孫雅麗，趙 妍，楊 艷，張明暉，馬艷青，楊春潔，魏海波

內(nèi)蒙古醫(yī)科大學(xué)附屬赤峰醫(yī)院腫瘤內(nèi)三科，內(nèi)蒙古 赤峰 024000

檢測同型半胱氨酸在不同分期結(jié)腸癌患者血漿中的變化

孫雅麗，趙 妍，楊 艷，張明暉，馬艷青，楊春潔，魏海波

內(nèi)蒙古醫(yī)科大學(xué)附屬赤峰醫(yī)院腫瘤內(nèi)三科，內(nèi)蒙古 赤峰 024000

目的 檢測不同分期結(jié)腸癌患者血漿中同型半胱氨酸(homocysteine,Hcy)水平，分析腫瘤分期與Hcy的關(guān)系,并初步探討其在結(jié)腸癌患者中的臨床意義。方法 選取2013年9月-2014年10月就診于內(nèi)蒙古醫(yī)科大學(xué)附屬赤峰醫(yī)院經(jīng)病理學(xué)(結(jié)腸鏡)確診的未行任何治療的結(jié)腸癌患者為試驗組，選取同期健康體檢者為對照組。電化學(xué)發(fā)光方法檢測試驗組及對照組血漿Hcy水平。結(jié)果 經(jīng)確診的80例結(jié)腸癌患者中，Hcy升高者26例，平均值為(14.62±3.24)μmol/ml。對照組80名健康人中，升高者2名，平均值為(10.25±2.01)μmol/ml。兩者相比較,差異有顯著性統(tǒng)計學(xué)意義(P<0.01)。在Hcy升高的結(jié)腸癌患者中，隨著腫瘤分期的升高，Hcy隨之升高，差異有統(tǒng)計學(xué)意義(P<0.01)。結(jié)論 對于確診結(jié)腸癌的患者，Hcy有望成為結(jié)腸癌的標(biāo)志物，能夠輔助診斷、評價療效、監(jiān)測腫瘤復(fù)發(fā)。

結(jié)腸癌；同型半胱氨酸；腫瘤分期

同型半胱氨酸(homocysteine,Hcy)是一種與半胱氨酸同系的四碳氨基酸，是蛋氨酸分解合成代謝的中間產(chǎn)物，本身不參與體內(nèi)蛋白質(zhì)的合成[1]。在臨床上，Hcy主要應(yīng)用于心腦血管病危險性的評估。國內(nèi)外也有報道，Hcy與腫瘤有一定的關(guān)系[3]，其在乳腺癌、結(jié)直腸癌、原發(fā)性肝細(xì)胞癌、惡性淋巴瘤、胃癌、卵巢癌、胰腺癌等多種惡性腫瘤患者的血漿中均有升高[2-7]。Hcy在結(jié)腸癌患者血漿中有所升高，其升高水平與腫瘤分期是否有關(guān)，目前國內(nèi)外鮮有報道。本研究通過檢測結(jié)腸癌患者及健康成人血漿中Hcy水平，驗證結(jié)腸癌患者體內(nèi)有Hcy升高，進一步將Hcy升高的結(jié)腸癌患者進行臨床分期，觀察Hcy水平與腫瘤分期是否有關(guān)。

1 資料與方法

1.1 一般資料 收集2013年9月-2014年10月就診于內(nèi)蒙古醫(yī)科大學(xué)附屬赤峰醫(yī)院初次經(jīng)病理學(xué)(結(jié)腸鏡)確診的未行任何治療的結(jié)腸癌患者80例為試驗組，年齡50～60歲，男48例，女32例。對照組選自本院體檢的健康成人，共80名，男48名，女32名。納入標(biāo)準(zhǔn)：年齡50～60歲；無吸煙史、無嗜酒史及喝咖啡習(xí)慣、無心腦血管疾病、無糖尿病；未服用過影響葉酸及Hcy代謝藥物的健康成人。將試驗組根據(jù)Dukes分期系統(tǒng)[8]進行分期，其中Dukes Ⅰ期16例，Dukes Ⅱ期30例，Dukes Ⅲ期患者24例，Dukes Ⅳ期10例。

1.2 血漿Hcy測定 清晨空腹，肘靜脈采血，由檢驗科用電化學(xué)發(fā)光方法檢測(FPLA)檢測血漿中Hcy水平，Hcy正常值參考范圍4.44～13.56 μmol/ml。

1.3 統(tǒng)計學(xué)分析 采用SPSS 10.0統(tǒng)計軟件進行分析，顯著性比較采用t檢驗，P<0.01為差異有統(tǒng)計學(xué)意義。

2 結(jié)果

2.1 兩組Hcy水平比較 經(jīng)確診的80例結(jié)腸癌患者中，Hcy升高者26例，平均值為(14.62±3.24)μmol/ml。對照組的80名健康人中，升高者2例，平均值為(10.25±2.01)μmol/ml。兩者相比，差異有顯著性統(tǒng)計學(xué)意義(P<0.01，見圖1)。

圖1 結(jié)腸患者與健康人血漿Hcy水平Fig 1 Levels of plasma Hcy in colon cancer patients and healthy controls

2.2 不同分期結(jié)腸癌患者血漿Hcy水平 Dukes Ⅱ期結(jié)腸癌患者Hcy水平較Dukes Ⅰ期升高，差異有統(tǒng)計學(xué)意義(P<0.01)；Dukes Ⅲ期與Dukes Ⅱ、Dukes Ⅰ期比較，差異有統(tǒng)計學(xué)意義(P<0.01)；Dukes Ⅳ期較Dukes Ⅲ、Dukes Ⅱ、Dukes Ⅰ期升高，差異有統(tǒng)計學(xué)意義(P<0.01，見表1)。

表1 不同分期結(jié)腸癌患者血漿Hcy水平比較 ±s)Tab 1 Comparison of plasma Hcy levels in patients with colon cancer in different stages ±s)

3 討論

Hcy主要通過下面兩個途徑進行分解代謝[9]：(1) Hcy在胱硫醚合成酶 (CBS) 作用下以 VitB6 為輔助因子轉(zhuǎn)化為胱硫醚及半胱氨酸，最終分解為丙酮酸、 硫酸和水；(2) Hcy 在葉酸、 VitB12及亞甲基四氫葉酸還原酶 (MTHFR)作用下甲基化形成蛋氨酸而參加蛋氨酸循環(huán)。葉酸、VitB6、 VitB12缺乏或CBS 基因、MTHFR 基因突變，均可導(dǎo)致 Hcy 代謝和清除障礙，引起高Hcy血癥。

葉酸是DNA合成及其甲基化提供一碳單位，對生長發(fā)育等功能有重要影響。對于腫瘤患者來說，如果葉酸特別是Ⅳ-甲基四氫葉酸缺乏，可導(dǎo)致蛋氨酸循環(huán)受阻，Hcy升高[10]，蛋氨酸水平下降；繼而致S-腺苷蛋氨酸下降。S-腺苷蛋氨酸降低可導(dǎo)致DNA甲基化程度降低，誘導(dǎo)原癌基因如 c-myc、 c-fos 等的表達，最終導(dǎo)致腫瘤發(fā)生[11-12]。

本研究用FPLA檢測血漿中Hcy水平比較結(jié)腸癌患者與健康人，結(jié)果顯示結(jié)腸癌患者較健康人血漿Hcy水平升高，差異有統(tǒng)計學(xué)意義。同時將收集的病例根據(jù)Dukes系統(tǒng)進行分期，結(jié)果顯示，在Hcy升高的結(jié)腸癌患者中，隨著腫瘤分期的升高，Hcy隨之升高，差異有統(tǒng)計學(xué)意義。同型半胱氨酸有望成為結(jié)腸癌的標(biāo)志物，能夠輔助診斷、評價療效、監(jiān)測腫瘤復(fù)發(fā)。

[1]Weinstein SJ,Ziegler RG,Selhub J,et al. Elevated serum homocysteine levels and increased risk of invasive cervical cancer in US women [J]. Cancer Causes Control,2001,12(4): 317-324.

[2]Aleksic D,Djokic D,Golubicic I,et al. The importance of the blood levels of homocysteine,folic acid and vitamin B12 in children with malignant diseases [J]. J BUON,2013,18(4): 1019-1025.

[3]Naushad SM,Reddy CA,Kumaraswami K,et al. Impact of hyperhomocysteinemia on breast cancer initiation and progression: epigenetic perspective [J]. Cell Biochem Biophys，2014,68(2): 397-406.

[4]Miller JW,Beresford SA,Neuhouser ML,et al. Homocysteine,cysteine,and risk of incident colorectal cancer in the Women’s Health Initiative observational cohort [J]. Am J Clin Nutr,2013,97(4): 827-834.

[5]Bilici A,Sonkaya A,Ercan S,et al. The changing of serum vitamin B12 and homocysteine levels after gastrectomy in patients with gastric cancer: do they associate with clinicopathological factors [J]. Tumour Biol,2015,36(2): 823-828.

[6]Aviia MA,Berasain C,Torres L,et al. Reduced mRNA abuncance of the main enzymes invoived in methionine metaboiism in human iiver cirrhosis and hepatoceiiuiar carcinoma [J]. J Hepatoi,2000,33(6): 907-914.

[7]Kohaar I,Kumar J,Thakur N,et al. Homoeysteine levels are associated with cervical cancer independent of methylene tetrahydrofolate reduetase gene (MTHFR) polymorphisms in Indian population [J]. Biomarkers,2010,15(1): 61-68.

[8]Shi YK,Sun Y. Manual of medical oncology [M]. 6th ed. Beijing: People’s Medical Publishing House,2015: 8.

石元凱,孫燕. 臨床腫瘤內(nèi)科手冊[M]. 6版. 北京: 人民衛(wèi)生出版社,2015: 8.

[9]Selhb J. Homocysteine metabolism [J]．Ann Rev Nutr,1999,19(1): 217-246.

[10]Wu LL,Wu JT. Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker [J]. Clin Chim Acta,2002,322(1): 21-28．

[11]Wei Q,Shen H,Wang LE,et al. Association between low dietary folate intake and suboptimal cellular DNA repair capacity [J]. Cancer Epidemiol Biomarkers Prev,2003,12(10): 963-969．

[12]Jacob RA. Foiate,DNA methyiation and gene expression: factors and nurture [J]. Am J Ciin Nutr,2000,72(4): 903-904.

(責(zé)任編輯：陳香宇)

Changes of homocysteine in the plasma of colon cancer patients in different stages

SUN Yali,ZHAO Yan,YANG Yan,ZHANG Minghui,MA Yanqing,YANG Chunjie,WEI Haibo

Department of NO.3 Oncology,Chifeng Hospital of Affiliated Inner Mongolia Medical University,Chifeng 024000,China

Objective To detect the changes of homocysteine (Hcy) in the plasma of colon cancer patients in different stages,to analyze the relationship between tumor stages and Hcy,and to explore its clinical significance. Methods Colon cancer patients diagnosed by pathology (endoscopy) without any treatment in Chifeng Hospital of Affiliated Inner Mongolia Medical University from Jun. 2013 to Oct. 2014 were collected as experiment group,healthy people as controls group. Hcy levels in plasma of the experiment group and the control group were collected by electrochemiluminescence methods. Results There were 26 cases with increased Hcy in 80 cases of colon cancer,average level of Hcy was (14.62±3.24) μmol/ml. There were 2 cases with increased Hcy in 80 healthy people,average level of Hcy was (10.25±2.01) μmol/ml (P<0.01). In the colon cancer patients that Hcy elevated,with increasing the staging of tumor,the level of Hcy in plasma was increasing,there was statistically significant (P<0.01). Conclusion For patients with colon cancer,Hcy is expected as colon cancer markers which could auxiliary diagnose,evaluate curative effect and monitor tumor recurrence.

Colon cancer; Homocysteine; Tumor staging

10.3969/j.issn.1006-5709.2016.02.009

孫雅麗，主任醫(yī)師，研究方向：腫瘤內(nèi)科的綜合治療

趙妍，主治醫(yī)師，研究方向：胃腸道腫瘤、肺癌的內(nèi)科治療。E-mail: zhaoyan198642@163.com

R735.3+5

A

1006-5709(2016)02-0153-02

2015-06-30