王 倩 范文濤
(陜西中醫(yī)學(xué)院,咸陽(yáng),712046)
綜 述
馬齒莧多糖對(duì)潰瘍性結(jié)腸炎相關(guān)性結(jié)腸癌IL-6/STAT3信號(hào)通路的影響
王 倩 范文濤
(陜西中醫(yī)學(xué)院,咸陽(yáng),712046)
最新研究報(bào)道,慢性炎癥是導(dǎo)致腫瘤發(fā)生、發(fā)展的重要因素。結(jié)腸、直腸的慢性炎癥導(dǎo)致炎癥局部組織發(fā)生反復(fù)的損傷、修復(fù)、增生,最終引起癌變。因此,研究如何干預(yù)慢性炎癥癌變成為降低結(jié)直腸癌的發(fā)生的重要方法。本文探討馬齒莧對(duì)腸道炎癥及腫瘤發(fā)生、發(fā)展的影響,及其與IL-6/STAT3通路的關(guān)系。為預(yù)防炎癥性腸病癌變,提供新的研究思路。
馬齒莧多糖;潰瘍性結(jié)腸炎相關(guān)性結(jié)腸癌;IL-6/STAT3
結(jié)直腸慢性炎癥反復(fù)損傷、修復(fù)、增生,引起基因突變及細(xì)胞癌變。因此,炎癥性腸病的早期干預(yù)是預(yù)防癌變的重要途徑。本文探討馬齒莧對(duì)IL-6/STAT3信號(hào)通路的影響,為預(yù)防炎癥性腸病癌變,降低結(jié)直腸癌發(fā)病率,提供新的研究思路。
潰瘍性結(jié)腸炎(uleerativeeolitis,uc)是一種病因復(fù)雜的消化道疑難病,在西方國(guó)家的發(fā)病率高達(dá)234/10萬(wàn),在我國(guó)也呈逐年上升趨勢(shì)。由于結(jié)腸炎癥反復(fù)發(fā)作,遷延不愈,25月以上病程癌變率高達(dá)40%。慢性炎癥的反復(fù)損傷、修復(fù)、增生、引起基因突變,從而引起細(xì)胞癌變,大約有20%的人類癌癥來(lái)源于慢性炎癥[1]。據(jù)報(bào)道,上海市的結(jié)腸癌發(fā)病率、病死率均明顯升高,在眾多惡性腫瘤中其病死率已躍居第2位。因此,對(duì)于結(jié)腸炎癥的有效治療是阻止結(jié)腸炎向結(jié)腸癌演變的重要手段[2]。
炎癥因子在潰瘍性結(jié)腸炎癌變機(jī)制中起著舉足輕重的作用,潰瘍性結(jié)腸炎是一種慢性炎癥性病變,癌變模式為炎癥—不典型增生(低度、高度)—癌變。白介素等多種炎癥因子參與潰瘍性結(jié)腸炎的癌變過(guò)程[3]。臨床研究發(fā)現(xiàn),結(jié)腸癌患者的血清和癌組織中IL-6水平均增高,且IL-6的濃度與腫瘤大小、腫瘤轉(zhuǎn)移、預(yù)后和生存率相關(guān)[4]。這些結(jié)果提示IL-6可能與結(jié)腸癌發(fā)病有關(guān)。后繼的研究發(fā)現(xiàn),sIL-6R能夠通過(guò)調(diào)節(jié)結(jié)腸腫瘤細(xì)胞與血管內(nèi)皮的粘附促進(jìn)腫瘤轉(zhuǎn)移灶形成[5]。在炎性腸病患者中,IL-6信號(hào)通路下游關(guān)鍵調(diào)節(jié)子STAT3持續(xù)活化,而在多種人類腫瘤中也可觀察到STAT3持續(xù)激活,如宮頸鱗狀細(xì)胞癌[6]。甚至有學(xué)者因STAT3可以誘導(dǎo)培養(yǎng)細(xì)胞向癌細(xì)胞轉(zhuǎn)化以及在裸鼠中STAT3促腫瘤形成而將它歸為致癌基因[7]。目前認(rèn)為,STAT3促腫瘤機(jī)制可能是STAT3信號(hào)通路上游IL-6信號(hào)轉(zhuǎn)導(dǎo)失調(diào)導(dǎo)致p-STAT3增高,進(jìn)而引起通路下游抗凋亡基因和細(xì)胞周期相因子表達(dá)失調(diào),最終導(dǎo)致腫瘤的發(fā)生[8]。
IL-6/STAT3信號(hào)通路在結(jié)腸癌發(fā)病機(jī)制中扮演非常重要的角色,有可能成為新的治療靶點(diǎn)[9]。大量臨床和動(dòng)物實(shí)驗(yàn)證實(shí)阻斷IL-6/STAT3通路傳導(dǎo)是治療結(jié)腸癌的有效手段,研究發(fā)現(xiàn)阻斷IL-6/STAT3信號(hào)通路能夠抑制實(shí)驗(yàn)性黑色素瘤、小鼠前列腺癌以及胃腫瘤的發(fā)生,與其能夠下調(diào)下游Bcl-xl分子表達(dá)并誘導(dǎo)細(xì)胞凋亡有關(guān)[9]。這些研究證實(shí),調(diào)控IL-6/STAT3通路有潛在的抗腫瘤作用。對(duì)炎癥、癌癥中IL -6/STAT3通路的深入研究,為研發(fā)針對(duì)此通路的特異性藥物提供了理論基礎(chǔ)[10]。這些新的藥物可以靶向性的針對(duì)炎癥瀑布反應(yīng)中IL-6/STAT3信號(hào)通路的效應(yīng)因子產(chǎn)生作用,進(jìn)而抑制結(jié)腸癌的發(fā)生和發(fā)展。為結(jié)腸癌的診療提供新思路,并有可能成為結(jié)腸癌治療的有效手段[11]。
馬齒莧為馬齒莧科植物馬齒莧(Portulaca oleraceaL.)的干燥地上部分,首載于《神農(nóng)本草經(jīng)》。性味酸寒,歸肝、大腸經(jīng)。功效主治:清熱解毒,涼血止血,用于熱毒血痢[12]?,F(xiàn)代藥理研究發(fā)現(xiàn)馬齒莧包含多糖類、黃酮類、生物堿類等多種化學(xué)成分,其中馬齒莧多糖具有抗氧化活性、并能提高小鼠腹腔巨噬細(xì)胞的吞噬功能,促進(jìn)淋巴細(xì)胞轉(zhuǎn)化,調(diào)節(jié)機(jī)體的免疫功能[13]。能抑制炎癥趨化因子及其受體CINC-1及CXCR2的表達(dá),從而影響中性粒細(xì)胞向炎癥區(qū)域的趨化[14]。
多糖是由單糖基通過(guò)糖苷鍵連接而成的化合物[15]。越來(lái)越多的研究證明,多糖不但能治療使機(jī)體的免疫系統(tǒng)受到嚴(yán)重?fù)p傷的癌癥,還能治療多種免疫缺損疾病,如慢性病毒性肝炎和某些細(xì)菌和病毒引起的慢性病,還能治療風(fēng)濕病之類的疾病,有的多糖還能誘導(dǎo)干擾素的產(chǎn)生[16-17]??傊?,多糖具有調(diào)節(jié)免疫功能、抗腫瘤、抗病毒病菌、降血糖血脂、抗?jié)儯?8-19]。與其他植物多糖一樣,馬齒莧多糖具有廣泛的藥理作用,主要包括抗腫瘤、抗氧化與調(diào)節(jié)免疫功能等作用[20]。
馬齒莧多糖可以明顯促進(jìn)體外腹腔巨噬細(xì)胞的吞噬功能和NO及細(xì)胞因子IL-1的產(chǎn)生[21]。巨噬細(xì)胞表面存在有多糖受體,馬齒莧多糖可能通過(guò)與受體結(jié)合激活巨噬細(xì)胞,促進(jìn)巨噬細(xì)胞分泌NO和釋放效應(yīng)因子IL-1,表明馬齒莧多糖可通過(guò)活化巨噬細(xì)胞,增強(qiáng)機(jī)體的免疫反應(yīng)作用[22]。
馬齒莧多糖具有明確的抗腫瘤活性,可使小鼠T淋巴細(xì)胞數(shù)量增加,體外對(duì)肝癌細(xì)胞SMMC7721的增殖具有一定的抑制作用,體內(nèi)可使小鼠S180腹水瘤分裂指數(shù)顯著下降,并能明顯抑制小鼠S180移植性實(shí)體瘤生長(zhǎng)??擅黠@促進(jìn)淋巴細(xì)胞的轉(zhuǎn)化,增強(qiáng)小鼠腹腔巨噬細(xì)胞吞噬能力,可有效的增加荷瘤小鼠脾淋巴細(xì)胞的轉(zhuǎn)化和腹腔巨噬細(xì)胞的吞噬能力以及白介素-1(IL-1)和白介素-2(IL-2)的分泌。其作用機(jī)制是提高體內(nèi)細(xì)胞免疫功能而發(fā)揮抗腫瘤作用[23]。
因此,采用馬齒莧多糖早期調(diào)控IL-6/STAT3信號(hào)通路,能有效減少潰瘍性結(jié)腸炎癌變,降低結(jié)腸癌發(fā)病率,提高患者生存質(zhì)量,尋找防治結(jié)腸癌新的途徑。充分發(fā)揮中醫(yī)藥整體、多途徑、多層次、多靶點(diǎn)的優(yōu)勢(shì),促進(jìn)中醫(yī)藥現(xiàn)代化的發(fā)展。
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(2012-12-11收稿)
Effect of Purslane Polysaccharide on Ulcerative Colitis Associated Colorectal Cancer and IL-6/STAT3 Pathway
Wang Qian,F(xiàn)anWentao
(Shanxi University of Chinese Medicine,Xianyang 712046,China)
Latest reports showed that chronic inflammation is an important factor leading to tumors.Chronic inflammation of the colon and rectum would lead to repeated damage,repair and proliferation of the local tissues in inflammation area,and eventually cause cancer.Therefore,finding out how to intervene the chronic inflammation so as to decrease the occurrence of colorectal cancer has become an importantmethod.This article explored the effects of purslane on intestinal inflammation,occurrence and development of tumor,aswell as its relation to IL-6/STAT3 pathway.It provided new research ideas to the prevention of inflammatory bowel diseases.
Purslane polysaccharide;Ulcerative colitis associated colorectal cancer;IL-6/STAT3
10.3969/j.issn.1673-7202.2013.10.044
國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào):81202847)
王倩(1978—),女,博士,主治醫(yī)師,講師,主要從事消化系統(tǒng)疾病臨床與實(shí)驗(yàn)研究,E-mail:1404113637@qq.com