李　康(綜述),旦　增(審校)

(西藏自治區(qū)人民醫(yī)院內(nèi)四科,拉薩 850000)

?

細(xì)胞因子參與胃癌發(fā)生和發(fā)展研究進(jìn)展

李康※(綜述),旦增(審校)

(西藏自治區(qū)人民醫(yī)院內(nèi)四科,拉薩 850000)

摘要：細(xì)胞因子是一類(lèi)能在細(xì)胞間傳遞信息、發(fā)揮免疫調(diào)節(jié)的蛋白質(zhì)或小分子多肽；其表達(dá)異常誘發(fā)多種疾病，包括胃癌。細(xì)胞因子參與調(diào)控細(xì)胞的癌變、侵襲與轉(zhuǎn)移、血管生成，并通過(guò)調(diào)控腫瘤相關(guān)抗原的抗原遞呈、淋巴細(xì)胞的活化參與胃癌的免疫逃逸，且在胃癌細(xì)胞抵抗放化療治療中發(fā)揮重要作用。因此，調(diào)節(jié)機(jī)體細(xì)胞因子的水平，促使機(jī)體形成對(duì)胃癌的抗腫瘤也就成為胃癌治療的新方向。

關(guān)鍵詞：胃癌；細(xì)胞因子；免疫逃逸

細(xì)胞因子是由多種細(xì)胞產(chǎn)生的，具有廣泛調(diào)節(jié)細(xì)胞功能作用的多肽分子，細(xì)胞因子不僅作用于免疫系統(tǒng)和造血系統(tǒng)，還廣泛作用于神經(jīng)、內(nèi)分泌系統(tǒng)，對(duì)細(xì)胞間相互作用、細(xì)胞的增殖分化和效應(yīng)功能有重要的調(diào)節(jié)作用。細(xì)胞因子分為白細(xì)胞介素(interleukin,IL)、干擾素、腫瘤壞死因子 (tumor necrosis factor,TNF)超家族、集落刺激因子、趨化因子、生長(zhǎng)因子等。眾多細(xì)胞因子在體內(nèi)通過(guò)旁分泌、自分泌或內(nèi)分泌等方式發(fā)揮作用，具有多效性、重疊性、拮抗性、協(xié)同性等多種生理特性，形成了十分復(fù)雜的細(xì)胞因子調(diào)節(jié)網(wǎng)絡(luò)，參與人體多種重要的生理功能。研究表明，細(xì)胞因子的表達(dá)異常伴有炎癥反應(yīng)、組織壞死及腫瘤的發(fā)生。其中在惡性腫瘤發(fā)生中，細(xì)胞因子能促進(jìn)細(xì)胞的增殖、轉(zhuǎn)移、血管生成，并參與腫瘤的放、化療抵抗及腫瘤的免疫逃逸[1]。

胃癌是常見(jiàn)的惡性腫瘤之一，流行病學(xué)調(diào)查研究顯示胃癌的發(fā)病率在消化道腫瘤中居首，相關(guān)病死率位居腫瘤第2位[2]。我國(guó)是胃癌的高發(fā)地區(qū)，胃癌病死率男性為40.8/10萬(wàn)，女性為18.6/10萬(wàn)；分別是歐美等發(fā)達(dá)國(guó)家的4.2～7.9 和3.8～8.0倍[3-4]。病例報(bào)道顯示，多種細(xì)胞因子在胃癌患者中表達(dá)異常，并與腫瘤的分級(jí)、分期，腫瘤的預(yù)后不良密切相關(guān)[5-6]，提示細(xì)胞因子的異常參與了胃癌的發(fā)生、發(fā)展，并極可能發(fā)揮了重要作用，調(diào)節(jié)細(xì)胞的表達(dá)水平可能成為胃癌治療的新途徑?，F(xiàn)就細(xì)胞因子在胃癌發(fā)生、發(fā)展中的作用，以及利用細(xì)胞因子治療胃癌的最新研究進(jìn)展予以綜述，期望為胃癌的治療帶來(lái)新的啟示。

1細(xì)胞因子與胃癌發(fā)生、發(fā)展

1.1細(xì)胞因子參與的炎癥反應(yīng)與胃癌慢性炎癥被認(rèn)為是腫瘤發(fā)生的主要病因?qū)W之一，包括胃癌。其中75%的胃癌發(fā)生與幽門(mén)螺桿菌(Helicobacter pylori,Hp)感染有關(guān)，細(xì)菌的毒力因素和機(jī)體的免疫系統(tǒng)互相作用形成慢性炎癥反應(yīng)，導(dǎo)致胃萎縮、腸化生、胃癌發(fā)生[7]；其中多種細(xì)胞因子發(fā)揮促炎作用。Hp感染活化核苷酸結(jié)合寡聚化結(jié)構(gòu)域通路增強(qiáng)干擾素γ信號(hào)通路中的信號(hào)傳導(dǎo)與轉(zhuǎn)錄激活子(signal transducer and activator of transcription,STAT)1和人干擾素調(diào)節(jié)因子的表達(dá)，促進(jìn)炎性細(xì)胞因子IL-8和干擾素γ誘導(dǎo)表達(dá)，炎癥反應(yīng)加劇[8]。Hp感染導(dǎo)致少兒胃組織Toll樣受體(Toll like receptors,TLR)2、TLR-4、TLR-5和TLR-9表達(dá)顯著升高，細(xì)胞因子IL-8、IL-10 和 TNF-α 的表達(dá)也顯著增加，胃組織的慢性炎癥反應(yīng)增強(qiáng)[9]。Hp感染后，IL-1β活化表達(dá)誘導(dǎo)胃組織的炎癥反應(yīng)，并誘導(dǎo)多個(gè)基因的甲基化，促使腫瘤的發(fā)生[10]。此外，IL-32調(diào)控趨化因子配體分子1、趨化因子配體分子2、IL-8、核因子κB(nuc-lear factor κB，NF-κB)的表達(dá)參與Hp感染誘導(dǎo)的炎癥反應(yīng)[11]。同時(shí)細(xì)胞因子的多態(tài)性與胃癌發(fā)生的風(fēng)險(xiǎn)密切相關(guān),例如IL-1β及其受體基因的多態(tài)性影響Hp感染所致的炎癥反應(yīng)結(jié)果[12-13]；轉(zhuǎn)化生長(zhǎng)因子β1(transforming growth factor β1,TGF-β1)基因-509T胃癌具有更高易患性[14]；TNF-α-857C/T、IL-8-845T/C、IL-10-592C/A基因表型增強(qiáng)胃部的炎癥反應(yīng)和胃癌的發(fā)生[15]；TLR1- 602基因的多態(tài)性影響自然殺傷細(xì)胞和T細(xì)胞干擾素γ的產(chǎn)生，進(jìn)而影響Hp誘導(dǎo)的胃部炎癥反應(yīng)[16]；IL-6基因-174 C/G 和-572 C/G增加胃的炎癥反應(yīng)和胃癌發(fā)生的風(fēng)險(xiǎn)[17]；IL-10-592基因多態(tài)性影響胃組織的炎癥反應(yīng)，增加胃癌的易患性[18-19]。

自身免疫性胃炎是一種器官特異性的自身免疫病，常伴有胃酸匱乏、貧血、胃息肉、胃良性腫瘤、胃腺癌，TNF-α 和IL-21 是其發(fā)生的關(guān)鍵因素，它們誘導(dǎo)表達(dá)的細(xì)胞因子在胃癌的發(fā)生中起重要作用[20]。如炎性因子IL-1β、IL-2、 IL-4、IL-6、 IL-10、TNF-α和干擾素γ的表達(dá)增加胃癌發(fā)生率；IL-8的表達(dá)增加使胃癌發(fā)生率提高2倍[21]。IL-6/JAK2信號(hào)活化轉(zhuǎn)錄因子STAT3通過(guò)調(diào)控Skp2/p27/p21通路調(diào)控細(xì)胞的增殖和轉(zhuǎn)移[22]。三葉因子1是腫瘤抑制因子，表達(dá)于正常的胃上皮細(xì)胞中，主要維持上皮細(xì)胞結(jié)構(gòu)和功能；但在胃癌組織中，胃組織炎性因子IL-1β和TNF-α活化轉(zhuǎn)錄因子NF-κB顯著下調(diào)三葉因子1表達(dá)，加速胃癌組織癌變[23]。IL-26通過(guò)活化STAT3上調(diào)抗凋亡基因Bcl-2、 Bcl-xL和c-myc促進(jìn)細(xì)胞增殖[24]。炎性環(huán)境下TNF-α誘導(dǎo)NF-κB活化，使p65亞基結(jié)合組織中叉頭樣轉(zhuǎn)錄因子3(forkhead box protein 3,FOXP3)，抑制FOXP3結(jié)合p21到啟動(dòng)子區(qū)，抑制p21的表達(dá)，促進(jìn)胃癌細(xì)胞的生長(zhǎng)[25]。

1.2細(xì)胞因子參與調(diào)控細(xì)胞生長(zhǎng)、轉(zhuǎn)移與胃癌細(xì)胞因子具有調(diào)節(jié)細(xì)胞的生長(zhǎng)、轉(zhuǎn)移的功能，在胃癌發(fā)生、發(fā)展過(guò)程中細(xì)胞因子發(fā)揮了重要作用。Cten是細(xì)胞黏附分子，在正常組織中低表達(dá)；但腫瘤組織中?，F(xiàn)高表達(dá)并促進(jìn)腫瘤的侵襲和轉(zhuǎn)移，生長(zhǎng)因子能夠上調(diào)Cten的表達(dá)，介導(dǎo)腫瘤細(xì)胞的快速遷移[26]。IL-17調(diào)控腫瘤微環(huán)境，促進(jìn)腫瘤血管生成，參與胃癌進(jìn)程[27]。肝細(xì)胞生長(zhǎng)因子能誘導(dǎo)活化促胃液素釋放肽，介導(dǎo)轉(zhuǎn)錄因子Ets-1的活化上調(diào)IL-8的表達(dá)，促進(jìn)血管生成，腫瘤侵襲和轉(zhuǎn)移[28]；并具有活化腫瘤基質(zhì)纖維母細(xì)胞促進(jìn)胃癌的生成作用[29]。TGF-β1通過(guò)上調(diào)結(jié)蹄組織生長(zhǎng)因子的表達(dá)促進(jìn)腫瘤細(xì)胞的上皮間質(zhì)轉(zhuǎn)化，促進(jìn)腫瘤細(xì)胞黏附與腹膜間質(zhì)[30]。炎性因子前列腺素E2和IL-1處理SNU719細(xì)胞后，細(xì)胞表達(dá)的上皮鈣黏素減少，Snail表達(dá)增多，增強(qiáng)細(xì)胞的上皮間質(zhì)轉(zhuǎn)化，促進(jìn)細(xì)胞遷徙[31]。纖維母細(xì)胞生長(zhǎng)因子9能促進(jìn)多種細(xì)胞的分裂增殖，在胃癌中纖維母細(xì)胞生長(zhǎng)因子9高表達(dá)促進(jìn)胃癌的生長(zhǎng)和轉(zhuǎn)移[32]。

1.3細(xì)胞因子參與胃癌免疫逃逸與化療抵抗機(jī)體發(fā)揮抗腫瘤免疫應(yīng)答，主要通過(guò)DC細(xì)胞的抗原呈遞，激活機(jī)體的細(xì)胞免疫和體液免疫，形成對(duì)腫瘤的殺傷和清除腫瘤組織作用。但機(jī)體中存在復(fù)雜的免疫負(fù)調(diào)節(jié)，能形成免疫耐受，促進(jìn)腫瘤的生長(zhǎng)與轉(zhuǎn)移。細(xì)胞因子能參與調(diào)節(jié)機(jī)體的免疫應(yīng)答，在腫瘤免疫中形成正向或負(fù)向作用，腫瘤發(fā)生時(shí)常介導(dǎo)腫瘤的免疫逃逸。胃癌發(fā)生時(shí)，多種細(xì)胞因子誘導(dǎo)免疫耐受，促進(jìn)胃癌的生長(zhǎng)轉(zhuǎn)移。TGF-β1和 TGF-β2與胃癌的不良預(yù)后密切相關(guān)，在胃癌發(fā)生時(shí)，外周血淋巴細(xì)胞中TGF-β1和 TGF-β2表達(dá)升高，抑制外周血單核細(xì)胞的活性，促進(jìn)早期腫瘤的轉(zhuǎn)移[33]。黏著斑蛋白誘導(dǎo)表達(dá)的炎性因子IL-10、 IL-17b等能調(diào)控腫瘤相關(guān)巨噬細(xì)胞促進(jìn)腫瘤的轉(zhuǎn)移[34]。IL-32能促進(jìn)IL-6、IL-8和血管內(nèi)皮生長(zhǎng)因子分泌形成免疫耐受的微環(huán)境，促進(jìn)細(xì)胞免疫逃逸[6]。Hp感染后，免疫抑制性細(xì)胞因子IL-10 和TGF-β1的表達(dá)顯著上調(diào)，而殺傷性免疫因子干擾素γ表達(dá)下調(diào)，調(diào)節(jié)性T細(xì)胞CD4+IL-10+細(xì)胞 和CD4+CD25+FoxP3+細(xì)胞增多；同時(shí)參與胃組織修復(fù)的骨間充質(zhì)干細(xì)胞進(jìn)一步提高IL-10/干擾素γ、Treg/Th17比例，形成更強(qiáng)的免疫耐受；并活化Wnt和TGF-β信號(hào)，重新獲取和維持腫瘤干細(xì)胞生長(zhǎng)的優(yōu)越微環(huán)境，加速胃癌發(fā)生進(jìn)程[35-36]。此外，腫瘤細(xì)胞分泌細(xì)胞因子能增強(qiáng)胃癌的化療抵抗，如血管內(nèi)皮生長(zhǎng)因子介導(dǎo)腫瘤的侵襲和轉(zhuǎn)移，增加胃癌細(xì)胞化療抵抗能力[37-38]；TGF-β1外分泌能激活受損的胃上皮細(xì)胞中的成纖維細(xì)胞啟動(dòng)組織再生反應(yīng)，增加化療藥物的抵抗性[39]； IL-8過(guò)表達(dá)顯著促進(jìn)胃癌細(xì)胞MKN-45的快速增殖、侵襲轉(zhuǎn)移和化療藥物耐藥性[40]等。

2細(xì)胞因子與胃癌的靶向治療

細(xì)胞因子調(diào)控的炎癥反應(yīng)，細(xì)胞的生長(zhǎng)、侵襲轉(zhuǎn)移與胃癌的形成密切相關(guān)，干擾細(xì)胞因子調(diào)節(jié)腫瘤的生長(zhǎng)，形成的免疫耐受對(duì)胃癌的治療具有重要作用。IL-6家族在炎性相關(guān)腫瘤胃癌中活化gp130/STAT3信號(hào)，介導(dǎo)腫瘤的發(fā)生；IL-11是IL-6 家族成員之一，在胃癌組織中，IL-11與STAT3活化有很強(qiáng)的相關(guān)性，且是IL-6家族與胃癌發(fā)生的最主要成員，在裸鼠移植實(shí)驗(yàn)中，靶向抑制IL-11，能有效抑制STAT3的活化，抑制腫瘤細(xì)胞的增殖、侵襲和腫瘤的生長(zhǎng)，提示抑制IL-11可能是胃癌治療的靶標(biāo)[41]。細(xì)胞因子信號(hào)轉(zhuǎn)導(dǎo)抑制蛋白1(suppressor of cytokine signaling 1，SOCS1)是一個(gè)細(xì)胞因子活化的關(guān)鍵抑制分子，其通過(guò)DCs控制細(xì)胞因子反應(yīng)和抗原呈遞；使用SOCS1特異性地抑制性短肽pJAK2(1001-1013)能有效抑制JAK/STAT 信號(hào)活化，抑制SOCS1的生物學(xué)作用，上調(diào)DCs成熟標(biāo)記分子CD83和共刺激分子CD86的表達(dá)，增強(qiáng)DCs誘導(dǎo)T細(xì)胞增殖、分泌前炎性因子的能力，增強(qiáng)腫瘤抗原特異性殺傷作用，提示靶向抑制SOCS1可能成為抗胃癌治療的有效靶點(diǎn)[42]。荊棘是傳統(tǒng)中藥，主要治療水腫、化膿、疼痛等表皮性疾病，研究顯示其乙醇提取物能抑制腫瘤細(xì)胞的增殖和轉(zhuǎn)移，主要表現(xiàn)在活化p38絲裂原激活的蛋白激酶上調(diào)p21蛋白的表達(dá)、抑制細(xì)胞周期蛋白的表達(dá)，抑制TNF-α 誘導(dǎo)的NF-κB 和激活劑蛋白1的活化，基質(zhì)金屬蛋白酶9的表達(dá)[43]；而另一組研究則顯示，穩(wěn)定表達(dá)TNF-α的臍帶血間充質(zhì)干細(xì)胞可以有效地抑制裸鼠移植瘤的生長(zhǎng)，提示不同環(huán)境下調(diào)控TNF-α的表達(dá)可以發(fā)揮不同的抗腫瘤作用[44]。腫瘤壞死因子相關(guān)凋亡誘導(dǎo)配體分子能逆轉(zhuǎn)腫瘤耐藥基因多藥耐藥性 1、肺耐藥蛋白、谷胱甘肽S-轉(zhuǎn)移酶-π的表達(dá)，增加化療介導(dǎo)的細(xì)胞凋亡和生長(zhǎng)抑制，提示其可能成為反轉(zhuǎn)胃癌化療抵抗的有效靶點(diǎn)[45]。胃動(dòng)蛋白在胃黏膜防御，胃癌發(fā)生中發(fā)揮重要的抑制作用；胃動(dòng)蛋白的高表達(dá)能顯著抑制NF-κB和環(huán)加氧酶2的表達(dá)，調(diào)節(jié)細(xì)胞因子的表達(dá)，抑制腫瘤細(xì)胞的增殖和侵襲能力，促進(jìn)細(xì)胞的凋亡[46]。巨噬細(xì)胞具有兩種類(lèi)型，分別為M1型和M2型，M1型巨噬細(xì)胞抑制腫瘤生長(zhǎng)，而M2型則促進(jìn)腫瘤生長(zhǎng)；使用IL-12和干擾素γ處理前胃癌耐受小鼠M2巨噬細(xì)胞，促使小鼠巨噬細(xì)胞向M1轉(zhuǎn)化，回輸后能有效抑制前胃癌移植瘤的生長(zhǎng)，提示細(xì)胞因子處理巨噬細(xì)胞M1型轉(zhuǎn)化是一種胃癌免疫治療的可能手段[47]。趨化因子配體18(CCL18)是樹(shù)突狀細(xì)胞趨化細(xì)胞因子，表達(dá)于多種淋巴細(xì)胞中，作用的靶細(xì)胞為CD4+、CD8+、CD45RA+和B淋巴細(xì)胞，其可作為胃癌預(yù)后的特異性標(biāo)志物，CCL18的高表達(dá)預(yù)示著更好的預(yù)后，提示靶向上調(diào)CCL18的表達(dá)可以有效抑制胃癌的生長(zhǎng)[48]。綜上所述，細(xì)胞因子能從調(diào)控腫瘤細(xì)胞生長(zhǎng)、侵襲與轉(zhuǎn)移，機(jī)體的免疫系統(tǒng)殺傷等多角度抑制胃癌的生長(zhǎng)，達(dá)到抗腫瘤治療的目的。因此有理由相信，靶向調(diào)控細(xì)胞因子的水平可成為抗腫瘤治療的新途徑。

3小結(jié)

細(xì)胞因子具有調(diào)節(jié)細(xì)胞生成、細(xì)胞生長(zhǎng)以及損傷組織修復(fù)等多種功能。胃癌的發(fā)生、發(fā)展過(guò)程中，細(xì)胞因子調(diào)控細(xì)胞增殖轉(zhuǎn)移信號(hào)及腫瘤生長(zhǎng)微環(huán)境(炎癥反應(yīng)和免疫抑制)為胃癌的發(fā)生、發(fā)展提供了良好的“沃土”。靶向細(xì)胞因子調(diào)節(jié)腫瘤的生長(zhǎng)、侵襲與轉(zhuǎn)移，打破腫瘤的免疫耐受成為胃癌治療的新方向。但細(xì)胞因子與胃癌的關(guān)系還未闡明，多種細(xì)胞因子與胃癌的作用是雙向的，在胃癌發(fā)展不同時(shí)期分別發(fā)揮促進(jìn)或抑制胃癌的作用；因此未來(lái)應(yīng)重點(diǎn)關(guān)注這種多向分子，系統(tǒng)闡明調(diào)控這些細(xì)胞因子表達(dá)的機(jī)制，不同環(huán)境中細(xì)胞因子的生物學(xué)作用及其基因多態(tài)性與胃癌發(fā)生、發(fā)展的作用，逐步闡明胃癌不同時(shí)期細(xì)胞因子的作用機(jī)制；從而應(yīng)用細(xì)胞因子進(jìn)行胃癌的個(gè)體化靶向治療，為胃癌的治療提供新途徑。

參考文獻(xiàn)

[1]Yasmin R,Siraj S,Hassan A,etal.Epigenetic regulation of inflammatory cytokines and associated genes in human malignancies[J].Mediat Inflamm,2015,2015:201703.

[2]Jemal A,Bray F,Center MM,etal.Global cancer statistics[J].CA Cancer J Clin,2011,61(2):69-90.

[3]Ferlay J,Shin HR,Bray F,etal.Estimates of worldwide burden of cancer in 2008:GLOBOCAN 2008[J].Int J Cancer,2010,127(12):2893-2917.

[4]Cervantes A,Roda D,Tarazona N,etal.Current questions for the treatment of advanced gastric cancer[J].Cancer Treat Rev,2013,39(1):60-67.

[5]Saito H,Oyama K,Fushida S,etal.A case of gastric adenosquamous carcinoma producing granulocyte-colony stimulating factor[J].Gan To Kagaku Ryoho,2013,40(6):799-802.

[6]Ishigami S,Arigami T,Uchikado Y,etal.IL-32 expression is an independent prognostic marker for gastric cancer[J].Med Oncol,2013,30(2):472.

[7]Howlader N,Ries LA,Mariotto AB,etal.Improved estimates of cancer-specific survival rates from population-based data[J].J Natl Cancer Inst,2010,102(20):1584-1598.

[8]Allison CC,Ferrand J,McLeod L,etal.Nucleotide oligomerization domain 1 enhances IFN-gamma signaling in gastric epithelial cells during Helicobacter pylori infection and exacerbates disease sev-erity[J].J Immunol,2013,190(7):3706-3715.

[9]Lagunes-Servin H,Torres J,Maldonado-Bernal C,etal.Toll-Like Receptors and Cytokines are Upregulated during Helicobacter pylori Infection in Children[J].Helicobacter,2013,18(6):423-432.

[10]Huang FY,Chan AO,Lo RC,etal.Characterization of interleukin- 1beta in Helicobacter pylori-induced gastric inflammation and DNA methylation in interleukin-1 receptor type 1 knockout (IL-1R1-/-) mice[J].Eur J Cancer,2013,49(12):2760-2770.

[11]Sakitani K,Hirata Y,Hayakawa Y,etal.Role of interleukin-32 in Helicobacter pylori-induced gastric inflammation[J].Infect Immun,2012,80(11):3795-3803.

[12]Kimang′a AN.IL-1B-511 Allele T and IL-1RN-L/L Play a Pathological Role in Helicobacter Pylori (H.Pylori) Disease Outcome in the African Population[J].Ethiop J Health Sci,2012,22(3):163-169.

[13]Tahara T,Shibata T,Yamashita H,etal.Synergistic effect of IL-1beta and TNF-alpha polymorphisms on the H.pylori-related gastric pre-malignant condition[J].Hepatogastroenterology,2012,59(120):2416-2420.

[14]Li K,Xia F,Zhang K,etal.Association of a tgf-b1-509c/t polymorphism with gastric cancer risk:a meta-analysis[J].Ann Hum Genet,2013,77(1):1-8.

[15]de Oliveira JG,Rossi AF,Nizato DM,etal.Profiles of gene polymorphisms in cytokines and Toll-like receptors with higher risk for gastric cancer[J].Dig Dis Sci,2013,58(4):978-988.

[16]Yang CA,Scheibenbogen C,Bauer S,etal.A frequent Toll-like receptor 1 gene polymorphism affects NK- and T-cell IFN-gamma production and is associated with Helicobacter pylori-induced gastric disease[J].Helicobacter,2013,18(1):13-21.

[17]Wang F,Sun G,Zou Y.Associations between interleukin-6 gene -174 C/G and -572 C/G polymorphisms and risk of gastric cancer[J].J Surg Oncol,2013,107(7):789.

[18]Xue H,Wang YC,Lin B,etal.A meta-analysis of interleukin-10 -592 promoter polymorphism associated with gastric cancer risk[J].PLoS One,2012,7(7):e39868.

[19]Yuan LJ,Jin TB,Yin JK,etal.Polymorphisms of tumor-related genes IL-10,PSCA,MTRR and NOC3L are associated with the risk of gastric cancer in the Chinese Han population[J].Cancer Epidemiol,2012,36(6):e366-372.

[20]Nishiura H,Iwamoto S,Kido M,etal.Interleukin-21 and tumor necrosis factor-alpha are critical for the development of autoimmune gastritis in mice[J].J Gastroenterol Hepatol,2013,28(6):982-991.

[21]Epplein M,Xiang YB,Cai Q,etal.Circulating cytokines and gastric cancer risk[J].Cancer Causes Control,2013,24(12):2245-2250.

[22]Wei Z,Jiang X,Qiao H,etal.STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells[J].Cell Signal,2013,25(4):931-938.

[23]Soutto M,Belkhiri A,Piazuelo MB,etal.Loss of TFF1 is associated with activation of NF-kappaB-mediated inflammation and gastric neoplasia in mice and humans[J].J Clin Invest,2011,121(5):1753-1767.

[24]You W,Tang Q,Zhang C,etal.IL-26 promotes the proliferation and survival of human gastric cancer cells by regulating the balance of STAT1 and STAT3 activation[J].PLoS One,2013,8(5):e63588.

[25]Hao Q,Li W,Zhang C,etal.TNFα induced FOXP3-NFkappaB interaction dampens the tumor suppressor role of FOXP3 in gastric cancer cells[J].Biochem Biophys Res Commun，2013，430(1):436-441.

[26]Hung SY,Shih YP,Chen M,etal.Up-Regulated Cten by FGF2 Contributes to FGF2-Mediated Cell Migration[J].Mol Carcinog,2013,53(10):787-792.

[27]Meng XY,Zhou CH,Ma J,etal.Expression of interleukin-17 and its clinical significance in gastric cancer patients[J].Med Oncol,2012,29(5):3024-3028.

[28]Lee KH,Koh SA,Kim JR.Hepatocyte growth factor-mediated gastrin-releasing peptide induces IL-8 expression through Ets-1 in gastric cancer cells[J].Oncol Res,2013,20(9):393-402.

[29]Wu X,Chen X,Zhou Q,etal.Hepatocyte growth factor activates tumor stromal fibroblasts to promote tumorigenesis in gastric cancer[J].Cancer Lett,2013,335(1):128-135.

[30]Jiang CG,Lv L,Liu FR,etal.Connective tissue growth factor is a positive regulator of epithelial-mesenchymal transition and promotes the adhesion with gastric cancer cells in human peritoneal mesothelial cells[J].Cytokine,2013,61(1):173-180.

[31]Jee YS,Jang TJ,Jung KH.Prostaglandin E(2) and interleukin-1beta reduce E-cadherin expression by enhancing snail expression in gastric cancer cells[J].J Korean Med Sci,2012,27(9):987-992.

[32]Deng M,Tang HL,Lu XH,etal.miR-26a suppresses tumor growth and metastasis by targeting FGF9 in gastric cancer[J].PLoS One,2013,8(8):e72662.

[33]Ma GF,Miao Q,Zeng XQ,etal.Transforming growth factor-beta1 and -beta2 in gastric precancer and cancer and roles in tumor-cell interactions with peripheral blood mononuclear cells in vitro[J].PLoS One,2013,8(1):e54249.

[34]Shen Z,Ye Y,Kauttu T,etal.The novel focal adhesion gene kindlin-2 promotes the invasion of gastric cancer cells mediated by tumor-associated macrophages[J].Oncol Rep,2013,29(2):791-797.

[35]Lin R,Ma H,Ding Z,etal.Bone marrow-derived mesenchymal stem cells favor the immunosuppressive T cells skewing in a helicobacter pylori model of gastric cancer[J].Stem Cells Dev,2013,22(21):2836-2848.

[36]Nishimura K,Semba S,Aoyagi K,etal.Mesenchymal stem cells provide an advantageous tumor microenvironment for the restoration of cancer stem cells[J].Pathobiology,2012,79(6):290-306.

[37]Jun Cho H,Kim IK,Park SM,etal.VEGF-c mediates RhoGDI2‐induced gastric cancer cell metastasis and cisplatin resistance[J].Int J Cancer,2014,135(7):1553-1563.

[38]Hwang JE,Lee JH,Park MR,etal.Blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in gastric cancer cells[J].Yonsei Med J,2013,54(2):374-380.

[39]Tsukada T,Fushida S,Harada S,etal.Low-dose paclitaxel modulates tumour fibrosis in gastric cancer[J].Int J Oncol,2013,42(4):1167-1174.

[40]Kuai WX,Wang Q,Yang XZ,etal.Interleukin-8 associates with adhesion,migration,invasion and chemosensitivity of human gastric cancer cells[J].World J Gastroenterol,2012,18(9):979-985.

[41]Putoczki TL,Thiem S,Loving A,etal.Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically[J].Cancer Cell,2013,24(2):257-271.

[42]Wang Y,Wang S,Ding Y,etal.A suppressor of cytokine signaling 1 antagonist enhances antigen-presenting capacity and tumor cell antigen-specific cytotoxic T lymphocyte responses by human monocyte-derived dendritic cells[J].Clin Vaccine Immunol,2013,20(9):1449-1456.

[43]Lee SJ,Ryu DH,Jang LC,etal.Suppressive effects of an ethanol extract of Gleditsia sinensis thorns on human SNU-5 gastric cancer cells[J].Oncol Rep,2013,29(4):1609-1616.

[44]Mao W,Zhu X,Tang D,etal.TNF-alpha expression in the UCB-MSCs as stable source inhibits gastric cancers growth in nude mice[J].Cancer Invest,2012,30(6):463-472.

[45]Zhang KG,Qin CY,Wang HQ,etal.The effect of TRAIL on the expression of multidrug resistant genes MDR1,LRP and GST-pi in drug-resistant gastric cancer cell SGC7901/VCR[J].Hepatogastroenterology,2012,59(120):2672-2676.

[46]Yoon JH,Cho ML,Choi YJ,etal.Gastrokine 1 regulates NF-kappaB signaling pathway and cytokine expression in gastric cancers[J].J Cell Biochem,2013,114(8):1800-1809.

[47]Liu H,Wu X,Wang S,etal.In vitro repolarized tumor macrophages inhibit gastric tumor growth[J].Oncol Res,2013,20(7):275-280.

[48]Yuan R,Chen Y,He X,etal.CCL18 as an independent favorable prognostic biomarker in patients with colorectal cancer[J].J Surg Res,2013,183(1):163-169.

Progress in the Study of Cellular Factors Involved in the Occurrence and Development of Gastric CancerLIKang，DANZeng.(DepartmentFourofInternalMedicine,People′sHospitalofTibetAutonomousRegion,Lhasa850000,China)

Abstract：Cytokines are a kind of protein or small molecular peptides and play a role in passing information between the cells or regulating immune response.The abnormal expressions of cytokines often cause a variety of diseases,including stomach cancer.Cytokines are involved in the regulation of gastric cancer cells carcinogenesis,invasion and metastasis,angiogenesis and immune escape by regulating tumor related antigen presentation and lymphocytes activation.What′s more,cytokines also play an important role in gastric cancer cells resisting radiation and chemotherapy.Therefore,regulation of the body′s cytokines levels to form the antitumor effect of gastric cancer has become a new trend for the treatment of gastric cancer.

Key words：Gastric cancer; Cytokines; Immune escape

收稿日期:2015-01-28修回日期:2015-06-09編輯：薛惠文

基金項(xiàng)目：國(guó)家自然科學(xué)基金(81060165)

doi：10.3969/j.issn.1006-2084.2015.20.019

中圖分類(lèi)號(hào)：R34

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：1006-2084(2015)20-3697-04