p75NTR在胃癌組織中的表達(dá)及臨床意義

靳海峰，趙 敏，趙 亮，王 力，吳 崢，趙會(huì)懂，侯會(huì)池，朱焱華，孫 蓉，姚 欣，吳曉云，谷建芳

p75NTR在胃癌組織中的表達(dá)及臨床意義

靳海峰，趙 敏，趙 亮，王 力，吳 崢，趙會(huì)懂，侯會(huì)池，朱焱華，孫 蓉，姚 欣，吳曉云，谷建芳

目的 探討p75NTR在胃癌組織中的表達(dá)及臨床意義。方法 選擇2015年1月—2016年1月在解放軍白求恩國際和平醫(yī)院行手術(shù)切除的胃癌60例，將其胃癌組織標(biāo)本作為研究對象，根據(jù)患者淋巴結(jié)是否轉(zhuǎn)移及病灶浸潤深度進(jìn)行分組。統(tǒng)計(jì)比較淋巴結(jié)轉(zhuǎn)移陰性組、淋巴結(jié)轉(zhuǎn)移陽性組以及病灶浸潤肌層組、病灶浸潤全層組p75NTR檢測情況，并對淋巴結(jié)轉(zhuǎn)移陰性組和淋巴結(jié)轉(zhuǎn)移陽性組治療后生活質(zhì)量進(jìn)行比較。結(jié)果 淋巴結(jié)轉(zhuǎn)移陰性組p75NTR檢出陽性率顯著高于淋巴結(jié)轉(zhuǎn)移陽性組，兩組比較差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。病灶浸潤肌層組p75NTR檢出陽性率顯著高于病灶浸潤全層組，兩組比較差異亦具有統(tǒng)計(jì)學(xué)意義(P<0.05)。治療后淋巴結(jié)轉(zhuǎn)移陰性組日常生活能力評分、軀體功能評分、心理功能評分及社會(huì)功能評分均顯著高于淋巴結(jié)轉(zhuǎn)移陽性組，兩組比較差異均具有統(tǒng)計(jì)學(xué)意義(P<0.05)。結(jié)論 p75NTR水平檢測可提示胃癌組織淋巴結(jié)轉(zhuǎn)移情況以及病灶浸潤深度，p75NTR水平檢測可作為預(yù)測胃癌患者預(yù)后情況的依據(jù)。

胃腫瘤；p75NTR;基因表達(dá)

現(xiàn)已有文獻(xiàn)報(bào)道顯示，胃癌是世界范圍內(nèi)嚴(yán)重危害公眾健康的一種疾病，我國是胃癌高發(fā)國家，在我國各類惡性腫瘤疾病中胃癌發(fā)病率居第4位[1-3]。相關(guān)資料表明，p75NTR對多種腫瘤組織性質(zhì)判斷以及對多種腫瘤患者生存以及預(yù)后水平影響有重要意義[4-5]。為探討p75NTR在胃癌組織中的表達(dá)及臨床意義，本研究選擇胃癌60例的組織標(biāo)本作為研究對象進(jìn)行分析，并對患者的臨床資料進(jìn)行回顧分析，現(xiàn)報(bào)告如下。

1 資料與方法

1.1 一般資料 選擇2015年1月—2016年1月在解放軍白求恩國際和平醫(yī)院行手術(shù)切除的胃癌60例，男43例，女17例；年齡35～70(52.6±3.8)歲;病程1～3個(gè)月。所有患者皆經(jīng)胃鏡活組織病理檢查明確診斷，腫瘤位于胃體小彎及胃竇部，病理檢查均示腺癌，臨床分期T3NxM0。擇期行原發(fā)癌以及區(qū)域淋巴結(jié)切除(胃癌根治術(shù))治療，術(shù)前均未行系統(tǒng)性放化療干預(yù)。選取此60例胃癌組織標(biāo)本作為研究對象。本研究內(nèi)容經(jīng)院醫(yī)學(xué)倫理委員會(huì)批準(zhǔn)，且患者簽署知情同意書。

1.2 分組 根據(jù)患者術(shù)后病理檢查淋巴結(jié)是否轉(zhuǎn)移將60例分為淋巴結(jié)轉(zhuǎn)移陰性組(n=30)和淋巴結(jié)轉(zhuǎn)移陽性組(n=30)；根據(jù)患者術(shù)后病理檢查病灶浸潤深度將60例分為病灶浸潤肌層組(n=30)和病灶浸潤全層組(n=30)。

1.3 觀察指標(biāo)及方法 統(tǒng)計(jì)比較淋巴結(jié)轉(zhuǎn)移陰性組、淋巴結(jié)轉(zhuǎn)移陽性組以及浸潤肌層組、浸潤全層組p75NTR檢出情況，并對淋巴結(jié)轉(zhuǎn)移陰性組和淋巴結(jié)轉(zhuǎn)移陽性組治療后[均給予FOLFOX4(奧沙利鉑、亞葉酸鈣、氟尿嘧啶)方案化療8個(gè)周期]生活質(zhì)量進(jìn)行比較。采用SP法進(jìn)行免疫組織化學(xué)檢查，常規(guī)石蠟切片并經(jīng)二甲苯脫蠟，抗原微波修復(fù)后進(jìn)行孵育處理，p75NTR定位于細(xì)胞質(zhì)，以可見棕黃色改變或顯現(xiàn)棕褐色顆粒為陽性判斷依據(jù)。生活質(zhì)量采用日常生活能力(ADL)評分、軀體功能評分、心理功能評分及社會(huì)功能評分進(jìn)行評定。

2 結(jié)果

淋巴結(jié)轉(zhuǎn)移陰性組p75NTR檢出陽性率為100.00%(30/30)，顯著高于淋巴結(jié)轉(zhuǎn)移陽性組20.00%(6/30)，兩組比較差異有統(tǒng)計(jì)學(xué)意義(χ2=14.276，P<0.001)，兩組典型病例病理檢查結(jié)果見圖1、圖2。病灶浸潤肌層組p75NTR檢出陽性率為66.67%(20/30)，顯著高于病灶浸潤全層組43.33%(13/30)，兩組比較差異具有統(tǒng)計(jì)學(xué)意義(χ2=7.589，P<0.001)，兩組典型病例病理檢查結(jié)果見圖3、圖4。治療后淋巴結(jié)轉(zhuǎn)移陰性組ADL評分、軀體功能評分、心理功能評分及社會(huì)功能評分，均顯著高于淋巴結(jié)轉(zhuǎn)移陽性組，兩組比較差異均具有統(tǒng)計(jì)學(xué)意義(P<0.05)，見表1。

圖1 淋巴結(jié)轉(zhuǎn)移陰性胃癌患者p75NTR檢測情況(男，63歲；免疫組織化學(xué)×200)

圖2 淋巴結(jié)轉(zhuǎn)移陽性胃癌患者p75NTR檢測情況(男，55歲；免疫組織化學(xué)×200)

圖3 病灶浸潤肌層胃癌患者p75NTR檢測情況(女，61歲；免疫組織化學(xué)×200)

圖4 病灶浸潤全層胃癌患者p75NTR檢測情況(女，49歲；免疫組織化學(xué)×200)

表1 淋巴結(jié)是否轉(zhuǎn)移胃癌兩組治療后生活質(zhì)量評定比較±s，分)

3 討論

胃癌是常見惡性腫瘤，為侵襲性強(qiáng)、致死率高的難治性惡性腫瘤。胃癌發(fā)展到一定程度后就會(huì)發(fā)生轉(zhuǎn)移，胃癌早期多數(shù)患者癥狀不典型，而且胃癌病程較短，有相當(dāng)一部分胃癌患者在確診之時(shí)已有明顯轉(zhuǎn)移癥狀，并很快出現(xiàn)惡病質(zhì)[6-9]。有研究顯示，胃癌淋巴結(jié)轉(zhuǎn)移是胃癌轉(zhuǎn)移的重要途徑，而且發(fā)生較早。淋巴結(jié)轉(zhuǎn)移占胃癌轉(zhuǎn)移70%，胃下部癌腫常轉(zhuǎn)移至幽門下、胃下及腹腔動(dòng)脈旁等淋巴結(jié)，而上部癌腫常轉(zhuǎn)移至胰旁、賁門旁、胃上等淋巴結(jié)[10-11]。晚期胃癌可轉(zhuǎn)移至主動(dòng)脈周圍及膈上淋巴結(jié)。由于腹腔淋巴結(jié)與胸導(dǎo)管直接交通，故胃癌還可轉(zhuǎn)移至左鎖骨上淋巴結(jié)[12]。胃癌患者隨著癌腫增長，侵犯胃壁愈深愈廣，轉(zhuǎn)移機(jī)會(huì)就愈多。臨床上根據(jù)胃癌轉(zhuǎn)移的先后順序可將胃癌轉(zhuǎn)移部位分為3組：第一組距離瘤體最近，為貼于胃壁上的淺組淋巴結(jié)，一般發(fā)生在胃癌局限于黏膜下層時(shí)[13]；第二組系引流淺淋巴結(jié)的深組淋巴結(jié)，當(dāng)胃癌侵犯肌層時(shí)可發(fā)生第二組淋巴結(jié)轉(zhuǎn)移；第三組包括腹腔動(dòng)脈旁、腹主動(dòng)脈、肝門、腸系膜根部及結(jié)腸中動(dòng)脈周圍淋巴結(jié)，也可發(fā)生遠(yuǎn)處淋巴結(jié)轉(zhuǎn)移，如左鎖骨上淋巴結(jié)，此組轉(zhuǎn)移多為癌腫侵犯至漿膜時(shí)發(fā)生[14]。一般而言，發(fā)生第三組淋巴結(jié)轉(zhuǎn)移時(shí)胃癌患者已失去了根治的機(jī)會(huì)。因此，胃癌的綜合治療已受到廣泛重視，其中術(shù)前放化療成為臨床研究局部晚期胃癌治療的一大熱點(diǎn)。胃癌術(shù)前放化療的目的首先是使腫瘤瘤體縮小，其次是降低胃癌腫瘤分期，再次是提高腫瘤根治性切除率和手術(shù)切除完整性，然后是降低淋巴結(jié)轉(zhuǎn)移率和圍術(shù)期并發(fā)癥發(fā)生率，最后為提高生存率并降低殘端癌發(fā)生率。

p75NTR基因?qū)儆谀[瘤壞死因子家族成員之一[15]，是一種擁有死亡受體的結(jié)構(gòu)神經(jīng)營養(yǎng)因子受體，現(xiàn)有關(guān)p75NTR的功能研究主要集中在中樞神經(jīng)系統(tǒng)方面，主要作用是調(diào)控神經(jīng)細(xì)胞的生長、發(fā)育和分化等[15]。p75NTR可以表達(dá)于多種組織、器官和腫瘤中。它在腫瘤中的確切作用機(jī)制目前研究還未完全闡明，在胃癌中的表達(dá)和作用機(jī)制亦仍然不十分清楚。研究表明p75NTR可以介導(dǎo)多種不同類型細(xì)胞死亡和增殖，這主要依賴于細(xì)胞所處的環(huán)境[5]。除了神經(jīng)系統(tǒng)，它還表達(dá)于諸如乳腺癌[16]、急性淋巴細(xì)胞性白血病[17]、乳頭狀甲狀腺癌[18]、胰腺癌[19]和前列腺癌[20]等多種腫瘤組織。p75NTR作為潛在的腫瘤抑制因子之一，有報(bào)道顯示它可以有效抑制前列腺癌和膀胱癌細(xì)胞的生長和增殖[21]，但也有研究報(bào)道它可以作為生存受體促進(jìn)黑色素瘤細(xì)胞的腦轉(zhuǎn)移[22]，這一矛盾的研究結(jié)果提示p75NTR在不同環(huán)境以及不同腫瘤病灶中可能發(fā)揮不同作用[3]。腫瘤細(xì)胞增殖過程中細(xì)胞周期啟動(dòng)依賴于幾個(gè)經(jīng)典的細(xì)胞周期依賴激酶(cdks)，細(xì)胞周期蛋白(Cyclin)D與增殖細(xì)胞核抗原(PCNA)的復(fù)合物已被證實(shí)可以促進(jìn)細(xì)胞周期早期過程中Rb的磷酸化[23]，而在細(xì)胞周期的G1/S期的結(jié)尾，cyclin E與cdk2的復(fù)合物同樣可以促進(jìn)Rb的磷酸化[24-25]，這些都是p75NTR在部分腫瘤中抑制細(xì)胞增殖的作用機(jī)制[20]。同樣，既往也有研究表明，腫瘤侵襲和轉(zhuǎn)移需要腫瘤相關(guān)蛋白酶發(fā)揮作用，這些酶可以促進(jìn)腫瘤細(xì)胞周圍基質(zhì)和基底膜的降解[26]，這些酶包括尿激酶型纖維蛋白酶原激活劑(uPA)、基質(zhì)金屬蛋白酶(MMPs)及其抑制劑(TIMPs)，它們在胃癌等腫瘤細(xì)胞的侵襲和轉(zhuǎn)移過程中發(fā)揮了重要的作用[27-30]。

本研究結(jié)果顯示淋巴結(jié)轉(zhuǎn)移陰性組p75NTR檢出陽性率顯著高于淋巴結(jié)轉(zhuǎn)移陽性組，病灶浸潤肌層組p75NTR檢出陽性率顯著高于病灶浸潤全層組，治療后淋巴結(jié)轉(zhuǎn)移陰性組ADL評分、軀體功能評分、心理功能評分及社會(huì)功能評分均顯著高于淋巴結(jié)轉(zhuǎn)移陽性組。提示在胃癌組織中p75NTR與淋巴結(jié)轉(zhuǎn)移以及病灶浸潤深度均有密切的相關(guān)性，可作為胃癌臨床診斷與預(yù)后預(yù)測的重要依據(jù)之一，這與以往研究報(bào)道一致[22]。p75NTR是否通過調(diào)控細(xì)胞周期或者uPA和MMPs等因子參與胃癌細(xì)胞的生長和轉(zhuǎn)移？其調(diào)控的信號通路又是什么？還有待于進(jìn)一步的深入研究。

總之，本研究結(jié)果提示p75NTR水平檢測可提示胃癌組織淋巴結(jié)轉(zhuǎn)移情況以及病灶浸潤深度，p75NTR水平檢測可作為預(yù)測胃癌患者預(yù)后情況的依據(jù)。

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Expression and Clinical Significance of p75NTR in Gastric Cancer

JIN Hai-feng1a, ZHAO Min2, ZHAO Liang1b, WANG Li1c, WU Zheng3, ZHAO Hui-dong1d, HOU Hui-chi1e, ZHU Yan-hua1f, SUN Rong1a, YAO Xin1a, WU Xiao-yun1a, GU Jian-fang1f

(a. Department of Gastroenterology, b. Department of Cardiothoracic Surgery, c. Health Management Center, d. Editorial Department, e. Department of General Surgery, f. Department of Medical Affairs, Bethune International Peace Hospital of PLA, Shijiazhuang 050082, China; 2. Clinical Supervising Technician of Army Staff, Beijing 100042, China; 3. Department of Biotherapy, the Forth Hospital of Hebei Medical University, Shijiazhuang 050011, China)

Objective To analyze the expression and clinical significance of p75NTR in gastric cancer. Methods A total of 60 samples of gastric cancer undergoing surgical resection of gastric cancer during January 2015 and January 2016 were selected as the study subjects. The content of the study in accordance with the medical ethics will be approved and for patients to understand, signed an informed consent. Retrospective analysis of clinical data of all patients. The positive rate of p75NTR in patients with lymph node metastasis negative group, positive group and the depth of invasion of the muscle layer group, all patients were detected, the positive rate was statistically analyzed. The quality of life was compared between lymph node metastasis positive group and negative group after chemotherapy. Results The positive rate of p75NTR in lymph node metastasis negative group was significantly higher than that in lymph node metastasis positive group, and the difference was statistically significant (P<0.05). The positive rate of p75NTRin infiltration depth of muscular layer was significantly higher than that of the depth of infiltration whole layer group, and the difference was statistically significant (P<0.05). After treatment, the rating scales of viability, physical function, mental function and society function of lymph node metastasis negative patients were significantly higher than those of lymph node metastasis positive group, and the differences were statistically significant (P<0.05). Conclusion Expression of p75NTR in gastric carcinoma tissue can pretest cancerous tissue lymph node metastasis and invasion depth, and therefore clinical introduction of p75NTR index detection can basis as the effective prediction in prognosis of patients with gastric cancer.

Stomach neoplasms; p75NTR； Gene expression

全國優(yōu)秀博士學(xué)位論文作者專項(xiàng)資金資助項(xiàng)目(201363)

050082 石家莊，解放軍白求恩國際和平醫(yī)院消化內(nèi)科(靳海峰、孫蓉、姚欣、吳曉云)，心胸外科(趙亮)，健康管理中心(王力)，編輯部(趙會(huì)懂)，普通外科(侯會(huì)池)，醫(yī)務(wù)部(朱焱華、谷建芳)；100042 北京，陸軍參謀部門診部(趙敏)；050011 石家莊，河北醫(yī)科大學(xué)第四醫(yī)院生物治療中心(吳崢)

R593.23

A

1002-3429(2017)05-0094-04

10.3969/j.issn.1002-3429.2017.05.029

2017-02-22 修回時(shí)間：2017-03-21)