血清HGF和IL-6水平與非小細(xì)胞肺癌預(yù)后的相關(guān)性研究

孫　真，薛　穎，王東霞，王　英　(解放軍第二炮兵總醫(yī)院呼吸科，北京 100088)

血清HGF和IL-6水平與非小細(xì)胞肺癌預(yù)后的相關(guān)性研究

孫真，薛穎，王東霞，王英(解放軍第二炮兵總醫(yī)院呼吸科，北京 100088)

[摘要]目的研究非小細(xì)胞肺癌患者血清中HGF和IL-6水平與其預(yù)后的相關(guān)性。 方法我院2013年3月至2014年5月109例患者進(jìn)行肺癌根治手術(shù)，術(shù)前檢測(cè)血清中HGF和IL-6的濃度，術(shù)后對(duì)所有患者隨訪1年?；颊吣[瘤分期：Ⅰ-Ⅱ期組67例、Ⅲ期組38例及IV期組2例；腫瘤類型：腺癌(ADC)患者79例、鱗癌(SCC)患者26例以及4名其他非小細(xì)胞肺癌患者；TNM分期：pN(-)組72例、pN(+)組31例；pT(T1-T2)組77例、pT(T3-T4)組28例。結(jié)果血清中HGF和IL-6的平均濃度分別為860 pg/mL和2.7 pg/mL。生存分析顯示血清HGF水平并不影響非小細(xì)胞肺癌患者的腫瘤分期及分型，而鱗癌組患者血清IL-6水平明顯低于其他癌癥類型患者(P=0.001)。高HGF和IL-6組的患者總生存率要差于低HGF和IL-6組的患者，差異有統(tǒng)計(jì)學(xué)意義(HGF，P=0.019；IL-6，P=0.002)。Ⅲ期患者中分析顯示，與低HGF和IL-6組的患者比較，高HGF和IL-6組表現(xiàn)出較差的總生存率。結(jié)論HGF和IL-6的水平可作為預(yù)測(cè)非小細(xì)胞肺癌患者預(yù)后的有效指標(biāo)。

[關(guān)鍵詞]非小細(xì)胞肺癌；血清；肝臟生長(zhǎng)因子；白細(xì)胞介素

肺癌是世界上發(fā)病率較高的惡性腫瘤[1-2]，目前尚無(wú)有效針對(duì)肺癌的腫瘤標(biāo)志物以達(dá)到早期診斷、早期治療的目的。因此選取有效的血清學(xué)標(biāo)志預(yù)測(cè)Ⅲ期非小細(xì)胞肺癌患者的預(yù)后對(duì)于治療方案的選擇有重要的指導(dǎo)意義。肝細(xì)胞生長(zhǎng)因子(hepatic growth factor，HGF)是肝臟的再生過(guò)程釋放到血液中的一種因子[3-4]，可以通過(guò)增強(qiáng)腫瘤細(xì)胞的遷移能力和促進(jìn)血管生成，進(jìn)而促進(jìn)腫瘤的增殖和遷移[5]。大多數(shù)表皮細(xì)胞和癌細(xì)胞表明均有HGF受體(c-MET)和原癌基因表達(dá)產(chǎn)物[6]。血清或腫瘤組織中HGF的濃度與多種癌癥的進(jìn)展相關(guān)[7-10]。白細(xì)胞介素-6(interleukin-6，IL-6)具有多種功能并且在多種腫瘤中表現(xiàn)出促進(jìn)腫瘤進(jìn)展的能力[11]，可以通過(guò)激活小鼠肺泡上皮細(xì)胞的STAT3通路介導(dǎo)炎癥的發(fā)生和肺腺癌的發(fā)生[12]。人肺腺癌細(xì)胞突變的表皮生長(zhǎng)因子受體(EGFR)可以通過(guò)上調(diào)IL-6的表達(dá)進(jìn)而激活STAT3途徑[13]。目前對(duì)于血清中HGF和IL-6的水平能否作為非小細(xì)胞肺癌預(yù)后的因素目前仍不清楚。本研究旨在通過(guò)這項(xiàng)研究明確非小細(xì)胞肺癌患者血清中HGF和IL-6的水平和其生存率之間的關(guān)系。

1資料與方法

1.1臨床資料

我院2013年3月至2014年5月109例患者進(jìn)行肺癌根治手術(shù)，其中男67例，女42例。53例年齡大于66歲，55例小于等于66歲。按照UICC第7版的標(biāo)準(zhǔn)對(duì)腫瘤進(jìn)行病理學(xué)分期。按照腫瘤分期109例患者分為I-Ⅱ期組67例、Ⅲ期組38例及IV期組2例。109例患者包括腺癌(adenocarcinoma，ADC)患者79例、鱗癌(squamous carcinoma，SCC)患者26例以及4例其他非小細(xì)胞肺癌患者，分別為ADC組、SCC組和其它組。按照TNM分期109例患者分成pN(-)組72例、pN(+)組31例；pT(T1-T2)組77例、pT(T3-T4)組28例。

1.2檢測(cè)方法

109例患者手術(shù)前均采血，血樣在室溫靜置20 min，隨后5 800 g離心5 min，分離血清，于-70 ℃凍存。使用ELISA試劑盒(eBioscience公司)檢測(cè)血清中HGF和IL-6的水平。

1.3統(tǒng)計(jì)學(xué)分析

臨床結(jié)果的關(guān)系以及HGF和IL-6含量分析采用Mann Whitney或者Kruskal Wallis test方法分析。采用Spearman’s rank correlation test對(duì)相關(guān)性進(jìn)行分析。采用log-rank檢驗(yàn)對(duì)預(yù)后相關(guān)單因素進(jìn)行分析，采用Cox比例風(fēng)險(xiǎn)模型對(duì)預(yù)后相關(guān)的多因素進(jìn)行分析，最終采用SPSS 19.0軟件對(duì)數(shù)據(jù)進(jìn)行統(tǒng)計(jì)學(xué)分析。P<0.05為具有統(tǒng)計(jì)學(xué)差異。

2結(jié)果

2.1患者血清HGF和IL-6水平

血清HGF水平范圍為215～2 000 pg/mL，平均水平875 pg/mL。對(duì)于年齡、性別、腫瘤種類、腫瘤分期、pN及pT因素分組的患者的HGF水平比較，并無(wú)顯著性統(tǒng)計(jì)學(xué)差異(P=0.584，P=0.086)；血清IL-6水平范圍為0～62.0 pg/mL，中值水平2.7 pg/mL，平均水平5.0 pg/mL。SCC組患者及大于66歲患者的IL-6水平顯著性高于其他組，且不同腫瘤類型患者的IL-6水平也存在明顯統(tǒng)計(jì)學(xué)差異，P=0.001具有統(tǒng)計(jì)學(xué)差異。

2.2生存率相關(guān)分析

對(duì)各個(gè)分期的患者(Ⅰ期50例，Ⅱ期17例，Ⅲ期38例)進(jìn)行整體生存率分析比較，發(fā)現(xiàn)Ⅰ～Ⅱ期患者與Ⅲ期患者的生存率存在統(tǒng)計(jì)學(xué)差異(P<0.001)。雖然Ⅱ期患者人數(shù)較少，但Ⅱ期患者都接受了和I期患者同樣的手術(shù)，因此本研究中將Ⅰ期和Ⅱ期患者合并分析。腫瘤大小(T因素)也是一個(gè)非常重要的預(yù)后因子。

腺癌患者的預(yù)后明顯好于其他類的非小細(xì)胞肺癌患者(P=0.007)。女性患者的預(yù)后好于男性患者(P=0.023)。對(duì)單個(gè)因素進(jìn)行統(tǒng)計(jì)學(xué)分析發(fā)現(xiàn)：性別、分期、組織學(xué)分型、HGF水平、IL-6水平、pT和pN對(duì)整體生存率都有影響；對(duì)多因素進(jìn)行統(tǒng)計(jì)學(xué)分析發(fā)現(xiàn)：IL-6 (P=0.034，HR=3.46)，淋巴結(jié)轉(zhuǎn)移pN因素(P=0.004，HR=3.71)以及pT因素(P=0.001，HR=4.41)具有顯著性統(tǒng)計(jì)學(xué)差異(見(jiàn)表2)。

單因素分析結(jié)果顯示組織學(xué)分型、分期、pN因素以及pT因素都具有統(tǒng)計(jì)學(xué)差異；多因素分析結(jié)果顯示組織學(xué)分型(P=0.02，HR=2.40)和pN 因素(P=0.036，HR=2.41)具有統(tǒng)計(jì)學(xué)差異。

2.3Ⅲ期臨床患者生存率相關(guān)分析

對(duì)Ⅲ期臨床患者進(jìn)行整體生存率的多因素分析發(fā)現(xiàn)：高血清HGF水平(P=0.038，HR=3.97)以及高血清IL-6水平(P=0.045，HR=4.76)的患者預(yù)后較差。非ADC的NSCLC患者的預(yù)后相比ADC患者較差，盡管組織學(xué)分型會(huì)影響IL-6的血清水平，但納入IL-6后上述差異便沒(méi)有了統(tǒng)計(jì)學(xué)意義。另一方面，HGF和IL-6血清水平與Ⅰ～Ⅱ期患者整體生存率和無(wú)病生存率無(wú)關(guān)聯(lián)。

3討論

HGF是一個(gè)促浸潤(rùn)刺激因子，其可以誘導(dǎo)細(xì)胞分化，高血清HGF水平可作為潛在的轉(zhuǎn)移標(biāo)記[14-15]。也有報(bào)道[16]稱腫瘤細(xì)胞或炎癥細(xì)胞分泌的IL-6能夠刺激肺部成纖維細(xì)胞分泌HGF。IL-6直接刺激肺部腫瘤的發(fā)展[13]。還有文獻(xiàn)[17-18]報(bào)道稱IL-6水平會(huì)隨著NSCLC分期的進(jìn)展而增加，推測(cè)出低水平的血清IL-6與好的化學(xué)治療效果的相關(guān)性。若腫瘤細(xì)胞從初始腫瘤位點(diǎn)轉(zhuǎn)移，則會(huì)刺激局部釋放IL-6和HGF，這將會(huì)加劇疾病發(fā)生。本研究結(jié)果顯示了HGF和IL-6水平的相關(guān)性，認(rèn)為IL-6水平一定程度上可以反映HGF的血清水平。

無(wú)病生存率受這些細(xì)胞因子的影響，但癌癥復(fù)發(fā)率與這些細(xì)胞因子水平并無(wú)關(guān)聯(lián)?；瘜W(xué)治療將會(huì)影響整體生存率。Kasahara等[19]分析了晚期NSCLC患者的HGF血清水平。發(fā)現(xiàn)吉非替尼耐受與HGF的水平相關(guān)，這與前期研究[20-21]證明的HGF/MET信號(hào)通路在EGFR突變的NSCLC患者對(duì)吉非替尼耐受中起重要作用是一致的。IL-6也可作為前列腺癌癥患者耐受多靶點(diǎn)的受體酪氨酸激酶抑制劑的生物學(xué)標(biāo)志物[22]。本研究中，對(duì)可切除Ⅲ期NSCLC癌癥的患者使用紫杉醇和卡鉑進(jìn)行輔助化學(xué)治療，結(jié)果顯示HGF和IL-6會(huì)誘導(dǎo)對(duì)化學(xué)治療的耐受。已有報(bào)道[23-24]稱IL-6通過(guò)激活細(xì)胞內(nèi)PI3K/AKT和STAT3信號(hào)通路降低癌細(xì)胞對(duì)化學(xué)藥物的敏感度，例如紫杉醇和卡鉑；而HGF也具有相似的功能。

本研究發(fā)現(xiàn)，患者血清HGF水平并不影響非小細(xì)胞肺癌患者的腫瘤分期及分型。不同性別、年齡、TNM分期的患者HGF水平也無(wú)顯著性統(tǒng)計(jì)學(xué)差異。而鱗癌組患者血清IL-6水平明顯低于其他癌癥類型患者。對(duì)患者生存率的分析發(fā)現(xiàn)，高HGF和IL-6組的患者總生存率要差于低HGF和IL-6組的患者，差異有統(tǒng)計(jì)學(xué)意義。單獨(dú)在Ⅲ期患者中分析同樣顯示，相比低HGF和IL-6組的患者，高HGF和IL-6組同樣表現(xiàn)出較差的總生存率，說(shuō)明HGF和IL-6可作為癌癥治療的分子標(biāo)靶，低血清IL-6和HGF水平Ⅲ期NSCLC患者采用手術(shù)治療方案能獲得更長(zhǎng)的生存期。

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(編輯：左艷芳)

Correlation research between prognosis of NSCLC patient and serum levels of HGF and IL-6

SUN Zhen，XUE Ying，WANG Dong-xia，WANG Ying(Department of Respiratory Medicine，PLA Second Artillery General Hospital，Beijing 100088， China)

Abstract:ObjectiveTo study the correlation between prognosis of non-small cell lung cancer (NSCLC) patient and serum levels of HGF and IL-6. MethodsEligible 109 NSCLC patients and preoperative blood samples of each patient in our hospital from March 2013 to May 2014 were collected.Then the levels of HGF and IL-6 of serum samples were detected by using ELISA kit.All patients were followed up for 1 year.The neoplasm staging:67 cases were staging Ⅰ-Ⅱ,38 cases were staging Ⅲ,2 cases were staging IV.There were 79 cases with adenomatous carcinoma(ADC),26 cases with squamous carcinoma(SCC) and 4 cases with NSCLC.According to the TNM staging,there were 79 cases in pN(-) group,31 in pN(+) group,77 in pT(T1-T2) group and 28 in pT(T3-T4) group. ResultsThe average concentration of HGF and IL-6 in serum were 860 pg/mL and 2.7 pg/mL respectively.Analysis of survival indicated that，compared to those patient with lower serum level of HGF and IL-6，the survival rate of patient with high serum level was much lower.The difference was statistically significant (HGF，P=0.019;IL-6，P=0.002).The analysis of the patients with stage Ⅲ disease separately also indicated that survival rate of patient with lower serum of HGF and IL-6 was higher than others. ConclusionThe serum levels of HGF and IL-6 might be a effective indicators for predicting prognosis of the NSCLC paitents.

Keywords:NSCLC;Serum;HGF;IL-6

[收稿日期]2015-01-10[修回日期] 2015-02-07

[通訊作者]王英，E-mail：wangyingnet163@163.com

doi:10.11659/jjssx.01E015076

[中圖分類號(hào)]R734.2；R446.11

[文獻(xiàn)標(biāo)識(shí)碼]A

[文章編號(hào)]1672-5042(2015)04-0403-03