microRNAs在炎性反應(yīng)與腫瘤關(guān)系中的作用

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microRNAs在炎性反應(yīng)與腫瘤關(guān)系中的作用

胡光富張宏偉

(復(fù)旦大學(xué)附屬中山醫(yī)院普外科，上海200032)

Pathways Connecting Inflammation and Cancer: microRNAs may Serve as a Bridge

HUGuangfuZHANGHongweiDepartmentofGeneralSurgery，ZhongshanHospital，F(xiàn)udanUniversity，Shanghai200032，China

miroRNA(miRNA)由真核生物基因組編碼、RNA聚合酶II或III轉(zhuǎn)錄，依次經(jīng)細(xì)胞核中Drosha和細(xì)胞質(zhì)中Dicer酶(RNase III家族)剪切，最終形成約含22個核苷酸的小分子非編碼單鏈RNA[1-2]。miRNA作為一種重要的基因表達(dá)調(diào)控因子，主要在轉(zhuǎn)錄后水平負(fù)調(diào)控靶基因的表達(dá)。Virchow首次提出了慢性炎性反應(yīng)與癌變的關(guān)聯(lián)假說[3-4]，而Allavena等[5]將炎性反應(yīng)與腫瘤間相互作用的機(jī)制概括為基因調(diào)控和炎性反應(yīng)兩個途徑。近年來，miRNA在炎性反應(yīng)、腫瘤、免疫反應(yīng)中的作用逐漸被揭示[6]。miRNA是免疫系統(tǒng)的一把雙刃劍，既可維持機(jī)體內(nèi)環(huán)境穩(wěn)定，也可促進(jìn)疾病的惡性循環(huán)[7]。目前，有關(guān)炎性反應(yīng)與胃癌、結(jié)腸癌、肝癌、肺癌、食管癌、甲狀腺癌、宮頸癌、膀胱癌、前列腺癌等腫瘤的關(guān)系的研究已較多，而有關(guān)炎性反應(yīng)與乳腺癌的研究相對較少[3,8]。本文就miRNA在炎性反應(yīng)與腫瘤(尤其是乳腺癌)間的橋梁作用作一綜述。

1炎性反應(yīng)與腫瘤的關(guān)系

1.1腫瘤基因水平上引發(fā)的炎性反應(yīng)有文獻(xiàn)[9]將炎性反應(yīng)與腫瘤間的相互作用概括為內(nèi)外兩個途徑，其中內(nèi)途徑指的是腫瘤細(xì)胞在基因水平上引發(fā)炎性反應(yīng)，而炎性反應(yīng)微環(huán)境又進(jìn)一步干擾腫瘤細(xì)胞的基因穩(wěn)定性，進(jìn)而在基因?qū)用嫘纬蓯盒匝h(huán)。以往研究認(rèn)為，腫瘤的炎性反應(yīng)不同于之前流行病學(xué)中的炎性反應(yīng)，并認(rèn)為這種異常的炎性反應(yīng)可能是由腫瘤內(nèi)的癌變基因引發(fā)的；之后發(fā)現(xiàn)多個腫瘤癌變基因及其介導(dǎo)的信號通路參與了此炎性反應(yīng)的發(fā)生，如甲狀腺癌RET/PCT基因重排尤其是RET/PCT1基因重排能誘導(dǎo)活化細(xì)胞集落刺激因子(CSFs)、白介素-1(IL-1)、環(huán)氧化酶2(COX2)、趨化因子受體8(CXCR8)、CCL2、CCL20等炎性反應(yīng)因子參與募集巨噬細(xì)胞、樹突狀細(xì)胞，引發(fā)炎性反應(yīng)[10-11]。有趣的是，炎性反應(yīng)微環(huán)境可以促使腫瘤的發(fā)生發(fā)展。通過向Hela細(xì)胞內(nèi)轉(zhuǎn)導(dǎo)活化的ras基因，誘導(dǎo)其分泌過量的IL-8/CXCL8因子，可以促進(jìn)腫瘤血管新生[12]。誘導(dǎo)非小細(xì)胞肺癌 PTEN基因突變能上調(diào)低氧誘導(dǎo)因子(HIF-1)及HIF-1依賴的CXCR4基因表達(dá)，進(jìn)而促進(jìn)非小細(xì)胞肺癌轉(zhuǎn)移[13]。而且，越來越多的證據(jù)表明，炎性反應(yīng)細(xì)胞和炎性反應(yīng)介質(zhì)可以通過直接損傷DNA、干擾DNA修復(fù)系統(tǒng)和干擾細(xì)胞周期等方式促進(jìn)腫瘤的生成及發(fā)展[14]。錯配修復(fù)(mismatch repair，MMR)屬于堿基剪切修復(fù)(base excision repair，BER)，是重要的DNA修復(fù)系統(tǒng)之一。MMR家族成員可通過微衛(wèi)星不穩(wěn)定(microsatellite instability，MSI)現(xiàn)象發(fā)生基因沉默，從而增加基因的不穩(wěn)定性[15]。研究[16]顯示，炎性反應(yīng)微環(huán)境中常過表達(dá)BER相關(guān)酶，如酸性糖蛋白(AAG)、脫嘧啶核酸內(nèi)切酶(APE1)，通過促進(jìn)MSI抑制MMR，最終導(dǎo)致腫瘤發(fā)生。

1.2腫瘤相關(guān)炎性反應(yīng)微環(huán)境(cancer-relate inflammation，CRI)Colotta所指的炎性反應(yīng)與腫瘤間相互作用的外途徑即：炎性反應(yīng)微環(huán)境內(nèi)的炎性反應(yīng)細(xì)胞或炎性反應(yīng)因子可以協(xié)助腫瘤細(xì)胞增殖或轉(zhuǎn)移，而腫瘤細(xì)胞本身可通過自分泌或旁分泌形式維持或推進(jìn)炎性反應(yīng)進(jìn)程。炎性反應(yīng)微環(huán)境包括炎性反應(yīng)細(xì)胞和炎性反應(yīng)因子，前者主要包括腫瘤相關(guān)巨噬細(xì)胞(tumor-associated macrophages，TAM)、腫瘤相關(guān)樹突細(xì)胞(tumor-associated dendritic cells ，TADC)、腫瘤浸潤T細(xì)胞(tumor-infiltrating T cells，TIL)等，后者主要包括細(xì)胞因子[腫瘤壞死因子(TNF)、白細(xì)胞介素1(IL-1)、IL-6]和趨化因子(CXC型和CC型)等[3]。誘導(dǎo)腫瘤血管生成是炎性反應(yīng)細(xì)胞或炎性反應(yīng)因子促進(jìn)腫瘤增生的重要途徑之一。已有多項(xiàng)研究表明，炎性反應(yīng)細(xì)胞尤其是TAM浸潤與腫瘤血管生成及腫瘤進(jìn)展密切相關(guān)[17]。TAM還可以產(chǎn)生轉(zhuǎn)化生長因子(TGF)，直接或間接通過誘導(dǎo)血管內(nèi)皮生長因子(VEGF)刺激腫瘤血管增生；TNF、IL-1、IL-6、IL-8也可以誘導(dǎo)VEGF的表達(dá)增加[18]。

此外，炎性反應(yīng)因子或炎性反應(yīng)細(xì)胞參與腫瘤細(xì)胞轉(zhuǎn)移的多個環(huán)節(jié)。TNF、CC型趨化因子可以誘導(dǎo)產(chǎn)生多種細(xì)胞外蛋白酶，協(xié)助腫瘤細(xì)胞穿過細(xì)胞外基質(zhì)。而“逆向浸潤假說”認(rèn)為，炎性反應(yīng)細(xì)胞在浸潤腫瘤組織時遺留了其遷移途徑，腫瘤細(xì)胞可經(jīng)此途徑逆向轉(zhuǎn)移，從而脫離腫瘤組織[19]。研究[20]認(rèn)為，某些腫瘤細(xì)胞可利用黏附分子、細(xì)胞因子、趨化因子及受體等實(shí)現(xiàn)特定器官的遠(yuǎn)處轉(zhuǎn)移[20]。

2miRNA在炎性反應(yīng)與腫瘤間的橋梁作用

2.1miRNA在基因水平上對炎性反應(yīng)和腫瘤的橋梁作用miRNA是炎性反應(yīng)與腫瘤重要的調(diào)節(jié)因子。腫瘤可利用miRNA刺激炎性反應(yīng)發(fā)生，而炎性反應(yīng)可以通過調(diào)控miRNA基因表達(dá)從而引發(fā)癌變[6]。單個miRNA可以通過與靶基因mRNA 3’UTR不完全互補(bǔ)結(jié)合抑制靶基因翻譯，故單個miRNA可以同時調(diào)控多個通路上的基因表達(dá)。因此，miRNA的微小改變即可引起炎性反應(yīng)或腫瘤發(fā)生[21]。腫瘤通過miRNA介導(dǎo)引發(fā)炎性反應(yīng)，主要是因?yàn)閙iRNA在先天性和獲得性免疫系統(tǒng)中均發(fā)揮重要的調(diào)控作用。免疫細(xì)胞的正常分化和成熟需要miRNA的調(diào)控[7]。腫瘤發(fā)生時，機(jī)體免疫系統(tǒng)的平衡被打破，由抗瘤與促瘤平衡傾向于促瘤，并促發(fā)非自限性的腫瘤相關(guān)炎性反應(yīng)的發(fā)生[22]?？鼓[瘤微環(huán)境以Th1細(xì)胞和M1型巨噬細(xì)胞為主，而促腫瘤微環(huán)境則以Th2細(xì)胞和M2型巨噬細(xì)胞為主。同時，炎性反應(yīng)可以通過使多種miRNA基因表達(dá)改變而誘導(dǎo)腫瘤發(fā)生。研究[23-24]發(fā)現(xiàn)，炎性反應(yīng)因子IL-6可以通過JAK2/STAT3信號通路誘導(dǎo)miR-21的表達(dá)，而miR-21可以抑制多種抑癌基因的表達(dá)。內(nèi)毒素(LPS)、TNF-α、干擾素-β(IFN-β)均可通過誘導(dǎo)miR-155高表達(dá)而抑制p53信號通路，從而誘導(dǎo)腫瘤的發(fā)生[25-26]。

2.2miRNA在腫瘤相關(guān)炎性反應(yīng)微環(huán)境中的作用miRNA在調(diào)整和維護(hù)腫瘤相關(guān)炎性反應(yīng)微環(huán)境中扮演著重要的角色。由TAM所分泌的VEGF-A是與腫瘤增生和轉(zhuǎn)移有關(guān)的重要的調(diào)節(jié)因子。近來，Jafarifar等[27]報(bào)告了在腫瘤微環(huán)境內(nèi)，缺氧逆轉(zhuǎn)miRNA介導(dǎo)的VEGF-A表達(dá)沉默的新機(jī)制。他們發(fā)現(xiàn)，至少有4種miRNA靶向負(fù)調(diào)控位于VEGF-A 3'-UTR區(qū)域的CA富含元件(CA-rich element，CARE)，而不均一核糖核蛋白-L(hnRNP-L)結(jié)合于CARE；在TAM中，缺氧促使大量hnRNP-L從細(xì)胞核轉(zhuǎn)運(yùn)到細(xì)胞質(zhì)，與miR-297、miR-299競爭VEGF-A 3'-UTR區(qū)域的CARE，進(jìn)而促使TAM分泌VEGF-A。腫瘤細(xì)胞可通過募集免疫抑制細(xì)胞，如骨髓性抑制細(xì)胞(myeloid-derived suppressor cell，MDSC)，營造腫瘤相關(guān)炎性反應(yīng)微環(huán)境，實(shí)現(xiàn)腫瘤細(xì)胞的免疫逃逸。以往的研究發(fā)現(xiàn)，多種因子可以誘導(dǎo)骨髓前體細(xì)胞向MDSC分化。Wang等[28]研究顯示，腫瘤細(xì)胞可通過miR-34a及轉(zhuǎn)錄因子twist調(diào)節(jié)TGF-b和(或)IL-10的水平，從而促進(jìn)骨髓前體細(xì)胞向的MDSC分化。

3miRNA在炎性反應(yīng)與乳腺癌間的橋梁作用

3.1miRNA在基因水平上介導(dǎo)炎性反應(yīng)與乳腺癌的發(fā)生1999年Howe等[29]發(fā)現(xiàn)，轉(zhuǎn)染攜帶Wnt-1癌基因的逆轉(zhuǎn)錄病毒可上調(diào)小鼠乳腺上皮RAC311和C57MG細(xì)胞中COX-2的表達(dá)，進(jìn)而誘導(dǎo)細(xì)胞癌變，這個過程同COX-2促發(fā)腸癌相似。Gerger等[30]研究了432例乳腺癌患者中IL-10的基因多態(tài)性，Cox回歸分析顯示，IL-10 592C>A基因多態(tài)性可作為乳腺癌患者無病生存(disease-free survival，DFS)的有效預(yù)后指標(biāo)。Jiang[31]等發(fā)現(xiàn)，miR-155可通過直接抑制腫瘤抑制基因SOCS-1，促進(jìn)乳腺癌細(xì)胞增殖及裸鼠體內(nèi)成瘤，并激活聯(lián)系癌癥-炎性反應(yīng)的關(guān)鍵信號通路JAK/STAT3；他們同時發(fā)現(xiàn)，在IFN-γ、IL-6、LPS、poly(I:C)等炎性反應(yīng)因子刺激下，乳腺癌細(xì)胞中miR-155表達(dá)增加，提示miR-155可能在癌癥與炎性反應(yīng)間發(fā)揮橋梁作用。而研究[32]發(fā)現(xiàn)，miR-155通過激活STAT3和抑制miR-143，在轉(zhuǎn)錄和轉(zhuǎn)錄后水平調(diào)控Warburg效應(yīng)中的關(guān)鍵酶之一——己糖激酶-2(hexokinase-2)的表達(dá)，從而促進(jìn)腫瘤的發(fā)生。乳腺癌細(xì)胞中的miR-155不僅調(diào)控多種癌相關(guān)基因的表達(dá)，還通過靶向抑制C/EBPβ和Ets-1調(diào)控一系列癌相關(guān)miRNA，通過炎性反應(yīng)信號促進(jìn)乳腺癌細(xì)胞的增殖及遷移[33]。

3.2miRNA在乳腺癌炎性反應(yīng)微環(huán)境中的作用乳腺癌炎性反應(yīng)微環(huán)境中的TAM分泌大量的TNF-α，而乳腺癌細(xì)胞可合成胸苷磷酸化酶(thymidine phosphorylase，TP)。1998年Leek等[34]發(fā)現(xiàn)，TNF-a可以上調(diào)TP水平，這兩者均是促進(jìn)腫瘤血管生成的重要因子，從而揭示了乳腺癌炎性反應(yīng)微環(huán)境中TAM浸潤促進(jìn)腫瘤血管生成的分子機(jī)制。最近，Kong等[35]研究了miR-155在乳腺癌中調(diào)節(jié)腫瘤血管生成的作用，發(fā)現(xiàn)miR-155靶向負(fù)調(diào)控VHL腫瘤抑制基因，從而促進(jìn)人臍靜脈血管內(nèi)皮細(xì)胞網(wǎng)形成、增生、浸潤及遷移；體內(nèi)實(shí)驗(yàn)發(fā)現(xiàn)，異種移植高表達(dá)miR-155的乳腺脂肪墊可以促進(jìn)腫瘤血管增生，并募集TAM等多種炎性反應(yīng)細(xì)胞。Xiang等[36]發(fā)現(xiàn)，乳腺上皮細(xì)胞中存在一個由miR-146b參與調(diào)節(jié)的STAT3負(fù)反饋環(huán)：轉(zhuǎn)錄因子STAT3轉(zhuǎn)錄miR-146b，miR-146b抑制轉(zhuǎn)錄因子NF-kB轉(zhuǎn)錄IL-6，而IL-6又是轉(zhuǎn)錄因子STAT3的激活劑，即“IL-6、STAT3、miR-146b、NF-kB、IL-6”負(fù)反饋環(huán)；乳腺癌細(xì)胞中miR-146b的啟動子被甲基化失活，負(fù)反饋環(huán)失活使得STAT3過表達(dá)，從而促使乳腺癌炎性反應(yīng)微環(huán)境形成。Iliopoulos等[37]發(fā)現(xiàn)，炎性反應(yīng)因子在腫瘤蛋白和miRNA參與下形成一個正反饋環(huán)，可以在無其他致瘤因素下誘導(dǎo)乳腺細(xì)胞癌變，激活乳腺上皮MCF-10A細(xì)胞內(nèi)Scr蛋白，并通過NF-kB信號通路直接激活Lin28轉(zhuǎn)錄因子、降低let-7miRNA的表達(dá)水平，從而上調(diào)炎性反應(yīng)因子IL-6所介導(dǎo)的STAT3轉(zhuǎn)錄因子的水平，最終導(dǎo)致乳腺細(xì)胞發(fā)生表皮-間充質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition，EMT)。

3討論與展望

當(dāng)機(jī)體受到可控?fù)p傷時，免疫系統(tǒng)啟動炎性反應(yīng)反應(yīng)，經(jīng)過良性自限性過程修復(fù)損傷；當(dāng)損傷過度或免疫缺陷時，炎性反應(yīng)過激或低效、無效甚至反效，發(fā)生惡性非自限性過程，導(dǎo)致癌變[38]。miRNA作為核心調(diào)控因子，在炎性反應(yīng)與腫瘤、修復(fù)與癌變關(guān)系中起到了重要調(diào)控作用[39]。miRNA的這種調(diào)控作用可概括為基因調(diào)控、炎性反應(yīng)兩個途徑，miRNA似乎依托于免疫系統(tǒng)在炎性反應(yīng)與腫瘤間起到了重要的橋梁作用。從流行病學(xué)角度來看胃癌、結(jié)腸癌、肝癌等與慢性胃炎、慢性結(jié)腸炎、慢性肝炎等有較為明確的關(guān)系，而乳腺癌與慢性乳腺炎似乎沒有直接聯(lián)系。所以，此處乳腺癌炎性反應(yīng)微環(huán)境不完全等同與流行病學(xué)上的慢性炎性反應(yīng)。實(shí)際上，此炎性反應(yīng)與彼炎性反應(yīng)的異同和調(diào)節(jié)機(jī)制尚未完全明確[4]。另外，不同組織的腫瘤炎性反應(yīng)微環(huán)境也存在差異，其內(nèi)部發(fā)生機(jī)制可能存在明顯不同，而乳腺癌炎性反應(yīng)微環(huán)境還與激素水平密切相關(guān)[14,40]。未來的挑戰(zhàn)正是要揭示這些炎性反應(yīng)的本質(zhì)，理清免疫、炎性反應(yīng)、腫瘤間錯綜復(fù)雜的關(guān)系網(wǎng)，探索miRNA在其中的重要地位。

參考文獻(xiàn)

[1]Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function [J]. Cell,2004, 116(2): 281-297.

[2]Ambros V. The functions of animal microRNAs [J]. Nature, 2004, 431(7006):350-355.

[3]Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? [J]. Lancet, 2001, 357(9255): 539-545.

[4]Coussens LM, Werb Z. Inflammation and cancer [J]. Nature, 2002, 420(6917):860-867.

[5]Allavena P, Garlanda C, Borrello M, et al. Pathways connecting inflammation and cancer [J]. Curr Opin Genet Dev, 2008, 18 (1): 3-10.

[6]Schetter AJ, Heegaard NH, Harris CC. Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways [J]. Carcinogenesis, 2010, 31(1): 37-49.

[7]Lu LF, Liston A. MicroRNA in the immune system, microRNA as an immune system [J]. Immunology, 2009, 127(3): 291-298.

[8]Muller A, Homey B, Soto H, et al. Involvement of chemokine receptors in breast cancer metastasis [J]. Nature, 2001, 410(6824): 50-56.

[9]Colotta F, Allavena P, Sica A, et al. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability [J]. Carcinogenesis, 2009, 30 (7): 1073-1081.

[10]Borrello MG, Alberti L, Fischer A, et al. Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene [J]. Proc Natl Acad Sci U S A, 2005, 102(41): 14825-14830.

[11]Scarpino S, Stoppacciaro A, Ballerini F, et al. Papillary carcinoma of the thyroid: hepatocyte growth factor (HGF) stimulates tumor cells to release chemokines active in recruiting dendritic cells [J]. Am J Pathol, 2000, 156(3): 831-837.

[12]Sparmann A, Bar-Sagi D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis [J]. Cancer Cell, 2004, (65): 447-458.

[13]Phillips RJ, Mestas J, Gharaee-Kermani M, et al. Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha [J]. J Biol Chem, 2005, 280(23): 22473-22481.

[14]Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation [J]. Nature, 2008, 454(7203): 436-444.

[15]Hakem R. DNA-damage repair: the good, the bad, and the ugly [J]. EMBO J, 2008, 27(4): 589-605.

[16]Hofseth LJ, Khan MA, Ambrose M, et al. The adaptive imbalance in base excision-repair enzymes generates microsatellite instability in chronic inflammation[J]. J Clin Invest, 2003, 112(12): 1887-1894.

[17]Ford CA, Petrova S, Pound JD, et al. Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma [J]. Curr Biol, 2015, 225 (5): 577-588.

[18]Keane MP, Strieter RM. The role of CXC chemokines in the regulation of angiogenesis [J]. Chem Immunol, 1999, 72: 86-101.

[19]Opdenakker G, Van Damme J. Chemotactic factors, passive invasion and metastasis of cancer cells [J]. Immunol Today, 1992, 13(11): 463-464.

[20]Martin-Padura I, Mortarini R, Lauri D, et al. Heterogeneity in human melanoma cell adhesion to cytokine activated endothelial cells correlates with VLA-4 expression [J]. Cancer Res, 1991, 51(8): 2239-2241.

[21]Selbach M, Schwanhausser B, Thierfelder N, et al. Widespread changes in protein synthesis induced by microRNAs [J]. Nature, 2008, 455(7209): 58-63.

[22]Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer [J] . Cell, 2010, 140(6): 883-899.

[23]Loffler D, Brocke-Heidrich K, Pfeifer G, et al. Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer [J]. Blood, 2007, 110 (4): 1330-1333.

[24]Si ML, Zhu S, Wu H, et al. miR-21-mediated tumor growth [J]. Oncogene, 2007, 26 (19): 2799-2803.

[25]Tili E, Michaille JJ, Cimino A, et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock [J]. J Immunol, 2007, 179 (8): 5082-5089.

[26]Gironella M, Seux M, Xie MJ, et al. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development [J]. Proc Natl Acad Sci U S A, 2007, 104(41): 16170-16175.

[27]Jafarifar F, Yao P, Eswarappa SM, et al. Repression of VEGFA by CA-rich element-binding microRNAs is modulated by hnRNP L [J]. EMBO J, 2011; 30(7): 1324-1334.

[28]Wang X, Chang X, Zhuo G, et al. Twist and miR-34a are involved in the generation of tumor-educated myeloid-derived suppressor cells [J]. Int J Mol Sci, 2013, 14(10): 20459-20477.

[29]Howe LR, Subbaramaiah K, Chung WJ, et al. Transcriptional activation of cyclooxygenase-2 in Wnt-1-transformed mouse mammary epithelial cells [J]. Cancer Res, 1999, 59(7): 1572-1577.

[30]Gerger A, Renner W, Langsenlehner T, et al. Association of interleukin-10 gene variation with breast cancer prognosis [J]. Breast Cancer Res Treat, 2010, 119(3): 701-705.

[31]Jiang S, Zhang HW, Lu MH, et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene [J]. Cancer Res, 2010, 70(8): 3119-3127.

[32]Jiang S, Zhang LF, Zhang HW, et al. A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells [J]. EMBO J, 2012, 31(8): 1985-1998.

[33]Hu S, Zhu W, Zhang LF, et al. MicroRNA-155 broadly orchestrates inflammation-induced changes of microRNA expression in breast cancer [J]. Cell Res, 2014, 24(2): 254-257.

[34]Leek RD, Landers R, Fox SB, et al. Association of tumour necrosis factor alpha and its receptors with thymidine phosphorylase expression in invasive breast carcinoma [J]. Br J Cancer, 1998, 77(12): 2246-2251.

[35]Kong W, He L, Richards EJ, et al. Upregulation of miRNA-155 promotes tumour angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative breast cancer [J]. Oncogene, 2014, 33(6): 679-689.

[36]Xiang M, Birkbak NJ, Vafaizadeh V, et al. STAT3 induction of miR-146b forms a feedback loop to inhibit the NF-kappaB to IL-6 signaling axis and STAT3-driven cancer phenotypes [J]. Sci Signa,l 2014, 7(310):a11.

[37]Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation [J]. Cell, 2009, 139(4): 693-706.

[38]Dvorak HF. Tumors: wounds that do not heal: similarities between tumor stroma generation and wound healing [J]. N Engl J Med, 1986, 315(26): 1650-1659.

[39]Iliopoulos D. MicroRNA circuits regulate the cancer-inflammation link [J]. Sci Signalc, 2014, 7(318): e8.

[40]Mantovani A. Cancer: an infernal triangle [J]. Nature, 2007, 448(7153):547-548.

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中圖分類號R 73.3

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