夏兵祥，李 凡，徐 健，袁振華，鄭蘇文，張業(yè)偉

(南京醫(yī)科大學(xué)附屬腫瘤醫(yī)院/江蘇省腫瘤醫(yī)院/江蘇省腫瘤防治研究所普外科，南京 210009)

白細(xì)胞介素-33和血管內(nèi)皮生長(zhǎng)因子C在胃癌中的表達(dá)及臨床意義*

夏兵祥，李 凡，徐 健，袁振華，鄭蘇文，張業(yè)偉△

(南京醫(yī)科大學(xué)附屬腫瘤醫(yī)院/江蘇省腫瘤醫(yī)院/江蘇省腫瘤防治研究所普外科，南京 210009)

目的 探討白細(xì)胞介素-33(IL-33)和血管內(nèi)皮生長(zhǎng)因子C(VEGF-C)在胃癌患者組織標(biāo)本及血清中表達(dá)，以及二者與胃癌淋巴結(jié)轉(zhuǎn)移的關(guān)系。方法 分別應(yīng)用免疫組織化學(xué)SP法和酶聯(lián)免疫雙抗夾心法(ELISA)檢測(cè)98例胃癌患者和36名健康體檢者胃黏膜組織標(biāo)本及血清中IL-33和VEGF-C水平。結(jié)果 胃癌組織中IL-33和VEGF-C的陽(yáng)性表達(dá)率分別為67.35%和74.49%，顯著高于正常胃組織(47.22%和61.11%)，比較差異有統(tǒng)計(jì)學(xué)意義(P<0.01)。IL-33和VEGF-C表達(dá)在不同的腫瘤分化程度、組織浸潤(rùn)、淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移及臨床分期間比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。胃癌淋巴結(jié)轉(zhuǎn)移患者的IL-33和VEGF-C的表達(dá)陽(yáng)性率高于未發(fā)生淋巴結(jié)轉(zhuǎn)移患者(P<0.05)。胃癌患者血清IL-33和VEGF-C水平為(50.24±13.08)pg/mL和(210.73±58.35)pg/mL，高于健康體檢者(P<0.05)；淋巴結(jié)轉(zhuǎn)移患者血清IL-33和VEGF-C水平高于未發(fā)生淋巴結(jié)轉(zhuǎn)移患者，比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。結(jié)論 胃癌患者血清中高水平IL-33可能誘導(dǎo)VEGF-C分泌，促進(jìn)胃癌淋巴結(jié)轉(zhuǎn)移，可作為評(píng)估胃癌預(yù)后的重要指標(biāo)。

胃腫瘤；血管內(nèi)皮生長(zhǎng)因子C；白細(xì)胞介素33；淋巴結(jié)轉(zhuǎn)移

胃癌是消化道最常見(jiàn)的惡性腫瘤，病死率居惡性腫瘤的第2位[1]。胃癌患者死亡的主要原因是腫瘤復(fù)發(fā)和轉(zhuǎn)移，其中最常見(jiàn)的轉(zhuǎn)移途徑為淋巴結(jié)轉(zhuǎn)移。臨床上有超過(guò)80%的進(jìn)展期胃癌患者出現(xiàn)淋巴結(jié)轉(zhuǎn)移，研究證明其是胃癌患者預(yù)后不良的獨(dú)立危險(xiǎn)因素[2]。近年來(lái)有關(guān)腫瘤侵襲轉(zhuǎn)移的機(jī)制研究發(fā)現(xiàn)，血管內(nèi)皮生長(zhǎng)因子C(VEGF-C)與腫瘤的淋巴結(jié)轉(zhuǎn)移密切相關(guān)[3-4]，同時(shí)白細(xì)胞介素-33(IL-33)可刺激并誘導(dǎo)白細(xì)胞和肥大細(xì)胞VEGF mRNA表達(dá)與VEGF蛋白分泌，促進(jìn)胃癌細(xì)胞侵襲和轉(zhuǎn)移[5]。然而，關(guān)于IL-33、VEGF-C與腫瘤淋巴結(jié)轉(zhuǎn)移的研究少有報(bào)道。因此，本研究通過(guò)檢測(cè)胃癌患者組織標(biāo)本和血清中IL-33和VEGF-C表達(dá)情況，分析IL-33和VEGF-C與胃癌淋巴結(jié)轉(zhuǎn)移的關(guān)系，探討其在胃癌淋巴結(jié)轉(zhuǎn)移中的作用，以及二者表達(dá)水平的相關(guān)性及臨床意義。

1 資料與方法

1.1 一般資料 收集2012年1月至2014年12月在本院接受胃癌根治手術(shù)的98例胃癌患者(胃癌組)手術(shù)切除標(biāo)本，術(shù)前未接受任何放、化療等。其中男50例，女48例；年齡42.0～86.0歲，中位年齡60.8歲；腫瘤直徑1.0～10.0 cm，中位直徑4.6 cm，所有標(biāo)本經(jīng)病理學(xué)證實(shí)為胃癌。根據(jù)WHO(2010年)胃癌組織學(xué)分類標(biāo)準(zhǔn)[6]，管狀腺癌(高、中分化)35例，低分化腺癌40例，黏液腺癌14例，印戒細(xì)胞癌9例；根據(jù)國(guó)際抗癌聯(lián)盟(UICC)胃癌TNM分期標(biāo)準(zhǔn)[6]，Ⅰ期20例，Ⅱ期27例，Ⅲ期38例，Ⅳ期13例；早期胃癌16例，進(jìn)展期胃癌82例；有淋巴結(jié)轉(zhuǎn)移76例；有遠(yuǎn)處轉(zhuǎn)移16例。另選取同期36名在本院門診體檢的健康人，胃鏡下取正常胃黏膜組織為對(duì)照組,均知情同意，自愿參與。本研究經(jīng)過(guò)南京醫(yī)科大學(xué)倫理委員會(huì)批準(zhǔn)，批準(zhǔn)編號(hào)(2011)132號(hào)。

納入標(biāo)準(zhǔn)：經(jīng)病理診斷為胃癌，年齡、性別不限，入院行D2淋巴結(jié)清掃的胃切除術(shù)患者。排除標(biāo)準(zhǔn)：合并嚴(yán)重心腦血管疾?。缓喜⒍喾N腫瘤病史；外科手術(shù)前接受放療、化療、靶向藥物治療等其他治療手段；有研究者認(rèn)為影響預(yù)后、評(píng)估及難以完成臨床觀察的其他嚴(yán)重疾病或殘疾。

1.2 方法 胃癌組患者于術(shù)前3 d采集清晨空腹靜脈血2 mL，對(duì)照組采集1次空腹靜脈血2 mL，采血后靜置離心(1 000 r/min，10 min)，分離血清，置20 ℃保存待測(cè)。所有組織標(biāo)本均經(jīng)10%甲醛固定24 h，行常規(guī)石蠟包埋，連續(xù)切取4 μm厚的切片，采用免疫組織化學(xué)SP法染色，具體步驟按說(shuō)明書(shū)進(jìn)行。每批染色過(guò)程中均設(shè)磷酸鹽緩沖液(PBS)代替一抗的陰性對(duì)照組。以細(xì)胞質(zhì)呈清晰的棕黃色顆粒且其染色強(qiáng)度高于背景非特異染色者為陽(yáng)性細(xì)胞。由兩位經(jīng)驗(yàn)豐富的病理科醫(yī)生在相同條件下觀察，正常胃組織計(jì)數(shù)細(xì)胞(500)中的陽(yáng)性細(xì)胞數(shù)，以百分率表示。無(wú)陽(yáng)性反應(yīng)細(xì)胞或陽(yáng)性反應(yīng)細(xì)胞數(shù)小于10%者為陰性，陽(yáng)性反應(yīng)細(xì)胞數(shù)大于或等于10%者為陽(yáng)性。酶聯(lián)免疫吸附試驗(yàn)(ELISA)檢測(cè)血清IL-33和VEGF-C濃度，免疫組織化學(xué)染色SP法檢測(cè)IL-33和VEGF-C在胃癌中的表達(dá)情況。人IL-33和人VEGF-C ELISA試劑盒均購(gòu)自上海潤(rùn)裕生物科技有限公司，兔抗人IL-33和VEGF-C多克隆抗體及S-P試劑盒均購(gòu)自Dako公司，操作步驟嚴(yán)格按照說(shuō)明書(shū)進(jìn)行。

2 結(jié) 果

2.1 IL-33和VEGF-C在胃癌組織及正常胃組織中的表達(dá) 光鏡下正常胃黏膜上皮細(xì)胞質(zhì)中IL-33和VEGF-C染色弱或呈陰性。胃癌組織細(xì)胞內(nèi)IL-33和VEGF-C呈彌漫性或簇狀分布的棕黃色顆粒，瘤間質(zhì)中有時(shí)可見(jiàn)IL-33和VEGF-C呈簇狀的淺棕色染色，瘤旁正常胃黏膜中少見(jiàn)IL-33和VEGF-C染色。低分化腺癌中IL-33和VEGF-C染色程度較高、中分化腺癌略深(圖1)。IL-33和VEGF-C在正常胃組織和進(jìn)展期胃癌及淋巴結(jié)陽(yáng)性組胃癌間的表達(dá)有統(tǒng)計(jì)學(xué)意義(P<0.05)；早期胃癌及淋巴結(jié)陰性組胃癌與正常胃組織間表達(dá)比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；早期胃癌和進(jìn)展期胃癌，淋巴結(jié)無(wú)轉(zhuǎn)移組和淋巴結(jié)轉(zhuǎn)移組胃癌中IL-33和VEGF-C表達(dá)比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)，見(jiàn)表1～3。

A～E:SP法(×100)；F：SP法(×400)。

圖1 IL-33與VEGF-C在胃癌組織及正常胃組織中的表達(dá)

表1 IL-33和VEGF-C在胃癌組織及正常胃組織中的表達(dá)[n(%)]

2.2 IL-33和VEGF-C表達(dá)與胃癌臨床病理指標(biāo)之間的關(guān)系 IL-33和VEGF-C表達(dá)與胃癌患者性別、年齡、腫瘤位置和大小無(wú)相關(guān)性(P>0.05)，但與腫瘤分化程度、組織浸潤(rùn)、淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移及UICC分期有相關(guān)性(P<0.05)。腫瘤分化程度越低、組織浸潤(rùn)越嚴(yán)重、UICC分期越晚，IL-33和VEGF-C水平越高(P<0.05)；有淋巴結(jié)轉(zhuǎn)移的胃癌IL-33和VEGF-C水平顯著高于無(wú)淋巴結(jié)轉(zhuǎn)移者(P<0.05)；有遠(yuǎn)處轉(zhuǎn)移的胃癌中IL-33和VEGF-C水平明顯高于無(wú)遠(yuǎn)處轉(zhuǎn)移者(P<0.05)，見(jiàn)表4。

表2 IL-33和VEGF-C表達(dá)與胃癌分期的關(guān)系[n(%)]

表3 IL-33和VEGF-C表達(dá)與胃癌淋巴結(jié)轉(zhuǎn)移的關(guān)系[n(%)]

表4 IL-33和VEGF-C表達(dá)與胃癌臨床病理指標(biāo)之間的關(guān)系[n(%)]

2.3 胃癌組織標(biāo)本中IL-33和VEGF-C表達(dá)情況的相關(guān)性 98例胃癌組織標(biāo)本中IL-33和VEGF-C共陽(yáng)性為54例，66例IL-33陽(yáng)性患者中VEGF-C陽(yáng)性率為81.82%,32例IL-33陰性患者中VEGF-C陽(yáng)性率為59.38%，二者表達(dá)水平呈正相關(guān)(tau-b等級(jí)相關(guān)系數(shù)Kendall′s tau-b=0.241，P=0.025)。

2.4 胃癌組與對(duì)照組間血清IL-33和VEGF-C濃度的比較 98例胃癌患者血清IL-33和VEGF-C水平分別為(50.24±13.08)pg/mL和(210.73±58.35) pg/mL，與對(duì)照組血清IL-33和VEGF-C水平[(26.38±9.10)pg/mL和(82.26±35.79)pg/mL]相比，差異有統(tǒng)計(jì)學(xué)意義(P<0.01)。

2.5 胃癌患者血清IL-33和VEGF-C水平與胃癌淋巴結(jié)轉(zhuǎn)移的關(guān)系 本研究98例胃癌患者中，76例患者經(jīng)組織病理學(xué)證實(shí)有淋巴結(jié)轉(zhuǎn)移，22例未發(fā)生淋巴結(jié)轉(zhuǎn)移。淋巴結(jié)轉(zhuǎn)陰性患者血清IL-33水平和VEGF-C水平分別為(38.37±7.45)pg/mL和(157.97±34.66)pg/mL，較健康人[IL-33：(26.38±9.10)pg/mL，VEGF-C：(82.26±35.79)pg/mL]有升高趨勢(shì)，但比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.427、0.734)。淋巴結(jié)轉(zhuǎn)陽(yáng)性患者血清IL-33和VEGF-C水平分別為(50.24±13.08)pg/mL和(226.00±54.91)pg/mL，較健康人和淋巴結(jié)陰性患者明顯升高，比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。

3 討 論

胃癌作為消化道最常見(jiàn)的惡性腫瘤，已嚴(yán)重威脅到人類健康。但胃癌的發(fā)生與轉(zhuǎn)移是一個(gè)涉及多步驟、多因素的復(fù)雜過(guò)程，有關(guān)其復(fù)發(fā)轉(zhuǎn)移機(jī)制尚不明確，持續(xù)存在的慢性炎癥刺激在胃癌的發(fā)生、發(fā)展及促進(jìn)腫瘤復(fù)發(fā)、轉(zhuǎn)移過(guò)程中發(fā)揮重要作用。IL-33具有抑制和(或)促進(jìn)炎癥反應(yīng)的雙重生理效應(yīng)[7-8]，在炎癥、腫瘤等多種疾病中發(fā)揮重要的調(diào)控作用[9-10]。VEGF-C可誘導(dǎo)腫瘤中心部位新生淋巴管生成[11-12]，并在早期胃癌中均有高表達(dá)，與腫瘤浸潤(rùn)和淋巴結(jié)轉(zhuǎn)移顯著相關(guān)[13-15]。

近年來(lái)研究結(jié)果表明，IL-33可通過(guò)致癌抑制因子2-細(xì)胞外調(diào)解蛋白激酶1/2(ST2-ERK1/2)和c-Jun氨基末端激酶(JNK)信號(hào)通路促進(jìn)胃癌細(xì)胞侵襲和轉(zhuǎn)移[16]，體內(nèi)IL-33及其受體ST2表達(dá)水平的變化對(duì)胃癌等惡性腫瘤患者的病情進(jìn)展、診斷及預(yù)后具有重要的參考價(jià)值[17-20]。本研究發(fā)現(xiàn)胃癌患者血清及組織標(biāo)本中IL-33表達(dá)水平明顯高于健康人，而且其升高程度與胃癌的惡性程度呈正相關(guān)，這進(jìn)一步證實(shí)IL-33與胃癌的侵襲和轉(zhuǎn)移密切相關(guān)。

VEGF-C是血管內(nèi)皮生長(zhǎng)因子家族最強(qiáng)的促血管生成因子之一，其主要通過(guò)刺激新生血管生成，促進(jìn)血管內(nèi)皮細(xì)胞增生和遷移，增加微血管通透性及促進(jìn)細(xì)胞外基質(zhì)的降解等途徑促進(jìn)腫瘤血管生成、浸潤(rùn)及轉(zhuǎn)移[21-22]。諸多研究發(fā)現(xiàn)，VEGF-C在胃癌組織中高表達(dá)，其表達(dá)程度與淋巴結(jié)轉(zhuǎn)移、淋巴管浸潤(rùn)、靜脈浸潤(rùn)及腫瘤浸潤(rùn)生長(zhǎng)方式、患者預(yù)后呈顯著相關(guān)性[23-26]。本研究結(jié)果與其一致，VEGF-C在胃癌組織及血清標(biāo)本中表達(dá)水平明顯高于健康人，并且胃癌患者血清VEGF-C濃度與淋巴結(jié)轉(zhuǎn)移、病理分期及分化程度等密切相關(guān)，表明VEGF-C可作為反映胃癌侵襲轉(zhuǎn)移能力的重要指標(biāo)。

血管生成是許多生理和病理過(guò)程的基本事件之一，其中病理性血管生成是腫瘤形成、增殖與轉(zhuǎn)移的關(guān)鍵環(huán)節(jié)[27-28]。血管生成是一個(gè)涉及微血管結(jié)構(gòu)和功能上一系列變化的復(fù)雜過(guò)程，與多種生長(zhǎng)因子相關(guān)，如細(xì)胞因子、促血管生成因子、黏附分子等[29]。 IL-33能誘導(dǎo)內(nèi)皮細(xì)胞增生、遷移和組織分化，從而促進(jìn)新生血管生成[30]，同時(shí)還與上皮細(xì)胞浸潤(rùn)密切相關(guān)，參與腫瘤的發(fā)生和發(fā)展[31]。

綜上所述，胃癌組織及血清中IL-33和VEGF-C表達(dá)水平升高，二者之間存在正相關(guān)，并與胃癌的惡性進(jìn)展、淋巴結(jié)轉(zhuǎn)移等生物學(xué)行為有關(guān)，提示IL-33參與腫瘤新生血管的形成及腫瘤的浸潤(rùn)和轉(zhuǎn)移，可能成為胃癌靶向治療的潛在靶點(diǎn)之一。

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Expression of interleukin-33 and vascular endothelial growth factor-C in gastric cancer and its clinical significance*

XiaBingxiang,LiFan,XuJian,YuanZhenhua,ZhengSuwen,ZhangYewei△

(DepartmentofGeneralSurgery,TumorHospitalAffiliatedtoNanjingMedicalUniversity/JiangsuProvincialCancerHospital/JiangsuProvincialCancerResearchInstitute,Nanjing,Jiangsu210009,China)

Objective To investigate the expression of interleukin-33 (IL-33) and vascular endothelial growth factor C (VEGF-C) in gastric cancer tissues and serum,and to explore the relationship between these two indicators and gastric cancer lymph node metastasis.Methods The levels of IL-33 and VEGF-C in the tissues of gastric mucosa and serum were detected by immunohistochemical SP method and enzyme-linked immunosorbent assay (ELISA) in 98 patients with gastric cancer and 36 healthy subjects.Results The expression rates of IL-33 and VEGF-C in gastric cancer were 67.35% and 74.49%,which were significantly higher than the rates in normal gastric tissue (47.22% and 61.11%).The difference was statistically significant (P<0.01).The expression of IL-33 and VEGF-C was correlated with the degree of tumor differentiation,tissue infiltration,lymph node metastasis,distant metastasis and clinical stage(P<0.05).The positive rates of IL-33 and VEGF-C in gastric cancer lymph node metastasis group were higher than those in non-lymph node metastasis group(P<0.05).The serum concentrations of IL-33 and VEGF-C in patients with gastric cancer were (50.24±13.08)pg/mL and(210.73±58.35)pg/mL,respectively，which were higher than those in healthy control group(P<0.05);the expressions of serum concentration of IL-33 and VEGF-C in the cases with lymph node metastasis were higher than those without lymph node metastasis and the difference was statistically significant(P<0.05).Conclusion High levels of IL-33 in gastric carcinoma patients might induce the secretion of VEGF-C,promote lymph node metastasis,and be applied as an important index of the appraisal to the prognosis of gastric cancer.

stomach neoplasms；vascular endothelial growth factor C；interleukins 33；lymph node metastasis

10.3969/j.issn.1671-8348.2017.15.014

國(guó)家自然科學(xué)基金面上項(xiàng)目(61371066)； 江蘇省醫(yī)學(xué)重點(diǎn)人才資助項(xiàng)目(RC2011090)；江蘇省重點(diǎn)研發(fā)計(jì)劃(社會(huì)發(fā)展-面上項(xiàng)目)(BE2015720);江蘇省六大高峰人才項(xiàng)目(WSW-041)。 作者簡(jiǎn)介：夏兵祥(1988-)，住院醫(yī)師，在讀碩士，主要從事普外腫瘤基礎(chǔ)與臨床研究方面研究?！?/p>

，E-mail:zhangyewei@njmu.edu.cn。

R735.2

A

1671-8348(2017)15-2056-04

2016-11-22

2017-01-10)