乳癌病人血清sB7-H3表達及其臨床意義

2021-08-18 20:52于超周小鳳呂志棟毛艷韓清昕吳琍
青島大學學報(醫學版) 2021年3期
關鍵詞:病理學血清診斷

于超 周小鳳 呂志棟 毛艷 韓清昕 吳琍

[摘要] 目的

探討乳癌病人血清可溶性人B7同源體3(sB7-H3)表達及其臨床意義。

方法 采用ELISA法,檢測106例乳癌病人(乳癌組)和43例健康體檢者(健康組)血清中sB7-H3表達,并分析乳癌病人血清sB7-H3表達與病理參數的關系。

結果 乳癌組血清sB7-H3表達明顯高于健康組,差異有顯著意義(t=8.530,P<0.01);血清sB7-H3最佳診斷截斷值為21.73 μg/L。單因素分析顯示,血清中sB7-H3表達與乳癌病人術后的病理分期(pTNM)、是否有淋巴結轉移以及腫瘤浸潤淋巴細胞表達高低有關(t=-2.219~2.067,P<0.05),而與腫瘤大小、組織學分級、分子分型等無關(P>0.05)。

結論 血清sB7-H3可能成為篩選乳癌的重要腫瘤標志物,高表達的血清sB7-H3可能與乳癌預后不良有關。

[關鍵詞] 乳房腫瘤;sB7-H3;血清;診斷;病理學,臨床

[中圖分類號] R737.9

[文獻標志碼] A

[文章編號] 2096-5532(2021)03-0361-04

doi:10.11712/jms.2096-5532.2021.57.087

[開放科學(資源服務)標識碼(OSID)]

[網絡出版] https://kns.cnki.net/kcms/detail/37.1517.R.20210426.1111.003.html;2021-04-26 16:17:22

EXPRESSION OF SERUM SOLUBLE HUMAN B7 HOMOLOG 3 AND ITS CLINICAL VALUE IN BREAST CANCER PATIENTS

YU Chao, ZHOU Xiaofeng, L Zhidong, MAO Yan, HAN Qingxin, WU Li

(Breast Center, The Affiliated Hospital of Qingdao University, Qingdao 266100, China)

[ABSTRACT]Objective To investigate the expression of serum soluble human B7 homolog 3 (sB7-H3) and its clinical va-

lue in breast cancer patients.

Methods ELISA was used to measure the expression of sB7-H3 in the serum of 106 breast cancer patients (breast cancer group) and 43 healthy subjects who underwent physical examination (healthy group), and the association between serum sB7-H3 expression and pathological parameters was analyzed for breast cancer patients.

Results The breast can-

cer group had significantly higher expression of serum sB7-H3 than the healthy group (t=8.530,P<0.01), and the optimal cut-off value for diagnosis was 21.73 μg/L. The univariate analysis showed that the expression of sB7-H3 in serum was associated with postoperative pathological staging, presence or absence of lymph node metastasis, and expression of tumor-infiltrating lymphocytes (t=-2.219 to 2.067,P<0.05), while it was not associated with tumor size, histological grade, and molecular typing (P>0.05).

Conclusion Serum sB7-H3 is expected to become an important tumor marker for breast cancer screening, and highly expressed serum sB7-H3 may be associated with the poor prognosis of breast cancer.

[KEY WORDS]breast neoplasms; sB7-H3; serum; diagnosis; pathology, clinical

目前,乳癌已成為全球女性癌癥死亡的第二大原因[1],并占全球女性癌癥病例總數的1/4[2]。在中國,乳癌的致死人數逐年增加,已成為導致45歲以下女性死亡的主要原因和發病率較高的女性疾病[3-5]。乳癌早期診斷不理想[6]。近幾年研究發現,血清中可溶性人B7同源體3(sB7-H3)在多種癌癥病人中異常高表達[7-9],并與腫瘤惡性進展和預后密切相關[10-11]。sB7-H3對于癌癥診斷和預后評價可能有重要價值。本研究探討乳癌病人血清中sB7-H3表達及其臨床意義,為乳癌早期診斷提供依據。

1 資料和方法

1.1 對象與分組

2018年8月—2019年4月,選取我院收治乳癌病人106例作為研究對象(乳癌組),均為女性。納入標準:①自愿參加本次研究;②病歷及術后病理資料完整;③穿刺及術后病理診斷為浸潤性乳癌。排除標準:①伴有其他惡性腫瘤、自身免疫系統疾病和炎癥性疾病;②術前有新輔助治療史;③近3個月有藥物應用史。以同期來我院體檢中心體檢的健康者43例作為對照組,所有對象均為女性。乳癌組病人年齡25~76歲,平均(53.42±10.26)歲;對照組年齡為19~62歲,平均(44.53±11.28)歲。本文研究取得醫院倫理委員會批準和病人知情同意,并簽署知情同意書。

1.2 檢測指標及方法

采集受檢者清晨空腹靜脈血5 mL,靜置0.5 h后,以3 000 r/min離心5 min,取血清并將其保存于-80 ℃冰箱內備用。應用ELISA法測定標本中sB7-H3表達,試劑盒購自江蘇寶萊生物科技有限公司,操作參照說明書進行。

1.3 統計學方法

使用SPSS 21.0軟件進行統計學分析,計量資料數據以±s表示,兩組數據間比較采用t檢驗,多組數據間比較采用單因素方差分析。采用Med Calc 19.0.2軟件繪制ROC曲線。以P<0.05為差異有統計學意義。

2 結? 果

2.1 兩組血清sB7-H3表達比較

乳癌組、對照組血清sB7-H3表達量分別為(26.27±4.21)、(19.44±4.91) μg/L,兩組比較差異有顯著性(t=8.530,P<0.01)。

2.2 血清中sB7-H3表達篩選乳癌的最佳截斷值

ROC曲線分析顯示,曲線下面積為0.854(95%CI=0.787~0.907,P<0.01); 最佳診斷截斷值為21.73 μg/L,靈敏度為84.0%,特異度為76.7%,約登指數0.607。即以血清sB7-H3水平21.73 μg/L作為區分乳癌和健康人的篩選界值時,診斷價值最高。見圖1。

2.3 乳癌病人sB7-H3表達與臨床病理參數的關系

pTNM分期較高(Ⅲ期和Ⅳ期)的乳癌病人血清中sB7-H3表達高于分期較低乳癌病人(Ⅰ期和Ⅱ期),差異有統計學意義(t=-2.219,P<0.05)。淋巴結有轉移的病人血清sB7-H3明顯高于無淋巴結轉移病人,差異有統計學意義(t=-2.205,P<0.05)。腫瘤浸潤淋巴細胞(TILS)≤5%的病人sB7-H3表達高于TILS>5%的病人,差異有統計學意義(t=2.067,P<0.05)。而腫瘤大小、組織學分級、分子分型等病理特征與sB7-H3表達無關(P>0.05)。見表1。

3 討? 論

近年來,人們致力于與腫瘤的診斷和預后評價具有較高臨床相關性的血液生物標志物研究[12]。B7-H3為一種表達于人體各類免疫細胞膜上的Ⅰ型跨膜蛋白,愈來愈多研究證實其具有免疫相關作用[13]。對B7-H3生物學功能的研究發現,B7-H3在調節T細胞活化過程同時具有共刺激和共抑制作用[14-16];同時有研究顯示,B7-H3在特異性和非特異性免疫調節中均具有重要意義[17]。但B7-H3的作用機制仍不明確。有研究顯示,B7-H3與T細胞上的髓樣細胞(TREM-)樣轉錄物(TLT-2)分子上表達的受體結合可增強T細胞增殖、細胞因子產生和細胞毒性[18]。但這一觀點并沒有被普遍接受。一些研究人員認為,T細胞上可能有其他潛在受體[19-20]。B7-H3抑制T細胞活化的相關機制尚需進一步研究。

有研究顯示,B7-H3在人體體液中的可溶性形式sB7-H3能夠與B7-H3受體結合。正常人血清,甚至人的成骨細胞和骨髓基質細胞的上清液和前列腺分泌物中均可檢測到sB7-H3的表達[21-22],多種疾病病人體內檢測到sB7-H3表達水平與健康人群不同[23]。對于sB7-H3的來源,絕大多數研究認為,其是通過基質金屬蛋白酶(MMP)切割單核細胞、樹突細胞、活化的T細胞和腫瘤細胞細胞膜上的B7-H3而釋放出來,其支持證據是MMP抑制劑能夠增強B7-H3在細胞膜上的表達[21]。

關于sB7-H3的生物學功能,有研究認為在腫瘤的發生、發展中,外周血中的游離sB7-H3可以競爭性地與T細胞表面上的B7-H3受體結合,阻斷B7-H3的T細胞活化作用,從而具有與B7-H3相反的免疫調節功能[24-25]。CHEN等[9]研究結果顯示,剪切型sB7-H3能夠抑制T細胞增殖,減少細胞因子的分泌。

而XIE等[12]研究結果證明,sB7-H3通過TLR4/NF-κB途徑促進胰腺癌細胞的侵襲和轉移。提示sB7-H3可能與人體免疫調節有關,并可能在腫瘤發生、發展過程中發揮重要作用。

本研究結果顯示,乳癌組血清sB7-H3表達明顯高于健康組,提示血清sB7-H3檢測可作為乳癌篩選和輔助診斷的潛在標志物;同時對血清sB7-H3與臨床病理參數的關系分析顯示,血清中sB7-H3表達與乳癌病人pTNM分期、是否有淋巴結轉移以及TILS表達高低等有關,而與年齡、腫瘤大小及組織學分級等無關,sB7-H3高表達可能提示乳癌分期更高,預后更差。

大量研究認為,TILS是人體對腫瘤抗原進行免疫反應的標志,其具有潛在預測乳癌病人預后的價值[26-27]。尤其在三陰性與Her-2陽性乳癌病灶中TILS浸潤程度較高,可能與這兩種類型腫瘤的免疫原性相對較高有關[28]。值得注意的是,本研究結果顯示,血清sB7-H3表達與乳癌組織中TILS水平有關,提示sB7-H3可能參與調節T細胞對乳癌腫瘤細胞的免疫反應,并有可能抑制T細胞活化,這與SUN等[25]研究結果類似。此外有研究發現,MMP除可能參與切割mB7-H3產生sB7-H3,還介導組成腫瘤微環境的細胞外基質的降解,使乳癌組織間質中T細胞穿透細胞外基質形成的屏障,促進其免疫活性[29],提示血清sB7-H3可能與腫瘤浸潤微環境形成存在某種聯系。其具體作用機制需要進一步研究。

綜上所述,sB7-H3在乳癌病人中高表達,具有成為篩查乳癌血清標志物的良好前景;sB7-H3與乳癌病人術后病理參數存在密切相關性,提示其具有預測乳癌病人臨床預后的潛力。sB7-H3可能通過抑制B7-H3對T細胞的活化功能,促進腫瘤細胞的免疫逃逸,其具體機制尚需進一步研究證實。

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(本文編輯 黃建鄉)

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