以導(dǎo)致錯配修復(fù)基因失活, 加強(qiáng)腫瘤細(xì)胞耐藥性。例如：在順鉑耐藥的卵巢癌細(xì)胞中, 編碼DNA錯配修復(fù)酶的hMLH1基因啟動子的甲基化水平升高, 基因表達(dá)水平下降; 用甲基轉(zhuǎn)移酶抑制劑處理該細(xì)胞,可恢復(fù)hMLH1表達(dá), 并能部分恢復(fù)耐藥細(xì)胞對順鉑的敏感性[5,6]。比較臨床卵巢癌患者在化療前和復(fù)發(fā)時的血漿hMLH1啟動子甲基化水平, 發(fā)現(xiàn)25%的患者在化療前無hMLH1甲基化而復(fù)發(fā)時hMLH1發(fā)生甲基化并伴有微衛(wèi)星不穩(wěn)定性[7]。

乳腺癌易感基因 BRCA1被認(rèn)為是基因組的看護(hù)者, 在DNA損傷修復(fù)、細(xì)胞周期調(diào)控等過程中發(fā)揮重要作用[8]。當(dāng)細(xì)胞內(nèi)發(fā)生DNA雙鏈斷裂, H2AX快速磷酸化, 將BRCA1募集到DNA損傷位點(diǎn), 與Rad51、BRCA2、Rad50/Mre11/p95等相互作用, 對損傷 DNA進(jìn)行修復(fù)[9,10]。有研究報道, BRCA1的DNA損傷修復(fù)功能參與了腫瘤耐藥。在MCF7的順鉑耐藥細(xì)胞中BRCA1高表達(dá), DNA修復(fù)能力明顯增強(qiáng); 用siRNA下調(diào)耐藥細(xì)胞中BRCA1表達(dá)水平, 順鉑處理所產(chǎn)生的DNA損傷不能被及時修復(fù), 凋亡增多, 細(xì)胞對順鉑的耐藥性下降[11]。臨床研究也發(fā)現(xiàn),乳腺癌和卵巢癌患者的 BRCA1表達(dá)水平可作為化療藥物的選擇依據(jù), BRCA1功能缺失的腫瘤細(xì)胞對DNA靶向的化療藥物及紡錘體毒性藥物更敏感[12]。啟動子區(qū)甲基化異常是造成 BRCA1表達(dá)改變的主要原因之一[13]。BRCA1基因啟動子區(qū)的甲基化水平和卵巢癌患者對鉑類化療的敏感性呈正相關(guān)[14]。

1.2 凋亡相關(guān)基因的異常甲基化與腫瘤耐藥

多數(shù)化療藥物可通過誘導(dǎo)細(xì)胞凋亡來殺死腫瘤細(xì)胞, 反之, 腫瘤細(xì)胞也可通過逃逸或拮抗凋亡獲得生存[15]。凋亡酶激活因子-1(APAF1)是一種促凋亡基因, 在線粒體參與的凋亡途徑中具有重要作用。APAF1陰性的黑色素瘤細(xì)胞對各種化療藥物均有不同程度的耐受, 用DNA甲基轉(zhuǎn)移酶抑制劑處理, 可恢復(fù)其表達(dá), 腫瘤細(xì)胞對化療的敏感性也隨之升高[16,17]。CASP8也是一種促凋亡基因, 是死亡受體介導(dǎo)的凋亡途徑中的關(guān)鍵啟動子。研究發(fā)現(xiàn), 在多種腫瘤細(xì)胞中 CASP8基因的啟動子均被甲基化, DNA甲基轉(zhuǎn)移酶抑制劑處理可逆轉(zhuǎn) CASP8的高甲基化, 提高腫瘤細(xì)胞對多種化療藥物如阿霉素、依托泊苷、順鉑等的敏感性[18]。Chaopatchayakul等[19]檢測了化療敏感和耐受的宮頸癌患者樣本中一系列凋亡基因的甲基化水平, 發(fā)現(xiàn)化療耐受組患者的死亡相關(guān)蛋白激酶基因(DAPK)和腫瘤壞死因子受體超家族成員(FAS)的甲基化水平更高。DAPK和 FAS基因的高甲基化導(dǎo)致其表達(dá)沉默, 使腫瘤細(xì)胞可以逃逸化療藥物引起的凋亡反應(yīng)從而獲得生存。腫瘤細(xì)胞內(nèi)凋亡信號通路上相關(guān)基因的甲基化異常可引起凋亡反應(yīng)能力的改變, 治療前及治療過程中監(jiān)測這些基因的甲基化水平, 可為優(yōu)化腫瘤患者化療方案及預(yù)后評估提供重要依據(jù)。

1.3 藥物轉(zhuǎn)運(yùn)及藥物代謝基因的異常甲基化與腫瘤耐藥

ATP結(jié)合盒(ATP-binding cassette, ABC)轉(zhuǎn)運(yùn)蛋白是ATP依賴性藥物外排泵, 利用ATP作為能源跨膜轉(zhuǎn)運(yùn)許多物質(zhì), 如離子、氨基酸、蛋白質(zhì)、糖類、磷脂和藥物等, 其表達(dá)或功能異常是腫瘤細(xì)胞產(chǎn)生多藥耐藥的重要機(jī)制。目前已知人類基因組共包含48個具有轉(zhuǎn)錄活性的ABC轉(zhuǎn)運(yùn)子基因, 其中與多藥耐藥相關(guān)的主要有MDR1(ABCB1)、MRPs(ABCC家族)、BCRP(ABCG2)等[20]。藥物轉(zhuǎn)運(yùn)基因啟動子的低甲基化可以促進(jìn)這些基因的表達(dá), 增強(qiáng)細(xì)胞泵出藥物的能力, 降低腫瘤細(xì)胞內(nèi)的藥物濃度, 削弱藥物的細(xì)胞毒性[20]。臨床資料顯示, 膀胱癌病人化療后MDR1的表達(dá)比化療前升高3.5～5.7倍, 89%的復(fù)發(fā)病人MDR1高表達(dá), 且MDR1的表達(dá)水平與基因啟動子甲基化水平呈顯著負(fù)相關(guān)[21]。Kusaba等[22]用長春新堿和阿霉素處理鱗狀細(xì)胞癌KB3-1誘導(dǎo)得到長春新堿耐藥細(xì)胞 KB/VJ300和阿霉素耐藥細(xì)胞KB-C1, 發(fā)現(xiàn)與敏感細(xì)胞相比, 兩株耐藥細(xì)胞中MDR1基因啟動子甲基化水平下降, 其表達(dá)顯著升高。ABCG2是另一個與耐藥有關(guān)的轉(zhuǎn)運(yùn)蛋白。ABCG2高甲基化的腫瘤細(xì)胞對其底物化療藥物如米托蒽醌、拓?fù)涮婵档让舾? 而ABCG2低甲基化的腫瘤細(xì)胞對這些化療藥耐受[23]。Bram等[24]發(fā)現(xiàn)用柳氮磺吡啶和拓?fù)涮婵堤幚戆籽〖?xì)胞和卵巢癌細(xì)胞12～24 h可誘導(dǎo)ABCG2基因啟動子的完全去甲基化,使ABCG2轉(zhuǎn)錄升高235倍從而獲得ABCG2依賴性的耐藥表型, 這表明化療藥處理后 ABCG2的表觀激活是腫瘤細(xì)胞耐藥性產(chǎn)生的早期事件。其他一些研究也都發(fā)現(xiàn)類似結(jié)果[25], 即化療藥物處理可引起腫瘤細(xì)胞內(nèi) ABC家族基因的啟動子甲基化水平下降從而表達(dá)升高, 獲得更強(qiáng)的藥物泵出能力, 產(chǎn)生化療耐藥。

藥物進(jìn)入體內(nèi), 會經(jīng)過一系列復(fù)雜的過程, 包括藥物的吸收、分布、代謝、排泄等。多數(shù)藥物經(jīng)過代謝后藥理作用減弱或消失, 少數(shù)藥物經(jīng)過代謝變?yōu)榛钚孕问桨l(fā)揮治療作用。藥物代謝酶(Cytochrome P450 proteins, CYP)的表達(dá)紊亂或活性變化, 是引起腫瘤耐藥的重要因素。長春堿類化療藥物經(jīng) CYP3A4代謝后為無毒性形式, 在大腸癌細(xì)胞 LS174T中誘導(dǎo) CYP3A4表達(dá)后, 可明顯增強(qiáng)細(xì)胞對長春花堿的耐受性[26]。另外, CYP3A可以通過減弱紫杉醇的藥理活性, 使大腸癌細(xì)胞耐受[27]。CYP基因在不同情況下(如腫瘤、吸煙等)甲基化水平會發(fā)生改變[28,29], 但耐藥腫瘤細(xì)胞中CYP基因的異常表達(dá)是否由啟動子甲基化改變所致, 則需要進(jìn)一步的研究證實。

1.4 腫瘤干細(xì)胞標(biāo)志基因的異常甲基化與腫瘤耐藥

腫瘤干細(xì)胞學(xué)說認(rèn)為腫瘤組織中存在一群比例很小但具有自我更新能力和無限增殖潛能的細(xì)胞,即腫瘤干細(xì)胞, 它們不僅是腫瘤發(fā)生的始動細(xì)胞,而且可能是導(dǎo)致腫瘤耐藥的主要原因[30,31]。已知干性因子OCT4、SOX2等在腫瘤干細(xì)胞形成和干性維持過程中發(fā)揮重要作用[32～35], 且這些基因的表達(dá)都受甲基化調(diào)控[36,37], 提示干細(xì)胞標(biāo)志基因的甲基化水平改變可能會影響腫瘤細(xì)胞對化療藥物的敏感性。Wang等[38]發(fā)現(xiàn)耐藥的肝癌組織中OCT4轉(zhuǎn)錄水平明顯升高; 在敏感細(xì)胞內(nèi)過表達(dá)或在耐藥細(xì)胞內(nèi)干擾 OCT4表達(dá), 可相應(yīng)增強(qiáng)或降低腫瘤細(xì)胞對化療藥物的耐藥性。進(jìn)一步實驗發(fā)現(xiàn), 耐藥腫瘤細(xì)胞內(nèi)OCT4啟動子甲基化水平下降導(dǎo)致了OCT4轉(zhuǎn)錄水平的升高。這些結(jié)果提示, DNA甲基化水平異常可能通過影響腫瘤干細(xì)胞形成或維持進(jìn)而改變化療敏感性。

總之, 細(xì)胞的多種生物學(xué)機(jī)制是否正常有效地發(fā)揮作用, 決定了細(xì)胞對外界環(huán)境包括藥物的反應(yīng)性。腫瘤細(xì)胞在其形成過程以及接受藥物處理過程中發(fā)生的表觀遺傳學(xué)改變, 在很大程度上賦予部分腫瘤細(xì)胞特定的生存優(yōu)勢, 形成耐藥表型。與腫瘤耐藥相關(guān)的一些異常甲基化改變見表1。

2 全基因組甲基化水平異常與腫瘤耐藥

耐藥的腫瘤細(xì)胞內(nèi)除了發(fā)生某些特定基因的甲基化水平異常, 同時還會發(fā)生全基因組甲基化水平的異常。Nyce等[42]選用多種化療藥物處理肺癌細(xì)胞HTB-54和橫紋肌肉瘤細(xì)胞 CCI-136, 發(fā)現(xiàn)依托泊苷、阿霉素、長春新堿、順鉑、5-氟尿嘧啶、甲氨喋呤等可使HTB-54和CCI-136的全基因組甲基化水平明顯升高。Kastl等[43]用多西紫杉醇誘導(dǎo)MDAMB-231和 MCF7細(xì)胞得到兩株多西紫杉醇耐藥細(xì)胞, 檢測發(fā)現(xiàn) MCF7耐藥細(xì)胞中全基因組甲基化水平升高, 而 MDA-MB-231耐藥細(xì)胞中略下降。Segura-Pacheco等[44]在 MCF7的阿霉素耐藥細(xì)胞中也檢測到全基因組甲基化水平升高, 降低全基因組甲基化水平可部分恢復(fù)耐藥細(xì)胞對阿霉素的敏感性。本實驗室也觀察到類似現(xiàn)象, 與敏感細(xì)胞相比, MDA-MB-231的紫杉醇耐藥細(xì)胞中全基因組甲基化水平下降; 而在 MCF7的紫杉醇耐藥細(xì)胞中全基因組甲基化水平升高[45]。

表1 與腫瘤耐藥相關(guān)的異常甲基化

化療藥物引起基因組 DNA甲基化水平改變的機(jī)制尚不清楚。Nyce等[42]認(rèn)為化療藥物會引起全基因組甲基化水平升高可能是因為這些藥物能引起復(fù)制叉停滯, DNA甲基轉(zhuǎn)移酶(DNA methyltransferases, DNMTs)與新合成的DNA作用時間延長, 更多的胞嘧啶發(fā)生甲基化, 其研究結(jié)果也證實了上述推測。

DNA甲基轉(zhuǎn)移酶的表達(dá)改變也能直接影響全基因組甲基化水平。DNA甲基轉(zhuǎn)移酶的表達(dá)受多種轉(zhuǎn)錄因子調(diào)控, 如雌激素受體(Estrogen receptor alpha, ERα)。Cui等[46]發(fā)現(xiàn), ERα可增強(qiáng)DNMT3b基因的轉(zhuǎn)錄活性。用 10-8M的雌激素處理子宮內(nèi)膜癌細(xì)胞可上調(diào)DNMT3b的表達(dá), 細(xì)胞的DNA從頭甲基化能力增強(qiáng); 用 ERα抑制劑預(yù)處理, 可抑制雌激素引起的 DNMT3b過表達(dá), 表明雌激素激活DNMT3b是ERα依賴性的。本實驗室研究結(jié)果發(fā)現(xiàn), ERα可增強(qiáng) DNMT1基因啟動子的活性[45]。ERα在很多耐藥的腫瘤細(xì)胞中表達(dá)異常, ERα表達(dá)或活性的改變會引起其靶基因DNMT1和DNMT3b的表達(dá)異常, 進(jìn)而影響全基因組甲基化水平。由此可以推測, 任意一種影響ERα的表達(dá)或活性的藥物均可能影響細(xì)胞內(nèi)全基因組甲基化水平, 進(jìn)而影響細(xì)胞對藥物的反應(yīng)性。

全基因組甲基化水平的升高或下降都會影響腫瘤細(xì)胞對化療藥物的敏感性。全基因組異常高甲基化對腫瘤耐藥的作用機(jī)制目前還沒有很好的闡述,可能通過沉默特定基因進(jìn)而干擾DNA損傷修復(fù)、細(xì)胞凋亡和細(xì)胞周期等關(guān)鍵信號通路促進(jìn)腫瘤耐藥。全基因組異常低甲基化可造成基因組不穩(wěn)定[47～49],促進(jìn)耐藥亞群細(xì)胞的產(chǎn)生, 作用機(jī)制尚不很清楚,可能通過以下兩方面：(1)激活反轉(zhuǎn)座元件：分散在真核生物基因組中的大量逆轉(zhuǎn)座子是引起基因組不穩(wěn)定的重要因素, 可引起基因序列缺失、擴(kuò)增、易位等[50～52]。LINE-1是一種自主性逆轉(zhuǎn)座子, 在人類基因組中廣泛分布, 能編碼ORF1和ORF2兩種蛋白,其中ORF2具有核酸內(nèi)切酶活性, 可以導(dǎo)致DNA雙鏈斷裂以及基因組不穩(wěn)定。在大多數(shù)情況下, LINE-1啟動子因高度甲基化而處于沉默狀態(tài), 但在某些特殊情況下 LINE-1啟動子可發(fā)生去甲基化而被激活; (2)中心粒周圍異染色質(zhì)去凝集, 形成可以重組的染色質(zhì)構(gòu)象[53]：異染色質(zhì)中的組蛋白去乙?；虳NA高度甲基化使其處于高度壓縮致密狀態(tài), 當(dāng)基因組DNA去甲基化, 異染色質(zhì)區(qū)結(jié)構(gòu)松散, 基因組不穩(wěn)定性升高[54,55]。目前認(rèn)為全基因組異常低甲基化會促進(jìn)基因組不穩(wěn)定, 但有趣的是, 本課題組在全基因組甲基化升高的MCF7耐藥細(xì)胞中也發(fā)現(xiàn)了拷貝數(shù)變異顯著增加, 顯示基因組不穩(wěn)定性升高。顯然, 全基因組甲基化水平應(yīng)處在一個穩(wěn)態(tài)范圍內(nèi),過高或過低都將削弱基因組穩(wěn)定性。

基因組不穩(wěn)定性是一種以遺傳改變頻率升高為特點(diǎn)的細(xì)胞狀態(tài), 包括突變、重復(fù)或缺失、易位、異倍體等[56]。在許多腫瘤中, 如乳腺癌、大腸癌、肺癌, 基因組不穩(wěn)定性與原發(fā)性耐藥、獲得性耐藥以及腫瘤的不良預(yù)后相關(guān)[57～59]。腫瘤細(xì)胞的基因組不穩(wěn)定有利于細(xì)胞在面對外界不利的生存壓力時產(chǎn)生適應(yīng)性改變從而存活, 并且這種改變是可以遺傳的。惡性細(xì)胞的演化本質(zhì)上都符合達(dá)爾文進(jìn)化規(guī)律,基因組不穩(wěn)定性和腫瘤所處微環(huán)境的選擇壓力, 使腫瘤細(xì)胞處在不斷的進(jìn)化演變中[60]?；蚪M不穩(wěn)定所產(chǎn)生的腫瘤異質(zhì)性是腫瘤進(jìn)化所需的原材料, 而選擇壓力則是加速這一過程的推動力?；熕幬锏拇嬖趯δ[瘤細(xì)胞群體是一種強(qiáng)烈的選擇壓力, 這種選擇壓力會加快進(jìn)化速度, 將本來存在的適應(yīng)性克隆篩選富集出來(原發(fā)性耐藥), 或者誘導(dǎo)產(chǎn)生新的適應(yīng)性改變(獲得性耐藥)。

全基因組 DNA甲基化異常與特定基因甲基化異常在腫瘤耐藥性形成過程中并不是相互排斥、相互獨(dú)立, 而是相輔相成、相互影響。重復(fù)序列LINE-1約占人類基因組的 20%[61], 其甲基化水平可在相當(dāng)程度上代表全基因組甲基化水平[62,63]。LINE-1可位于基因間也可位于基因內(nèi), 據(jù)統(tǒng)計, 有超過2000個活性LINE-1位于基因內(nèi)[64]。位于基因內(nèi)部的LINE-1被認(rèn)為是一種順式調(diào)控元件, 其調(diào)節(jié)基因表達(dá)的主要機(jī)制之一是LINE-1自身表觀修飾的改變[61]。位于基因啟動子區(qū)的LINE-1甲基化水平的變化, 可影響基因啟動子活性進(jìn)而調(diào)節(jié)其表達(dá)。特定基因的甲基化異常是整體基因組甲基化水平異常的部分體現(xiàn),全基因組甲基化異常也會影響特定基因的甲基化水平。

腫瘤細(xì)胞中的DNA甲基化模式發(fā)生改變, 這些改變不僅在腫瘤的發(fā)生發(fā)展過程中發(fā)揮重要作用,也是導(dǎo)致腫瘤耐藥的重要因素。如, 錯配修復(fù)基因hMLH1的異常高甲基化被認(rèn)為在微衛(wèi)星不穩(wěn)定性結(jié)直腸癌的形成過程中發(fā)揮重要作用, 是其癌變過程中的早期事件[65]; hMLH1異常甲基化也是導(dǎo)致腫瘤耐藥的重要因素, 錯配修復(fù)系統(tǒng)失活使腫瘤細(xì)胞監(jiān)測DNA損傷的能力下降, 不能激活凋亡反應(yīng), 對化療藥物耐受性增強(qiáng)[7,66]。促凋亡基因APAF-1異常高甲基化所致細(xì)胞凋亡能力下降, 是促進(jìn)腫瘤形成和腫瘤耐藥的重要分子機(jī)制[17]。然而, 腫瘤發(fā)生過程中產(chǎn)生的 DNA甲基化改變與耐藥過程中發(fā)生的DNA甲基化改變不可能完全相同, 是由于這兩種過程所涉及的細(xì)胞生物學(xué)改變和分子機(jī)制不盡相同,導(dǎo)致其改變的表觀遺傳修飾必有差異。例如, BRCA1是一個具有多重功能的蛋白, 在DNA損傷修復(fù)、轉(zhuǎn)錄調(diào)控中的功能最為顯著。BRCA1基因啟動子的高甲基化導(dǎo)致其表達(dá)下降, 與乳腺癌和卵巢癌的發(fā)生密切相關(guān)[13,67], 而BRCA1基因啟動子的低甲基化改變與腫瘤耐藥密切相關(guān), BRCA1甲基化程度越低,表達(dá)越高, 細(xì)胞損傷修復(fù)能力越強(qiáng), 對鉑類化療藥物的耐受性越好[14]。因此鑒定腫瘤發(fā)生發(fā)展過程及腫瘤耐藥過程中的DNA異常甲基化改變, 具有重要的理論意義和臨床應(yīng)用潛力。

3 對克服腫瘤耐藥的提示

DNA甲基化是一種可逆的表觀修飾, 認(rèn)識和探討DNA甲基化與腫瘤耐藥的關(guān)系及機(jī)制, 為臨床上控制腫瘤耐藥提供了新的可能性。一種可能是利用一些靶向 DNA甲基轉(zhuǎn)移酶的小分子化合物調(diào)節(jié)甲基轉(zhuǎn)移酶活性, 改變基因啟動子的甲基化狀態(tài)從而逆轉(zhuǎn)耐藥。例如：地西他濱是一種胞嘧啶脫氧核糖類似物, 能整合到DNA分子中, 與DNA甲基轉(zhuǎn)移酶形成加合物抑制其活性。除了在臨床骨髓增生異常綜合征和白血病的治療中取得了很好的療效[68,69],地西他濱還可以降低 hMLH1基因啟動子甲基化水平, 恢復(fù)細(xì)胞錯配修復(fù)功能, 從而逆轉(zhuǎn)卵巢癌細(xì)胞A2780/cp70對DDP的耐藥[5]。美國食品和藥品管理局已于2007年批準(zhǔn)地西他濱用于臨床試驗, 同期批準(zhǔn)使用的還有維達(dá)扎, 一種胞嘧啶核糖類似物[70]。另一種控制腫瘤耐藥的可能途徑是抑制或降低DNA甲基轉(zhuǎn)移酶的表達(dá)水平。已知DNA甲基轉(zhuǎn)移酶的表達(dá)受多種轉(zhuǎn)錄因子調(diào)控, 如雌激素受體 ERα可調(diào)節(jié)DNMT1和DNMT3b的轉(zhuǎn)錄水平[45,46], 因此可利用ERα拮抗劑間接調(diào)控基因組DNA 甲基化水平, 如能特異性下調(diào)ERα表達(dá)的氟維司群[71]。關(guān)于ERα及其拮抗劑氟維司群在乳腺癌耐藥中的作用已有一些研究, ERα與基因組甲基化改變及耐藥的關(guān)系和機(jī)制值得進(jìn)一步探討。

通過靶向 DNA甲基轉(zhuǎn)移酶逆轉(zhuǎn)腫瘤耐藥因特異性差而受到很大局限性, 在用于臨床治療時會產(chǎn)生較大的毒副作用。因此尋找特異性改變DNA甲基化的方法顯得尤為重要。最新研究發(fā)現(xiàn), 某些長鏈非編碼RNA能與DNMT1蛋白相互作用, 改變靶基因的DNA甲基化水平[72]。CEBPA基因可以轉(zhuǎn)錄一種不含 polyA 的額外編碼的 RNA(extra-coding CEBPA, ecCEBPA), 這種RNA在細(xì)胞核內(nèi)富集, 不被翻譯。當(dāng) DNMT1靠近 CEBPA基因啟動子時, ecCEBPA能與DNMT1蛋白相互作用, 阻止DNMT1與啟動子的結(jié)合, 防止CEBPA基因被甲基化, 上調(diào)其轉(zhuǎn)錄水平。這種相互作用不只局限于CEBPA基因,在細(xì)胞內(nèi)存在很多這種與 DNMT1相互作用的不含polyA的 RNA, 能調(diào)節(jié)特定基因的甲基化水平。暫不考慮ecRNA如何產(chǎn)生或用于臨床治療的可操作性如何, 它的出現(xiàn)意味著特異性改變靶基因的甲基化水平成為可能。

4 結(jié)語與展望

DNA甲基化異常在腫瘤耐藥性形成過程中發(fā)揮著重要作用。鑒于DNA甲基化可能影響不同的基因, 產(chǎn)生完全相反的效應(yīng), 因此, 利用 DNA甲基化機(jī)制逆轉(zhuǎn)腫瘤耐藥面臨著巨大挑戰(zhàn), 即確定具有生物標(biāo)志物性質(zhì)的甲基化模式。這意味著必須確定哪些或哪一組基因, 或什么程度的基因組甲基化改變是特定腫瘤細(xì)胞耐藥的驅(qū)動力, 哪些甲基化變化僅僅是伴隨出現(xiàn)的現(xiàn)象, 這將幫助確定哪些患者適合表觀遺傳治療, 這一目標(biāo)需要遺傳學(xué)研究和臨床醫(yī)生的聯(lián)手努力方可達(dá)成。

[1] Raguz S, Yague E. Resistance to chemotherapy: new treatments and novel insights into an old problem. Br J Cancer, 2008, 99(3): 387–391.

[2] Mellor HR, Callaghan R. Resistance to chemotherapy in cancer: a complex and integrated cellular response. Pharmacology, 2008, 81(4): 275–300.

[3] Aebi S, Kurdi-Haidar B, Gordon R, Cenni B, Zheng H, Fink D, Christen RD, Boland CR, Koi M, Fishel R, Howell SB. Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res, 1996, 56(13): 3087–3090.

[4] Fink D, Aebi S, Howell SB. The role of DNA mismatch repair in drug resistance. Clin Cancer Res, 1998, 4(1): 1–6.

[5] Plumb JA, Strathdee G, Sludden J, Kaye SB, Brown R. Reversal of drug resistance in human tumor xenografts by 2′-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res, 2000, 60(21): 6039–6044.

[6] Strathdee G, MacKean MJ, Illand M, Brown R. A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer. Oncogene, 1999, 18(14): 2335–2341.

[7] Gifford G, Paul J, Vasey PA, Kaye SB, Brown R. The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin Cancer Res, 2004, 10(13): 4420–4426.

[8] Li D, Kumaraswamy E, Harlan-Williams LM, Jensen RA. The role of BRCA1 and BRCA2 in prostate cancer. Front Biosci (Landmark Ed), 2013, 18(4): 1445–1459.

[9] Paull TT, Rogakou EP, Yamazaki V, Kirchgessner CU, Gellert M, Bonner WM. A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol, 2000, 10(15): 886–895.

[10] Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer, 2012, 12(12): 801–817.

[11] Husain A, He G, Venkatraman ES, Spriggs DR. BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II). Cancer Res, 1998, 58(6): 1120–1123.

[12] Kennedy RD, Quinn JE, Mullan PB, Johnston PG, Harkin DP. The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst, 2004, 96(22): 1659–1668.

[13] Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst, 2000, 92(7): 564–569.

[14] Teodoridis JM, Hall J, Marsh S, Kannall HD, Smyth C, Curto J, Siddiqui N, Gabra H, McLeod HL, Strathdee G, Brown R. CpG island methylation of DNA damage response genes in advanced ovarian cancer. Cancer Res, 2005, 65(19): 8961–8967.

[15] Tolomeo M, Simoni D. Drug resistance and apoptosis in cancer treatment: development of new apoptosis-inducing agents active in drug resistant malignancies. Curr Med Chem Anticancer Agents, 2002, 2(3): 387–401.

[16] Jones PA. Cancer: death and methylation. Nature, 2001, 409(6817): 141–144.

[17] Soengas MS, Capodieci P, Polsky D, Mora J, Esteller M,Opitz-Araya X, McCombie R, Herman JG, Gerald WL, Lazebnik YA, Cordon-Cardo C, Lowe SW. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature, 2001, 409(6817): 207–211.

[18] Fulda S, Kufer MU, Meyer E, van Valen F, Dockhorn-Dworniczak B, Debatin KM. Sensitization for death receptor- or drug-induced apoptosis by re-expression of caspase-8 through demethylation or gene transfer. Oncogene, 2001, 20(41): 5865–5877.

[19] Chaopatchayakul P, Jearanaikoon P, Yuenyao P, Limpaiboon T. Aberrant DNA methylation of apoptotic signaling genes in patients responsive and nonresponsive to therapy for cervical carcinoma. Am J Obstet Gynecol, 2010, 202(3): 281.e1–281.e9.

[20] Glavinas H, Krajcsi P, Cserepes J, Sarkadi B. The role of ABC transporters in drug resistance, metabolism and toxicity. Curr Drug Deliv, 2004, 1(1): 27–42.

[21] Tada Y, Wada M, Kuroiwa K, Kinugawa N, Harada T, Nagayama J, Nakagawa M, Naito S, Kuwano M. MDR1 gene overexpression and altered degree of methylation at the promoter region in bladder cancer during chemotherapeutic treatment. Clin Cancer Res, 2000, 6(12): 4618–4627.

[22] Kusaba H, Nakayama M, Harada T, Nomoto M, Kohno K, Kuwano M, Wada M. Association of 5' CpG demethylation and altered chromatin structure in the promoter region with transcriptional activation of the multidrug resistance 1 gene in human cancer cells. Eur J Biochem, 1999, 262(3): 924–932.

[23] To KK, Zhan Z, Bates SE. Aberrant promoter methylation of the ABCG2 gene in renal carcinoma. Mol Cell Biol, 2006, 26(22): 8572–8585.

[24] Bram EE, Stark M, Raz S, Assaraf YG. Chemotherapeutic drug-induced ABCG2 promoter demethylation as a novel mechanism of acquired multidrug resistance. Neoplasia, 2009, 11(12): 1359–1370.

[25] Ji N, Yuan J, Liu J, Tian S. Developing multidrug-resistant cells and exploring correlation between BCRP/ABCG2 over-expression and DNA methyltransferase. Acta Biochim Biophys Sin (Shanghai), 2010, 42(12): 854–862.

[26] Yao D, Ding S, Burchell B, Wolf CR, Friedberg T. Detoxication of vinca alkaloids by human P450 CYP3A4-mediated metabolism: implications for the development of drug resistance. J Pharmacol Exp Ther, 2000, 294(1): 387–395.

[27] Martinez C, Garcia-Martin E, Pizarro RM, Garcia-Gamito FJ, Agundez JA. Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy. Br J Cancer, 2002, 87(6): 681–686.

[28] Anttila S, Hakkola J, Tuominen P, Elovaara E, Husgafvel-Pursiainen K, Karjalainen A, Hirvonen A, Nurminen T. Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. Cancer Res, 2003, 63(24): 8623–8628.

[29] Habano W, Gamo T, Sugai T, Otsuka K, Wakabayashi G, Ozawa S. CYP1B1, but not CYP1A1, is downregulated by promoter methylation in colorectal cancers. Int J Oncol, 2009, 34(4): 1085–1091.

[30] Abdullah LN, Chow EK. Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med, 2013, 2(1): 3.

[31] Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer, 2005, 5(4): 275–284.

[32] Schoenhals M, Kassambara A, De Vos J, Hose D, Moreaux J, Klein B. Embryonic stem cell markers expression in cancers. Biochem Biophys Res Commun, 2009, 383(2): 157–162.

[33] Tian T, Zhang Y, Wang S, Zhou J, Xu S. Sox2 enhances the tumorigenicity and chemoresistance of cancer stem-like cells derived from gastric cancer. J Biomed Res, 2012, 26(5): 336–345.

[34] Bareiss PM, Paczulla A, Wang H, Schairer R, Wiehr S, Kohlhofer U, Rothfuss OC, Fischer A, Perner S, Staebler A, Wallwiener D, Fend F, Fehm T, Pichler B, Kanz L, Quintanilla-Martinez L, Schulze-Osthoff K, Essmann F, Lengerke C. SOX2 expression associates with stem cell state in human ovarian carcinoma. Cancer Res, 2013, 73(17): 5544–5555.

[35] Chen YC, Hsu HS, Chen YW, Tsai TH, How CK, Wang CY, Hung SC, Chang YL, Tsai ML, Lee YY, Ku HH, Chiou SH. Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS ONE, 2008, 3(7): e2637.

[36] Alonso MM, Diez-Valle R, Manterola L, Rubio A, Liu D, Cortes-Santiago N, Urquiza L, Jauregi P, Lopez de Munain A, Sampron N, Aramburu A, Tejada-Solis S, Vicente C, Odero MD, Bandres E, Garcia-Foncillas J, Idoate MA, Lang FF, Fueyo J, Gomez-Manzano C. Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas. PLoS ONE, 2011, 6(11): e26740.

[37] Zhang HJ, Siu MK, Wong ES, Wong KY, Li AS, Chan KY, Ngan HY, Cheung AN. Oct4 is epigenetically regulated by methylation in normal placenta and gestational trophoblastic disease. Placenta, 2008, 29(6): 549–554.

[38] Wang XQ, Ongkeko WM, Chen L, Yang ZF, Lu P, Chen KK, Lopez JP, Poon RT, Fan ST. Octamer 4 (Oct4) me-diates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway. Hepatology, 2010, 52(2): 528–539.

[39] Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, Mok SC, D'Andrea AD. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat Med, 2003, 9(5): 568–574.

[40] Lee KD, Pai MY, Hsu CC, Chen CC, Chen YL, Chu PY, Lee CH, Chen LT, Chang JY, Huang TH, Hsiao SH, Leu YW. Targeted Casp8AP2 methylation increases drug resistance in mesenchymal stem cells and cancer cells. Biochem Biophys Res Commun, 2012, 422(4): 578–585.

[41] Tian K, Wang Y, Huang Y, Sun B, Li Y, Xu H. Methylation of WTH3, a possible drug resistant gene, inhibits p53 regulated expression. BMC Cancer, 2008, 8: 327.

[42] Nyce J. Drug-induced DNA hypermethylation and drug resistance in human tumors. Cancer Res, 1989, 49(21): 5829–5836.

[43] Kastl L, Brown I, Schofield AC. Altered DNA methylation is associated with docetaxel resistance in human breast cancer cells. Int J Oncol, 2010, 36(5): 1235–1241.

[44] Segura-Pacheco B, Perez-Cardenas E, Taja-Chayeb L, Chavez-Blanco A, Revilla-Vazquez A, Benitez-Bribiesca L, Duenas-Gonzalez A. Global DNA hypermethylationassociated cancer chemotherapy resistance and its reversion with the demethylating agent hydralazine. J Transl Med, 2006, 4: 32.

[45] Shi JF, Li XJ, Si XX, Li AD, Ding HJ, Han X, Sun YJ. ER alpha positively regulated DNMT1 expression by binding to the gene promoter region in human breast cancer MCF-7 cells. Biochem Biophys Res Commun, 2012, 427(1): 47–53.

[46] Cui M, Wen Z, Yang Z, Chen J, Wang F. Estrogen regulates DNA methyltransferase 3B expression in Ishikawa endometrial adenocarcinoma cells. Mol Biol Rep, 2009, 36(8): 2201–2207.

[47] Richards KL, Zhang B, Baggerly KA, Colella S, Lang JC, Schuller DE, Krahe R. Genome-wide hypomethylation in head and neck cancer is more pronounced in HPV-negative tumors and is associated with genomic instability. PLoS ONE, 2009, 4(3): e4941.

[48] Li J, Harris RA, Cheung SW, Coarfa C, Jeong M, Goodell MA, White LD, Patel A, Kang SH, Shaw C, Chinault AC, Gambin T, Gambin A, Lupski JR, Milosavljevic A. Genomic hypomethylation in the human germline associates with selective structural mutability in the human genome. PLoS Genet, 2012, 8(5): e1002692.

[49] Rodriguez J, Frigola J, Vendrell E, Risques RA, Fraga MF, Morales C, Moreno V, Esteller M, Capella G, Ribas M, Peinado MA. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Res, 2006, 66(17): 8462–9468.

[50] Gasior SL, Wakeman TP, Xu B, Deininger PL. The human LINE-1 retrotransposon creates DNA double-strand breaks. J Mol Biol, 2006, 357(5): 1383–1393.

[51] Daskalos A, Nikolaidis G, Xinarianos G, Savvari P, Cassidy A, Zakopoulou R, Kotsinas A, Gorgoulis V, Field JK, Liloglou T. Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer. Int J Cancer, 2009, 124(1): 81–87.

[52] Kazazian HH, Jr, Goodier JL. LINE drive. Retrotransposition and genome instability. Cell, 2002, 110(3): 277–280.

[53] Wang D, Zhou J, Liu X, Lu D, Shen C, Du Y, Wei FZ, Song B, Lu X, Yu Y, Wang L, Zhao Y, Wang H, Yang Y, Akiyama Y, Zhang H, Zhu WG. Methylation of SUV39H1 by SET7/9 results in heterochromatin relaxation and genome instability. Proc Natl Acad Sci USA, 2013, 110(14): 5516–5521.

[54] Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet, 2002, 3(6): 415–428.

[55] Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science, 2003, 300(5618): 455.

[56] Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature, 1998, 396(6712): 643–649.

[57] McClelland SE, Burrell RA, Swanton C. Chromosomal instability: a composite phenotype that influences sensitivity to chemotherapy. Cell Cycle, 2009, 8(20): 3262–3266.

[58] Swanton C, Tomlinson I, Downward J. Chromosomal instability, colorectal cancer and taxane resistance. Cell Cycle, 2006, 5(8): 818–823.

[59] Lee AJ, Endesfelder D, Rowan AJ, Walther A, Birkbak NJ, Futreal PA, Downward J, Szallasi Z, Tomlinson IP, Howell M, Kschischo M, Swanton C. Chromosomal instability confers intrinsic multidrug resistance. Cancer Res, 2011, 71(5): 1858–1870.

[60] Gillies RJ, Verduzco D, Gatenby RA. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer, 2012, 12(7): 487–493.

[61] Cordaux R, Batzer MA. The impact of retrotransposons on human genome evolution. Nat Rev Genet, 2009, 10(10): 691–703.

[62] Chalitchagorn K, Shuangshoti S, Hourpai N, Kongruttanachok N, Tangkijvanich P, Thong-ngam D, Voravud N, Sriuranpong V, Mutirangura A. Distinctive pattern of LINE-1 methylation level in normal tissues and theassociation with carcinogenesis. Oncogene, 2004, 23(54): 8841–8846.

[63] Pattamadilok J, Huapai N, Rattanatanyong P, Vasurattana A, Triratanachat S, Tresukosol D, Mutirangura A. LINE-1 hypomethylation level as a potential prognostic factor for epithelial ovarian cancer. Int J Gynecol Cancer, 2008, 18(4): 711–717.

[64] Wanichnopparat W, Suwanwongse K, Pin-On P, Aporntewan C, Mutirangura A. Genes associated with the cis-regulatory functions of intragenic LINE-1 elements. BMC Genomics, 2013, 14: 205.

[65] Miyakura Y, Sugano K, Konishi F, Ichikawa A, Maekawa M, Shitoh K, Igarashi S, Kotake K, Koyama Y, Nagai H. Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability. Gastroenterology, 2001, 121(6): 1300–1309.

[66] Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS, Ho JC. hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with highfrequency microsatellite instability. Cancer Res, 1999, 59(1): 159–164.

[67] Rice JC, Ozcelik H, Maxeiner P, Andrulis I, Futscher BW. Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens. Carcinogenesis, 2000, 21(9): 1761–1765.

[68] Cashen AF, Schiller GJ, O'Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol, 2010, 28(4): 556–561.

[69] Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R, Shen L, Nimer SD, Leavitt R, Raza A, Saba H. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer, 2006, 106(8): 1794–1803.

[70] Kaminskas E, Farrell A, Abraham S, Baird A, Hsieh LS, Lee SL, Leighton JK, Patel H, Rahman A, Sridhara R, Wang YC, Pazdur R. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res, 2005, 11(10): 3604–3608.

[71] Oliveira CA, Nie R, Carnes K, Franca LR, Prins GS, Saunders PT, Hess RA. The antiestrogen ICI 182,780 decreases the expression of estrogen receptor-alpha but has no effect on estrogen receptor-beta and androgen receptor in rat efferent ductules. Reprod Biol Endocrinol, 2003, 1: 75.

[72] Di Ruscio A, Ebralidze AK, Benoukraf T, Amabile G, Goff LA, Terragni J, Figueroa ME, De Figueiredo Pontes LL, Alberich-Jorda M, Zhang P, Wu M, D'Alo F, Melnick A, Leone G, Ebralidze KK, Pradhan S, Rinn JL, Tenen DG. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature, 2013, 503(7476): 371–376.

(責(zé)任編委: 朱衛(wèi)國)

Aberrant DNA methylation and drug resistance of tumor cells

Xinxin Si, Yujie Sun

Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Cell Biology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China

Drug resistance is one of the major obstacles limiting the success of cancer chemotherapy. The underlying mechanisms are complex. In recent years, the contribution of epigenetic changes to drug resistance has drawn increasing attention. DNA methylation is an important epigenetic modification that plays an important role in regulating gene expression and maintaining genome stability. Primary or acquired resistance of tumor cells is usually accompanied by aberrant DNA methylation. Accumulating evidence has shown that aberrant DNA methylation is involved in drug resistance of tumor cells. In this review, we briefly review the relationship between DNA methylation and drug resistance of tumor cells as well as the underlying mechanisms.

cancer drug resistance; DNA methylation; genome stability; gene expression

2013-10-22;

2014-02-23

國家自然科學(xué)基金項目(編號：81172091)和江蘇省普通高校研究生科研創(chuàng)新計劃項目(編號：CXZZ13_0561)資助

司鑫鑫, 博士研究生, 研究方向：腫瘤耐藥與表觀遺傳。E-mail: sixinxin@njmu.edu.cn

孫玉潔, 教授, 博士生導(dǎo)師, 研究方向：腫瘤耐藥與表觀遺傳。E-mail: yujiesun@njmu.edu.cn

10.3724/SP.J.1005.2014.0411

時間: 2014-3-3 12:41:51

URL: http://www.cnki.net/kcms/detail/11.1913.R.20140303.1241.003.html