肺腺癌中CRP蛋白的表達(dá)及其預(yù)后意義

陳聆 杜海磊 李勇 程齊儉 陳中元 萬(wàn)歡英

肺腺癌中CRP蛋白的表達(dá)及其預(yù)后意義

陳聆1杜海磊2李勇1程齊儉1陳中元2萬(wàn)歡英1

目的 通過(guò)檢測(cè)肺腺癌患者腫瘤組織中CRP蛋白的表達(dá)量,探討CRP與肺腺癌患者術(shù)后復(fù)發(fā)及預(yù)后的相關(guān)性。方法 納入78例接受肺癌根治手術(shù)治療的肺腺癌患者(Ⅰb-Ⅲa期)，所有患者術(shù)前均未行新輔助化療及放療。采用免疫組化法檢測(cè)切除腫瘤組織中CRP的表達(dá)，據(jù)檢測(cè)結(jié)果分為CRP表達(dá)陽(yáng)性組及CRP表達(dá)陰性組。影像學(xué)評(píng)估患者術(shù)后復(fù)發(fā)情況。分析腫瘤組織CRP表達(dá)陽(yáng)性與陰性患者的術(shù)后生存率及復(fù)發(fā)率。結(jié)果 58%(55/78)的患者腫瘤組織中CRP表達(dá)陽(yáng)性。CRP表達(dá)陽(yáng)性與陰性組在患病年齡、性別、血清CRP水平、瘤體大小、淋巴結(jié)轉(zhuǎn)移等臨床病理因素上無(wú)統(tǒng)計(jì)學(xué)差異;兩組間患者外周血清CRP水平亦無(wú)統(tǒng)計(jì)學(xué)差異。肺腺癌CRP陽(yáng)性組患者5年生存率較CRP陰性組明顯下降(CRP+vsCRP- ；41%vs65%)，生存率的下降具有統(tǒng)計(jì)學(xué)差異(P<0.05)。肺腺癌CRP陽(yáng)性組患者術(shù)后復(fù)發(fā)率較CRP陰性組顯著升高(CRP+vsCRP-； 54.5%vs26.1%),兩組復(fù)發(fā)率具有統(tǒng)計(jì)學(xué)差異(P<0.05)。肺腺癌腫瘤中CRP的表達(dá)是患者術(shù)后復(fù)發(fā)的獨(dú)立因素(OR>1)。CRP陽(yáng)性復(fù)發(fā)組與CRP陰性復(fù)發(fā)組在術(shù)后患者初次復(fù)發(fā)部位上無(wú)差異。結(jié)論 肺腺癌組織中CRP的表達(dá)與術(shù)后較高的復(fù)發(fā)率及較差的生存率相關(guān)。CRP可能成為評(píng)估肺腺癌患者術(shù)后預(yù)后的重要標(biāo)志物。

肺腺癌;CRP;預(yù)后

血清C反應(yīng)蛋白(C-reactive protein，CRP)是一種急性時(shí)相反應(yīng)蛋白。它是經(jīng)典的炎癥反應(yīng)最靈敏的急性時(shí)相蛋白，在炎癥過(guò)程中濃度迅速增高[1]。近年來(lái)研究發(fā)現(xiàn)在腫瘤中CRP的表達(dá)亦有增高，CRP在診斷惡性腫瘤的意義逐漸受到重視。在肺癌中CRP增高被認(rèn)為具有一定的診斷價(jià)值[CRP英文5-8]。關(guān)于CRP與肺癌患者術(shù)后復(fù)發(fā)及預(yù)后的關(guān)系，目前研究尚鮮有報(bào)道。本研究采用免疫組化方法檢測(cè)肺腺癌腫瘤組織中CRP的表達(dá)，探討CRP表達(dá)與術(shù)后生存率及復(fù)發(fā)率的關(guān)系。研究設(shè)計(jì)：回顧性研究：病史查詢、得到78例患者，取其手術(shù)標(biāo)本行免疫組化檢測(cè)；前瞻性：對(duì)于病理顯示為肺腺癌的，行免疫組化檢測(cè)，并隨訪。

資料與方法

一、研究對(duì)象

入選標(biāo)準(zhǔn)：選擇2011年1月2日至2012年12月31日間在上海瑞金醫(yī)院住院接受手術(shù)治療的肺腺癌患者78例為研究對(duì)象。所有患者均經(jīng)病理組織學(xué)確診，術(shù)前均未接受放、化療。78例患者中男性24例，女性54例，年齡45-74歲，中位年齡56.5歲。按2009年UICC TNM分為IB期，IIA期，IIB期，IIIA期。

二、方法

采用免疫組化法檢測(cè)CRP的表達(dá)。CRP羊抗人多克隆抗體購(gòu)自美國(guó)Sigma公司，PV9000試劑盒和二氨基聯(lián)苯胺(DAB)顯色劑均購(gòu)自北京中杉生物技術(shù)有限公司。結(jié)果判定標(biāo)準(zhǔn)：CRP陽(yáng)性染色為在細(xì)胞膜或漿內(nèi)出現(xiàn)棕黃色顆粒。根據(jù)染色強(qiáng)度和陽(yáng)性細(xì)胞數(shù)進(jìn)行綜合評(píng)分，染色強(qiáng)度：1分:染色弱但明顯強(qiáng)于陰性對(duì)照；2分:染色清晰，中等程度；3分:染色程度強(qiáng)。陽(yáng)性細(xì)胞數(shù)：1分:陽(yáng)性細(xì)胞占11%-50%；2分:陽(yáng)性細(xì)胞占51%-80%；3分:陽(yáng)性細(xì)胞≥81%。上述兩項(xiàng)積分相加，O分為(-)，1-2分為(+)，3-4分為()，5-6分為()。(-)和(+)為陰性，()和()為陽(yáng)性。

三、統(tǒng)計(jì)

結(jié) 果

一、患者基本臨床特征

本次共有78例患者納入此項(xiàng)研究，男性24例，女性54例，年齡48-74歲，中位年齡56.5歲。IB期7例(%)，IIA期20例(%)，IIB期35(%)，IIIA期16例(%)。

二、CRP在肺腺癌組織中的表達(dá)與臨床病理因素的關(guān)系

58%(55/78)的肺腺癌患者腫瘤組織中CRP表達(dá)陽(yáng)性，(見(jiàn)圖1)。肺腺癌CRP表達(dá)陽(yáng)性與陰性組在患者年齡、性別、血清CRP、腫瘤大小、淋巴結(jié)轉(zhuǎn)移等臨床病理因素上無(wú)統(tǒng)計(jì)學(xué)差異。兩組間患者外周血清CRP的表達(dá)亦無(wú)統(tǒng)計(jì)學(xué)差異，(見(jiàn)表1)。

圖1 CRP在肺腺癌組織中的表達(dá)(200×)

表1 CRP表達(dá)與肺腺癌臨床病理特征的關(guān)系

三、CRP在肺腺癌組織中的表達(dá)對(duì)術(shù)后生存率的影響

肺腺癌CRP陽(yáng)性組患者5年生存率較CRP陰性組明顯下降(CRP+vsCRP- ；41%vs65%)，具有統(tǒng)計(jì)學(xué)差異，P<0.05，(見(jiàn)圖2)。

圖2 肺腺癌組織中CRP的表達(dá)與術(shù)后生存率的關(guān)系

四、CRP在肺腺癌組織中的表達(dá)對(duì)術(shù)后復(fù)發(fā)率的影響

肺腺癌CRP陽(yáng)性組患者術(shù)后復(fù)發(fā)率較CRP陰性組顯著升高(CRP+vsCRP-； 54.5%vs34.8%),兩組復(fù)發(fā)率具有統(tǒng)計(jì)學(xué)差異(P<0.05)。肺腺癌腫瘤中CRP的表達(dá)是患者術(shù)后復(fù)發(fā)的獨(dú)立因素(OR>1)，(見(jiàn)表1)。

討 論

肺癌是一種常見(jiàn)的惡性腫瘤，無(wú)論是發(fā)病率還是死亡率，多居全球惡性腫瘤首位，其中非小細(xì)胞肺癌發(fā)病率又占肺癌總發(fā)病率80%以上[1]。腺癌作為非小細(xì)胞肺癌中的第一大類(lèi)癌癥，由于早期即可出現(xiàn)淋巴結(jié)轉(zhuǎn)移，并且容易復(fù)發(fā)，因此如何發(fā)現(xiàn)新的分子標(biāo)志物以提高患者的預(yù)后監(jiān)測(cè)，實(shí)現(xiàn)早發(fā)現(xiàn)早治療，并最終實(shí)現(xiàn)延長(zhǎng)患者生存期就顯得尤為重要。

CRP是已為人熟知的經(jīng)典的急性時(shí)相反應(yīng)蛋白，由白介素6等細(xì)胞因子刺激肝臟合成，事實(shí)上，慢性炎癥刺激與肺癌發(fā)生之間的關(guān)系已被人們廣泛接受。目前人們也獲知血CRP水平的升高與多種惡性腫瘤的發(fā)生發(fā)展及生存預(yù)后是相關(guān)聯(lián)的[2]。腫瘤內(nèi)炎癥細(xì)胞及細(xì)胞因子的高表達(dá)主要?dú)w因于腫瘤的生長(zhǎng)、侵襲及免疫的抑制，相當(dāng)于處理有效的宿主抗腫瘤反應(yīng)[3]。事實(shí)上，大約15%的腫瘤是由慢性炎癥或感染刺激觸發(fā)，由于宿主的持續(xù)感染導(dǎo)致慢性炎癥，炎性細(xì)胞通過(guò)刺激產(chǎn)生自由基及氮化物造成DNA的破壞，進(jìn)一步引起細(xì)胞增殖化[4]。在體外實(shí)驗(yàn)中也發(fā)現(xiàn)炎癥前細(xì)胞因子可通過(guò)改變微環(huán)境中腫瘤細(xì)胞的生物學(xué)行為及活化基質(zhì)細(xì)胞促進(jìn)腫瘤細(xì)胞的生長(zhǎng)。CRP間接反映了宿主和腫瘤相互作用時(shí)炎癥介質(zhì)的作用，腫瘤和宿主相互作用可能與腫瘤轉(zhuǎn)移和副腫瘤綜合征等相關(guān)，炎癥標(biāo)志物升高的水平與腫瘤轉(zhuǎn)移和惡液質(zhì)的發(fā)展有關(guān)。因此炎癥標(biāo)志物的水平可能預(yù)示了宿主對(duì)腫瘤的系統(tǒng)炎癥反應(yīng)的強(qiáng)烈易感性。研究發(fā)現(xiàn)在腎臟、呼吸道、甲狀腺、血管平滑肌和肺泡巨細(xì)胞內(nèi)CRP局部表達(dá)[5-13]。然而關(guān)于肺腺癌組織中CRP的表達(dá)及意義目前報(bào)道較少。我們的研究發(fā)現(xiàn)在肺腺癌組織中CRP表達(dá)陽(yáng)性率較高，肺腺癌組織中CRP表達(dá)與患者年齡、性別、血清CRP、腫瘤大小、淋巴結(jié)轉(zhuǎn)移等臨床病理因素?zé)o關(guān)系。

近來(lái)國(guó)外研究報(bào)道食管鱗癌腫瘤組織中CRP的表達(dá)預(yù)示較差的生存預(yù)后[14]。通過(guò)隨訪患者術(shù)后生存的時(shí)間，我們進(jìn)一步研究探討肺腺癌組織中CRP 的表達(dá)與預(yù)后的關(guān)系。術(shù)后生存率研究表明肺腺癌組織中CRP表達(dá)陽(yáng)性患者5年生存率為41%，明顯低于肺腺癌組織中CRP表達(dá)陰性患者5年生存率65%。同時(shí)我們發(fā)現(xiàn)肺腺癌組織中CRP表達(dá)陽(yáng)性患者術(shù)后復(fù)發(fā)率卻顯著高于CRP陰性患者，進(jìn)一步的危險(xiǎn)因素分析表明肺腺癌組織中CRP的表達(dá)是患者術(shù)后復(fù)發(fā)的獨(dú)立因素(OR>1)。

我們的研究表明肺腺癌患者腫瘤組織中CRP的表達(dá)與患者術(shù)后預(yù)后相關(guān)，系統(tǒng)性炎癥反應(yīng)越強(qiáng)烈，CRP水平越高，患者的生存預(yù)后越差。同時(shí)高表達(dá)CRP的肺腺癌患者伴隨著較高的術(shù)后復(fù)發(fā)率。可見(jiàn)在肺腺癌中CRP的表達(dá)預(yù)示著較差的術(shù)后生存及較高的術(shù)后復(fù)發(fā)。CRP可能成為評(píng)估肺腺癌患者術(shù)后預(yù)后及監(jiān)測(cè)的重要分子標(biāo)志物。

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Expression of CRP protein in lung adenocarcinoma and its prognostic significance

CHENLin,DUHai-lei,LIYong,CHENQi-jian,CHENZhong-yuan,WANHuan-yin.

DepartmentofRespiration,NorthRuijinHospitalAffiliatedtoMedicineSchoolofShanghaiJiaotongUniversity,Shanghai200025,China

Objective To detect the expression of CRP protein in tumor tissues of lung adenocarcinoma patients and to investigate the correlation between CRP and postoperative recurrence and prognosis in patients with lung adenocarcinoma. Methods A total of 78 lung adenocarcinoma patients (stage Ⅰb-Ⅲa) with lung cancer undergoing radical lung cancer surgery were enrolled. Neoadjuvant chemotherapy and radiotherapy were not performed before operation in all patients. CRP expression was detected by immunohistochemistry, and they were divided into the CRP positive group and the CRP negative group according to the results. It used imageology to evaluate postoperative recurrence. The survival rate and recurrence of CRP positive and negative patients with tumor tissue were analyzed. Results 58% (55/78) of the patients had positive expression of CRP in the tumor tissues. There was no significant difference in the clinical pathological factors such as age, sex, serum CRP level, tumor size, and lymph node metastasis between the positive and negative groups in CRP expression. There was no significant difference in serum CRP level between the two groups. The 5-year survival rate of lung adenocarcinoma was significantly lower in the positive group than in the negative group (CRP-vsCRP+; 41%vs65%). The decline in survival rate was statistically significant (P<0.05). The recurrence of lung adenocarcinoma was significantly higher in the positive group than in negative group (CRP-vsCRP+; 54.5%vs26.1%). The recurrence of the two groups was statistically significant (P<0.05). The expression of CRP in lung adenocarcinoma tumors was an independent factor (OR>1) in patients with postoperative recurrence. There was no difference in the initial recurrence site between the CRP positive recurrence group and the CRP negative recurrence group. Conclusion The expression of CRP in lung adenocarcinoma tissues is related to the high recurrence and poor survival rate after operation. CRP may be an important marker for evaluating the prognosis of patients with lung adenocarcinoma after surgery.

lung adenocarcinoma; CRP; prognosis

10.3969/j.issn.1009-6663.2017.06.007

上海交通大學(xué)醫(yī)學(xué)院附屬瑞金北院課題資助(No 2014ZY08)

200025 上海，上海交通大學(xué)附屬瑞金醫(yī)院北院1.呼吸科、2.胸外科

程齊儉，E-mail：chengqijian@aliyun.com

2016-10-08]