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非小細(xì)胞肺癌患者血清熱休克蛋白90α的臨床意義研究

2015-02-21 10:50董鵬飛鄧曉明
中國(guó)全科醫(yī)學(xué) 2015年19期
關(guān)鍵詞:分型肺癌血清

董鵬飛,鄧曉明

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·中醫(yī)·中西醫(yī)結(jié)合研究·

非小細(xì)胞肺癌患者血清熱休克蛋白90α的臨床意義研究

董鵬飛,鄧曉明

目的 了解非小細(xì)胞肺癌(NSCLC)患者血清熱休克蛋白90α(HSP90α)的臨床意義。方法 選取2013年1月—2014年5月,在鄭州大學(xué)第一附屬醫(yī)院中西醫(yī)結(jié)合內(nèi)科、胸外科及呼吸內(nèi)科接受住院治療的NSCLC患者80例為肺癌組;另選取同時(shí)期在鄭州大學(xué)第一附屬醫(yī)院進(jìn)行體檢的健康成年人30例為對(duì)照組。比較并分析兩組血清HSP90α水平;比較不同腫瘤分期(TNM分期)患者血清HSP90α水平,探討TNM分期與血清HSP90α水平的相關(guān)關(guān)系;根據(jù)中醫(yī)辨證結(jié)果對(duì)肺癌組進(jìn)行中醫(yī)分型,比較不同中醫(yī)分型患者的血清HSP90α水平。結(jié)果 對(duì)照組與肺癌組血清HSP90α水平比較,差異有統(tǒng)計(jì)學(xué)意義(t=16.02,P<0.05)。不同TNM分期患者的血清HSP90α水平比較,差異有統(tǒng)計(jì)學(xué)意義(F=14.98,P=0.00);Spearman秩相關(guān)分析顯示,TNM分期與血清HSP90α水平呈正相關(guān)(rs=0.42,P<0.01)。不同中醫(yī)分型患者的血清HSP90α水平比較,差異有統(tǒng)計(jì)學(xué)意義(F=4.22,P<0.01)。結(jié)論 NSCLC患者的血清HSP90α水平較健康成年人高,TNM分期較高的患者,其血清HSP90α水平也較高。血清HSP90α水平可以反映NSCLC患者正邪、虛實(shí)的轉(zhuǎn)變,有望成為其中醫(yī)辨證論治的客觀(guān)依據(jù),可作為NSCLC患者的腫瘤標(biāo)志物,在預(yù)測(cè)疾病的發(fā)生、發(fā)展方面具有較高的臨床意義。

癌,非小細(xì)胞肺;HSP90熱休克蛋白質(zhì)類(lèi);腫瘤分期;辨證分型

董鵬飛,鄧曉明.非小細(xì)胞肺癌患者血清熱休克蛋白90α的臨床意義研究[J].中國(guó)全科醫(yī)學(xué),2015,18(19):2354-2356,2360.[www.chinagp.net]

Dong PF,Deng XM.Clinical significance of serum HSP90 α in patients with non-small-cell lung cancer[J].Chinese General Practice,2015,18(19):2354-2356,2360.

熱休克蛋白(HSPs)是機(jī)體在應(yīng)激反應(yīng)中產(chǎn)生的一種蛋白質(zhì)類(lèi)物質(zhì)[1]。熱休克蛋白90α(HSP90α)作為熱休克蛋白家族的一員,已經(jīng)被證實(shí)在非小細(xì)胞肺癌(NSCLC)[2]、胃癌[3]、胰腺癌[4]、腦膠質(zhì)瘤及腦膜瘤[5]等多種腫瘤組織細(xì)胞中含量增高。以往對(duì)HSP90α的研究多集中在腫瘤組織學(xué)方面,而對(duì)NSCLC患者血清HSP90α水平臨床意義的研究較少。目前,已經(jīng)有許多研究表明,腫瘤患者(如肺癌、胃癌)血清HSP90α水平會(huì)特異性升高,且與腫瘤的發(fā)生、發(fā)展及預(yù)后有密切關(guān)系[6-7]。本研究對(duì)80例NSCLC患者和30例健康成年人的血清HSP90α水平進(jìn)行分析,旨在探討NSCLC患者血清HSP90α水平的臨床意義。

1 對(duì)象與方法

1.2 研究方法 檢測(cè)肺癌組和對(duì)照組的血清HSP90α水平,并進(jìn)行比較和分析;比較不同腫瘤分期(TNM分期)患者的血清HSP90α水平,探討TNM分期與血清HSP90α水平的相關(guān)關(guān)系;根據(jù)中醫(yī)辨證結(jié)果對(duì)肺癌組進(jìn)行中醫(yī)分型,比較不同中醫(yī)分型患者的血清HSP90α水平。

1.2.1 HSP90α檢測(cè)方法 肺癌組和對(duì)照組均在清晨空腹?fàn)顟B(tài)下抽取靜脈血3 ml;在4 ℃情況下進(jìn)行離心處理,離心半徑=1 cm,3 000 r/min離心20 min,取上層血清1 ml;編號(hào)后,冷凍于-80 ℃冰箱中備用。由課題組采用雙抗夾心酶聯(lián)免疫吸附法進(jìn)行HSP90α檢測(cè),試劑為上海滬宇生物有限公司生產(chǎn),測(cè)定儀為Multishannk 3型全自動(dòng)酶免疫測(cè)定儀,操作過(guò)程嚴(yán)格按照試劑說(shuō)明書(shū)進(jìn)行。

1.2.2 NSCLC患者的中醫(yī)辨證分型 中醫(yī)分型標(biāo)準(zhǔn)參照《中藥新藥臨床研究指導(dǎo)原則》,具體分型標(biāo)準(zhǔn)和結(jié)果見(jiàn)表1。

表1 NSCLC患者的中醫(yī)辨證分型

2 結(jié)果

2.1 肺癌組和對(duì)照組血清HSP90α水平比較 對(duì)照組的血清HSP90α水平為(61.8±30.8)μg/L,肺癌組的血清HSP90α水平為(385.4±173.5)μg/L。兩組血清HSP90α水平比較,差異有統(tǒng)計(jì)學(xué)意義(t=16.02,P<0.05)。

2.2 血清HSP90α水平與TNM分期關(guān)系 肺癌組中TNM分期為Ⅰ~Ⅱ期、Ⅲ期及Ⅳ期的患者數(shù)分別為26、32、22例,其血清HSP90α水平分別為(324.0±180.0)、(394.9±184.2)、(444.3±127.3)μg/L。不同TNM分期患者的血清HSP90α水平比較,差異有統(tǒng)計(jì)學(xué)意義(F=14.98,P=0.00)。對(duì)TNM分期和血清HSP90α水平做Spearman秩相關(guān)分析,結(jié)果顯示兩者呈正相關(guān)(rs=0.42,P<0.01)。

2.3 不同中醫(yī)分型患者血清HSP90α水平比較 中醫(yī)分型為氣虛痰濕證、氣滯血瘀證、陰虛毒熱證及氣陰兩虛證的患者數(shù)分別為17、23、19、21例,其平均血清HSP90α水平分別為(301.4±153.2)、(408.9±150.5)、(479.5±194.4)、(342.6±155.5)μg/L。不同中醫(yī)分型患者的血清HSP90α水平比較,差異有統(tǒng)計(jì)學(xué)意義(F=4.22,P<0.01)。陰虛毒熱證患者與氣虛痰濕證和氣陰兩虛證患者的血清HSP90α水平比較,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。氣虛痰濕證患者與氣滯血瘀證患者的血清HSP90α水平比較,差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。

3 討論

HSP90是腫瘤組織中最為活躍的分子伴侶之一,可以比正常細(xì)胞高出2~10倍[8],主要以HSP90α為主,而HSP90 β保持不變[9-10]。現(xiàn)在認(rèn)為腫瘤細(xì)胞內(nèi)HSP90α占細(xì)胞總蛋白含量的3%~7%[11]。到目前為止,已經(jīng)證明的HSP90α受體蛋白有100多種,如蛋白激酶B、人類(lèi)表皮生長(zhǎng)因子受體2(Her-2)、低氧誘導(dǎo)因子-1α(HIF-1α)、bcr-abl融合基因、Raf-1蛋白激酶及p53突變體,這些受體蛋白是重要的信號(hào)轉(zhuǎn)導(dǎo)和細(xì)胞周期調(diào)控遞質(zhì),涉及腫瘤細(xì)胞的發(fā)生和發(fā)展[11]。

腫瘤細(xì)胞中的HSP90α,不僅存在于細(xì)胞內(nèi),更重要的是可以被腫瘤細(xì)胞主動(dòng)分泌到細(xì)胞外發(fā)揮作用[12-13]。主要表現(xiàn)在兩個(gè)方面:(1)細(xì)胞外的HSP90α同細(xì)胞內(nèi)的HSP90α一樣,發(fā)揮分子伴侶作用;(2)細(xì)胞外的HSP90α可以促進(jìn)腫瘤細(xì)胞的浸潤(rùn)和轉(zhuǎn)移[14-18]。如細(xì)胞外的HSP90α可以通過(guò)作用于細(xì)胞表面的原癌基因Her-2[19]和金屬基質(zhì)蛋白酶2,促進(jìn)腫瘤細(xì)胞的浸潤(rùn)和轉(zhuǎn)移[15-16,20-21]。還有研究發(fā)現(xiàn),細(xì)胞外的HSP90α可激活血纖維蛋白溶酶原,后者具有促進(jìn)腫瘤細(xì)胞轉(zhuǎn)移的作用[22]。不僅如此,肺癌組織細(xì)胞中的HSP90α蛋白表達(dá)與 HIF-1α蛋白表達(dá)呈正相關(guān)[2],二者的高表達(dá)可能參與了肺癌血管生成,細(xì)胞增殖、轉(zhuǎn)移、侵襲等活動(dòng)。HSP90α的這些生物學(xué)特點(diǎn)也為腫瘤的治療提供了新的切入點(diǎn),如17-烯丙胺-17-去甲氧基格爾德霉素等HSP90抑制劑的應(yīng)運(yùn)而生[21]。近期有研究表明,他汀類(lèi)物質(zhì)(3-羥基-3-戊二輔酶 A 還原酶抑制劑)通過(guò)抑制HSP90α來(lái)增強(qiáng)貝伐單抗在腸癌中的抗腫瘤作用[23]。

本研究對(duì)NSCLC患者和健康成年人的血清HSP90α水平進(jìn)行了比較和分析,發(fā)現(xiàn)NSCLC患者的血清HSP90α水平較健康成年人高。不同TNM分期患者的血清HSP90α水平比較,差異有統(tǒng)計(jì)學(xué)意義。且TNM分期與血清HSP90α水平呈正相關(guān),分期較高的患者,其血清HSP90α水平也較高。

中醫(yī)認(rèn)為正虛是肺癌發(fā)生的病機(jī),痰瘀毒結(jié)是其主要病理表現(xiàn),正虛邪實(shí)是其發(fā)病的根本原因,也是復(fù)發(fā)和轉(zhuǎn)移的關(guān)鍵。患者正氣不足,氣血陰陽(yáng)失調(diào),臟腑經(jīng)絡(luò)功能紊亂,導(dǎo)致邪氣趁虛而入,體內(nèi)水濕停滯,聚集成痰,或熱毒灼津,煎液成痰;氣血運(yùn)行不暢,血流淤滯,瘀血內(nèi)?;蛱禎駜?nèi)停,痰濕血瘀互結(jié)于肺而形成肺癌。到腫瘤晚期,因耗傷精氣、邪毒亢進(jìn),多表現(xiàn)為全身正氣虛衰、局部邪實(shí),患者虛實(shí)并重,腫瘤細(xì)胞極速擴(kuò)散、轉(zhuǎn)移,負(fù)荷較大,HSP90α大量分泌。研究過(guò)程中課題組觀(guān)察到NSCLC患者在初期正虛和邪實(shí)都比較弱,多表現(xiàn)為氣短乏力、咳嗽少痰、自汗盜汗,隨著痰濁、瘀血互結(jié)逐漸加重,病情逐漸向邪實(shí)方向發(fā)展,出現(xiàn)煩躁不安、氣短乏力、咳嗽、痰黏色黃、氣喘息粗及其他虛實(shí)夾雜表現(xiàn)。本研究結(jié)果顯示,陰虛毒熱證患者的血清HSP90α水平較氣虛痰濕證和氣陰兩虛證患者高,氣虛痰濕證患者的血清HSP90α水平較氣滯血瘀證患者低,提示HSP90α水平變化與中醫(yī)證型變化之間可能存在一定規(guī)律。

目前,中醫(yī)治療肺癌的準(zhǔn)則主要有兩種,以辨證論治為主和辨證與辨病相結(jié)合。但中醫(yī)辨證論治在腫瘤疾病的應(yīng)用難以全面反映出多數(shù)群體病例的共同診治規(guī)律。甚至存在無(wú)證可辨,有證可辨但辨而有誤等現(xiàn)象?,F(xiàn)代循證醫(yī)學(xué)的發(fā)展為中醫(yī)辨證論治提供了很好的發(fā)展模式,在搜集四診資料的同時(shí),結(jié)合現(xiàn)代實(shí)驗(yàn)室檢查(如腫瘤標(biāo)志物、免疫學(xué)指標(biāo)等)進(jìn)行中醫(yī)辨證論治,是有益的嘗試和探索[24]。本研究樣本量較小,各證型患者較少,故血清HSP90α水平與中醫(yī)證型的關(guān)系有待進(jìn)一步的研究。另外,血清HSP90α與其他腫瘤標(biāo)志物聯(lián)合應(yīng)用,以提高中醫(yī)辨證客觀(guān)性和準(zhǔn)確性的研究方向也具有較高臨床價(jià)值。

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(本文編輯:王鳳微)

Clinical Significance of Serum HSP90 α in Patients With Non-small-cell Lung Cancer

DONGPeng-fei,DENGXiao-ming.

DepartmentofIntegrativeChineseandWesternMedicine,theFirstAffiliatedHospitalofZhengzhouUniversity,Zhengzhou450052,China

Objective To investigate the clinical significance of serum HSP90 α in patients with non-small-cell lung cancer.Methods We enrolled 80 patients with NSCLC who were admitted into TCM and WM internal medicine department,chest surgery department and respiratory department of the First Affiliated Hospital of Zhengzhou University and assigned them into lung cancer group.And another 30 healthy adults were enrolled in the same hospital and time period as the control group.Serum HSP90 α was compared between the two groups and among patients in different TNM stages.The correlativity between TNM staging and serum HSP90 α were investigated.The subjects of lung cancer group were classified according to TCM classification standards,and patients of different TCM types were compared by serum HSP90 α level.Results Control group and lung cancer group were significantly different(t=16.02,P<0.05) in serum HSP90 α.Patients in different TNM stages were significantly different(F=14.98,P=0.00)in serum HSP90 α.The Spearman rank sum test showed that TNM staging and serum HSP90 α level were positively correlated(rs=0.42,P<0.01) with each other.Patients with different TCM types were significantly different(F=4.22,P<0.01) in serum HSP90 α level.Conclusion NSCLC patients are higher than healthy adults in serum HSP90 α level.Higher TNM staging causes higher serum HSP90 α level.Since serum HSP90 α level can be an indicator of the change between vital energy and evil qi and between deficiency and excess,it is expected to be an objective basis of TCM treatment based on syndrome differentiation and be taken as a marker of tumor in NSCLC patients.Serum HSP90 α level has a great clinical importance in the prediction of the occurrence and development of NSCLC.

Carcinoma,non-small-cell lung;HSP90 heat-shock proteins;Neoplasm staging;Syndrome differ classification

450052 河南省鄭州市,鄭州大學(xué)第一附屬醫(yī)院中西醫(yī)結(jié)合內(nèi)科

鄧曉明,450002 河南省鄭州市,鄭州大學(xué)第一附屬醫(yī)院中西醫(yī)結(jié)合內(nèi)科;E-mail:hndengxiaoming@126.com

R 730.26

A

10.3969/j.issn.1007-9572.2015.19.026

2015-03-02;

2015-05-05)

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