趙明慧,黃媛媛,孫姍姍,孔令平,王宇,郭文宇,周旋,王旭東,張侖
CDK5與EMT相關(guān)蛋白在頭頸部鱗狀細胞癌中異常表達的相關(guān)性研究
趙明慧,黃媛媛,孫姍姍,孔令平,王宇,郭文宇,周旋,王旭東,張侖△
目的探討頭頸部鱗狀細胞癌(HNSCC)中細胞周期素依賴蛋白激酶5(CDK5)及上皮間充質(zhì)轉(zhuǎn)化(EMT)相關(guān)蛋白N-鈣黏蛋白(N-cadherin)、波形蛋白(Vimentin)及E-鈣黏蛋白(E-cadherin)表達,以及CDK5的表達與患者預(yù)后的關(guān)系。方法免疫組化方法檢測55例HNSCC患者癌組織中CDK5及EMT相關(guān)蛋白的表達情況;分析不同臨床病理特征患者CDK5及EMT相關(guān)蛋白表達的差異,CDK5與EMT相關(guān)蛋白表達的相關(guān)性,以及CDK5表達與患者生存之間的關(guān)系。結(jié)果CDK5高表達率在有淋巴結(jié)轉(zhuǎn)移患者中高于無淋巴結(jié)轉(zhuǎn)移患者(91.67%vs 30.23%,P<0.05),在T3~T4期患者中高于T1~T2期患者(85%vs 20%,P<0.05);有淋巴結(jié)轉(zhuǎn)移患者N-cadherin、Vimentin高表達率高于無淋巴結(jié)轉(zhuǎn)移的患者(75.00%vs 6.98%;91.67%vs 27.91%,均P<0.05),E-cadherin高表達率低于無淋巴結(jié)轉(zhuǎn)移的患者(8.33%vs 86.05%,P<0.05);CDK5與N-cadherin、Vimentin表達呈正相關(guān),與E-cadherin表達呈負相關(guān)(rs分別為0.512、0.443、-0.363,均P<0.01);CDK5高表達患者3年生存率低于低表達患者(37.5%vs 87.0%,Logrankχ2=12.678,P<0.01)。結(jié)論CDK5及EMT相關(guān)蛋白在轉(zhuǎn)移性HNSCC中異常表達;CDK5的表達狀態(tài)對預(yù)測HNSCC患者的預(yù)后有一定價值。
頭頸部腫瘤;癌,鱗狀細胞;細胞周期蛋白依賴激酶5;鈣黏著糖蛋白類;波形蛋白;淋巴轉(zhuǎn)移
頭頸部惡性腫瘤是目前全球第六高發(fā)惡性腫瘤,其中90%以上為鱗狀細胞癌[1]。近幾十年來,盡管采取了積極的治療措施,頭頸部惡性腫瘤患者的5年生存率仍僅為50%左右[1]。頸部淋巴結(jié)轉(zhuǎn)移是頭頸部鱗狀細胞癌(HNSCC)患者預(yù)后不良的重要因素之一[2]。因此,闡明腫瘤轉(zhuǎn)移的分子機制,尋找抑制腫瘤轉(zhuǎn)移的新的治療方案愈發(fā)重要。上皮間充質(zhì)轉(zhuǎn)化(EMT)是腫瘤細胞發(fā)生遷移和侵襲的重要機制之一[3]。研究表明,EMT在HNSCC轉(zhuǎn)移過程中起到重要作用[4]。細胞周期素依賴蛋白激酶5(CDK5)能夠調(diào)控前列腺癌細胞的遷移、甲狀腺髓樣癌細胞的增殖及膠質(zhì)母細胞瘤的凋亡等[5]。抑制CDK5的活性可以逆轉(zhuǎn)腫瘤EMT進程[6]。然而,迄今為止尚鮮見HNSCC中CDK5與EMT相關(guān)蛋白N-鈣黏蛋白(N-cadherin)、波形蛋白(Vimentin)及E-鈣黏蛋白(E-cadherin)表達方面的研究。本研究初步探討了CDK5與EMT相關(guān)蛋白在HNSCC中表達的相關(guān)性及CDK5表達與預(yù)后的關(guān)系。
1.1 臨床資料 資料來源于2015年5月-2018年6月參與江西省婦幼保健院開展的“關(guān)愛母親公益活動”的3100例女性,所有女性均自愿接受宮頸HPV篩查。所有女性年齡范圍25-65歲,平均年齡(39.08±10.21)歲,納入標準包括:有性行為史;篩查時未懷孕;無宮頸上皮內(nèi)瘤變、子宮頸癌和子宮切除史。以25-29歲開始,之后每5歲為一個年齡段,到≥50歲組,分為6個年齡組。
1.1 病例與組織標本來源收集天津醫(yī)科大學(xué)腫瘤醫(yī)院2008年1月—2012年1月外科手術(shù)切除的HNSCC患者的腫瘤標本55例,其中男50例,女5例,年齡20~77歲,平均(57.25±10.78)歲,有淋巴結(jié)轉(zhuǎn)移HNSCC患者12例,無淋巴結(jié)轉(zhuǎn)移患者43例。入選標準:(1)組織病理診斷為鱗癌。(2)能夠按照2010年國際抗癌聯(lián)盟UICC標準行TNM分期。(3)臨床資料完整。隨訪時間為手術(shù)之日起至死亡或末次隨訪時間,截至2015年7月1日。總生存期定義為從疾病確診時間至患者失去隨訪或死亡時間。所有組織標本去除壞死組織,用生理鹽水洗去血污并經(jīng)福爾馬林固定后制作石蠟切片。
1.2 方法免疫組織化學(xué)法檢測組織標本中CDK5及EMT相關(guān)蛋白表達。石蠟切片常規(guī)脫蠟水化,枸櫞酸抗原修復(fù)(中杉金橋,北京),3%H2O2孵育,胎牛血清封閉,分別滴加CDK5、N-cadherin、Vimentin及E-cadherin一抗(CST,美國,1∶100稀釋),4℃孵育24 h;PBS充分洗滌,加入生物素標記的二抗(1∶100稀釋),37℃孵育30 min;PBS充分洗滌洗去二抗,加入辣根過氧化物酶標記的三抗(1∶100稀釋),37℃孵育30 min;DAB顯色劑顯色,蘇木素復(fù)染,梯度脫水,封片;DP-70倒置顯微鏡(Olympus,日本)采集圖像。
蛋白表達水平根據(jù)染色水平進行分級。染色結(jié)果根據(jù)染色陽性細胞百分比及染色強度兩個參數(shù)綜合評價。每張切片隨機觀察10個視野,每個視野計數(shù)100個細胞,以10個視野中平均陽性細胞數(shù)計算陽性細胞率。CDK5、N-cadherin及Vimentin表達判定標準[7]:陽性細胞率≤10%評分0,11%~25%評分1,26%~50%評分2,51%~75%評分3,>75%評分4。染色強度評分:無染色評分0;黃色評分1;棕黃色評分2;棕褐色評分3。染色陽性細胞率評分及染色強度評分相乘即為最后評分:0~3分定義為低表達,4~12定義為高表達。E-cadherin表達判定標準[7]:陽性細胞率<10%為低表達,≥10%為高表達。
2.4 HNSCC中CDK5的表達與患者預(yù)后的關(guān)系55例HNSCC患者隨訪時間為3~60個月,中位隨訪時間49個月,失訪1例。CDK5低表達患者和高表達患者的3年生存率分別為87.0%和37.5%,差異有統(tǒng)計學(xué)意義(Log-rank χ2=12.678,P<0.01),見圖2。
2.2 EMT相關(guān)蛋白在HNSCC組織中的表達情況與無淋巴結(jié)轉(zhuǎn)移的HNSCC相比,有淋巴結(jié)轉(zhuǎn)移HNSCC中EMT相關(guān)蛋白N-cadherin、Vimentin表達水平升高,E-cadherin表達水平降低,見圖1。有淋巴結(jié)轉(zhuǎn)移的患者中N-cadherin、Vimentin高表達率高于無淋巴結(jié)轉(zhuǎn)移的患者(75.00%vs 6.98%;91.67%vs 27.91%),E-cadherin高表達率低于無淋巴結(jié)轉(zhuǎn)移的患者(8.33%vs 86.05%),差異有統(tǒng)計學(xué)意義(P<0.05),不同性別、年齡、原發(fā)部位和T分期間EMT相關(guān)蛋白表達差異均無統(tǒng)計學(xué)意義,見表1。
Fig.1Expressions of CDK5 and EMT related proteins were determined by immunohistochemistry in the groups of non-lymph node metastasis(LN-)and lymph node metastasis(LN+)圖1 免疫組化法檢測CDK5與EMT相關(guān)蛋白在無淋巴結(jié)轉(zhuǎn)移及有淋巴結(jié)轉(zhuǎn)移的HNSCC中的表達(SP,×400)
Tab.1Basic characteristics of the 55 HNSCC patients and the expressions of CDK5 and EMT related proteins were determined by immunohistochemistry表1 55例HNSCC患者的臨床病理特征及免疫組化檢測CDK5與EMT相關(guān)蛋白的表達(例)
EMT是腫瘤發(fā)生侵襲、轉(zhuǎn)移的主要因素之一。在EMT過程中,腫瘤細胞由上皮表型向間充質(zhì)表型轉(zhuǎn)化,其特點為間充質(zhì)標志相關(guān)蛋白如N-cadherin、Vimentin表達水平均升高,上皮標志相關(guān)蛋白如E-cadherin表達水平降低[3]。近年來研究發(fā)現(xiàn)在HNSCC[12]、食管癌[7]、乳腺癌[13]、前列腺癌[14]、膀胱癌[15]、肺癌[16-17]、肝癌[18]、膽管癌[19]等多種腫瘤侵襲、轉(zhuǎn)移過程中均出現(xiàn)EMT過程。Zhang等[20]指出內(nèi)皮細胞通過分泌表皮生長因子(EGF)誘導(dǎo)HNSCC細胞的EMT過程,從而促進腫瘤轉(zhuǎn)移。Fujii等[12]發(fā)現(xiàn)在HNSCC中選擇性環(huán)氧化酶2(COX-2)抑制劑可以恢復(fù)E-cadherin的表達,抑制EMT過程,發(fā)揮抗腫瘤轉(zhuǎn)移的作用。本研究發(fā)現(xiàn),與無淋巴結(jié)轉(zhuǎn)移的HNSCC組織比較,有淋巴結(jié)轉(zhuǎn)移的組織中N-cadherin、Vimentin的高表達率升高,E-cadherin的高表達率降低。本研究與相關(guān)研究結(jié)果均表明在HNSCC中EMT相關(guān)蛋白與轉(zhuǎn)移有關(guān)。
率高于無淋巴結(jié)轉(zhuǎn)移的患者(91.67%vs 30.23%,P<0.05);T3~T4期組織中CDK5高表達率高于T1~T2期組織(85%vs 20%,P<0.05);不同性別、年齡和原發(fā)部位間CDK5的表達差異均無統(tǒng)計學(xué)意義。
不久,渡口處又修了一座橋,渡口徹底廢了。擺渡人無事可做,開始上岸活動,看村人播種收割。他喜歡秋天,他說秋天的田野一派金黃,有油畫的美感。
看花卻憶去年事,空堂聽履聲登登。 鼠姑萬朵香爛漫,文梓雙干陰清澄。 重尋古寺餞殘暑,低葵疏蓼秋花凝。 惟有青松與紅杏,摩挲畫卷情難勝。 倚樹老人捻須笑,龕中歲月傳千燈。 吾儕衣鉢今有托,藉湜幸免韓門憎。 壯游山水我更羨,秀語寒餓人將懲。 闍黎有意工閱客,展卷苦道題名曾。[11]
2.3 HNSCC中CDK5與EMT相關(guān)蛋白表達的相關(guān)性55例HNSCC組織標本中,CDK5與N-cadherin、Vimentin表達呈正相關(guān),與E-cadherin表達呈負相關(guān)(rs分別為0.512、0.443、-0.363,均P<0.01)。
1.3 統(tǒng)計學(xué)方法使用SPSS 18.0統(tǒng)計軟件處理數(shù)據(jù)。分類資料組間比較采用χ2檢驗。Spearman等級相關(guān)分析CDK5與EMT相關(guān)蛋白表達的相關(guān)性。Kaplan-Meier法分析CDK5表達與患者生存之間的關(guān)系。P<0.05為差異有統(tǒng)計學(xué)意義。
Fig.2CDK5 expression and Kaplan-Meier analysis圖2 CDK5表達與生存期分析
CDK5作為脯氨酸介導(dǎo)的絲/蘇氨酸蛋白激酶家族中的特殊一員,與p35或p39結(jié)合形成激活復(fù)合體,通過磷酸化黏著斑激酶(FAK)、踝蛋白(talin)、過氧化物酶體增殖物激活受體γ(PPRAγ)及c-Myc等蛋白質(zhì),在神經(jīng)細胞的發(fā)育和分化過程中發(fā)揮作用[8]。近來研究表明,CDK5在乳腺癌[8]、甲狀腺髓樣癌[9]、胰腺癌[10]、肝癌[5]、前列腺癌[11]等多種惡性腫瘤中高表達,在腫瘤的形成過程中起重要作用。Pozo等[9]在對甲狀腺髓樣癌的研究中發(fā)現(xiàn),CDK5可以通過磷酸化視網(wǎng)膜母細胞瘤蛋白(Rb)促進腫瘤的發(fā)生和發(fā)展。Feldmann等[10]發(fā)現(xiàn)在胰腺癌中存在CDK5及其激活因子p35的高表達,下調(diào)CDK5表達能夠抑制胰腺癌中的Ras-Ral信號通路,從而使腫瘤細胞遷移、侵襲能力下降,抑制腫瘤的發(fā)生和轉(zhuǎn)移。上述結(jié)果均表明CDK5的高表達可能是多種腫瘤發(fā)生過程中的分子事件之一,抑制其表達可能成為多種腫瘤基因治療的分子靶點。然而,CDK5在HNSCC中的作用尚不明確。本研究結(jié)果顯示,在HNSCC組織中CDK5的高表達率在有淋巴結(jié)轉(zhuǎn)移的組織中高于無淋巴結(jié)轉(zhuǎn)移的組織,在T分期高的組織中高于T分期低的組織,CDK5低表達的患者3年生存率較高,CDK5可以作為HNSCC患者預(yù)后的預(yù)測因子之一。
2.1 CDK5在HNSCC組織中的表達情況見圖1,表1。HNSCC組織中存在CDK5的表達,CDK5表達水平在有淋巴結(jié)轉(zhuǎn)移的組織中高于無淋巴結(jié)轉(zhuǎn)移的組織。在有淋巴結(jié)轉(zhuǎn)移的患者中CDK5高表達
CDK5可以通過磷酸化FAK的絲氨酸732位點促進EMT進程[8]。在耐藥性三陰乳腺癌中,CDK5能夠提高Vimentin活性,進而誘導(dǎo)EMT過程[21]。本研究發(fā)現(xiàn),HNSCC中CDK5的表達與EMT相關(guān)蛋白N-cadherin、Vimentin表達呈正相關(guān),與E-cadherin表達呈負相關(guān),表明CDK5可能通過某種機制促進HNSCC的EMT過程,進而提高腫瘤的侵襲、轉(zhuǎn)移能力。目前已有研究發(fā)現(xiàn)選擇性CDK抑制劑如Roscovitine(Seliciclib)能夠有效抑制CDK5的活性[22]。
綜上所述,在HNSCC中CDK5與EMT相關(guān)蛋白的表達具有高度相關(guān)性,CDK5可能是HNSCC侵襲、轉(zhuǎn)移的重要分子標志,并可以作為預(yù)測患者生存的指標,而其影響EMT的具體機制是今后進一步研究的方向。CDK5有希望成為HNSCC基因治療的
隨訪期內(nèi),12例(21.1%)患者出現(xiàn)硬膜下積液,硬膜下積液量平均(57.7±48.3) mL(12~167 mL)。其中,5例為少量硬膜下積液[(17±4.7)mL],4例為中等量硬膜下積液[(47.8±7.9)mL],3例為大量硬膜下積液[(128.3±40.1)mL]。
新靶點。
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(2015-08-05收稿 2015-08-26修回)
(本文編輯 李國琪)
CDK5 and epithelial-mesenchymal transition related proteins are abnormally expressed in head and neck squamous cell carcinoma
ZHAO Minghui,HUANG Yuanyuan,SUN Shanshan,KONG Lingping,WANG Yu,GUO Wenyu,ZHOU Xuan,WANG Xudong,ZHANG Lun△
Department of Maxillofacial&E.N.T(ear,nose,and throat)Oncology,Tianjin Medical University Cancer Institute and Hospital;National Clinical Research Center of Cancer;Key Laboratory of Cancer Prevention and Therapy,Tianjin 300060,China△
ObjectiveTo explore the expressions of Cyclin-dependent kinase 5(CDK5)and Epithelial-Mesenchymal Transition(EMT)related proteins including N-cadherin,Vimentin and E-cadherin in head and neck squamous cell carcino-
head and neck neoplasms;carcinoma,squamous cell;cyclin-dependent kinase 5;cadherins;vimentin;lymphatic metastasis
R739.6
A
10.11958/j.issn.0253-9896.2015.12.017
國家自然科學(xué)基金資助項目(81172573)
天津醫(yī)科大學(xué)腫瘤醫(yī)院頜面耳鼻咽喉腫瘤科,國家腫瘤臨床醫(yī)學(xué)研究中心,天津市腫瘤防治重點實驗室(郵編300060)
趙明慧(1990),女,碩士在讀,主要從事頭頸部腫瘤的診治研究
△通訊作者E-mail:Lun_zhang_jing@yahoo.com.cn
ma(HNSCC),and to determine the relationship between the expression of CDK5 and prognosis.MethodsThe expression levels of CDK5 and EMT related proteins were evaluated by immunohistochemistry in 55 patients who were diagnosed as HNSCC.They were also analyzed in different clinical pathological factors.The correlation of CDK5 and EMT related proteins as well as the relationship between the expression of CDK5 and prognosis were also analyzed.ResultsThe expression level of CDK5 was significantly higher in patients with lymph node metastasis than that in patients with non-lymph node metastasis(91.67%vs 30.23%,P<0.05).It’s also higher in T3-T4 stages than that in T1-T2 stages(85%vs 20%,P<0.05).The expression levels of N-cadherin and Vimentin were significantly higher in patients with lymph node metastasis than those in patients with non-lymph node metastasis(75.00%vs 6.98%;91.67%vs 27.91%,all P<0.05).However,the expression level of E-cadherin was significantly lower in patients with lymph node metastasis(8.33%vs 86.05%,P<0.05)compared to that in patients without.CDK5 was positively correlated with N-cadherin and Vimentin,but negatively correlated with E-cadherin(rs=0.512,0.443,-0.363,all P<0.01).The 3-year survival rates were significantly lower in patients with high expression of CDK5(37.5%)than that in patients with low expression of CDK5(87%,Log-rankχ2=12.678,P<0.01).Conclusion CDK5 and EMT related proteins were activated abnormally in HNSCC with lymph node metastasis.CDK5 may be a new biological marker for prognosis of HNSCC.