【摘要】： 目的:喉癌(laryngeal cancer)是來(lái)源于喉黏膜上皮組織的惡性腫瘤,是頭頸部常見的惡性腫瘤,發(fā)病率較高。其病因可能與吸煙、飲酒、空氣污染、職業(yè)因素、病毒感染、放射線等有關(guān)。近年來(lái)喉癌的發(fā)病率有日益增多的趨勢(shì)。喉癌的治療方式主要有手術(shù)、放療等,早期喉癌的治療效果好,晚期喉癌療效較差。喉癌發(fā)生轉(zhuǎn)移是引起病人死亡和治療失敗的主要原因。Raf-1激酶抑制蛋白(Raf-1 kinase inhibitor protein, RKIP )廣泛存在于人體的許多組織中,如:睪丸、腎上腺、肝、腎等。RKIP家族成員在序列上有高度的相似性,在人體中發(fā)揮重要的保守的生物學(xué)功能。最近,在對(duì)前列腺癌、結(jié)直腸癌、乳腺癌、惡性黑素瘤等的研究中,發(fā)現(xiàn)RKIP能夠抑制腫瘤細(xì)胞轉(zhuǎn)移,因此它被認(rèn)為是一種腫瘤轉(zhuǎn)移抑制基因,在惡性腫瘤的發(fā)展和預(yù)后中具有重要的作用。對(duì)于RKIP抑制腫瘤轉(zhuǎn)移的機(jī)制現(xiàn)尚不清楚,在體內(nèi),RKIP參與許多信號(hào)通路的調(diào)節(jié),發(fā)揮重要作用。如RKIP通過(guò)與Raf-1相互作用從而抑制絲裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信號(hào)通路的活性。我們知道MAPK信號(hào)通路參與調(diào)節(jié)細(xì)胞的許多主要功能,如:增殖、分化及凋亡。在30%的腫瘤中該通路發(fā)生改變,并在致癌性轉(zhuǎn)變、侵襲和轉(zhuǎn)移中發(fā)揮重要作用。該通路是通過(guò)Raf-1/MAPK激酶/細(xì)胞外信號(hào)調(diào)節(jié)激酶(extracellular signal-regulated kinase, ERK)三個(gè)激酶的級(jí)聯(lián)反應(yīng)來(lái)發(fā)揮作用的,Raf-1磷酸化后激活MAPK激酶,MAPK激酶磷酸化后進(jìn)一步激活ERK,最后一級(jí)的ERK磷酸化后發(fā)揮作用。本研究探討Raf-1激酶抑制蛋白在喉鱗癌組織、淋巴結(jié)轉(zhuǎn)移灶及正常喉鱗狀上皮中的表達(dá)及其臨床意義。同時(shí)檢測(cè)磷酸化的ERK (phospho-extracellular signal-regulated kinase, P-ERK)來(lái)驗(yàn)證在喉癌中RKIP是否通過(guò)MAPK通路發(fā)揮抑制喉癌轉(zhuǎn)移的作用。 方法:材料來(lái)源于白求恩國(guó)際和平醫(yī)院2007年1月-2009年2月喉癌住院手術(shù)患者41例,這些患者術(shù)前均未進(jìn)行化學(xué)治療和放射治療,所有病例臨床資料完整。采用免疫組化方法(PV法)檢測(cè)41例喉癌患者喉鱗癌組織、淋巴結(jié)轉(zhuǎn)移灶及正常喉黏膜中RKIP的表達(dá)情況。采用免疫組化方法(SP法)檢測(cè)41例喉癌患者喉鱗癌組織、淋巴結(jié)轉(zhuǎn)移灶及正常喉黏膜中P-ERK的表達(dá)情況。 結(jié)果: 1 RKIP的表達(dá) 1.1在正常喉黏膜的鱗狀上皮中,RKIP主要分布于棘細(xì)胞及顆粒細(xì)胞層,而在基底層中表達(dá)陰性。在高分化的腫瘤中,RKIP主要分布于棘細(xì)胞樣及顆粒細(xì)胞樣的腫瘤細(xì)胞中,而在基底層樣細(xì)胞中表達(dá)陰性。在低分化的腫瘤中,表達(dá)多為陰性。 1.2統(tǒng)計(jì)學(xué)分析結(jié)果顯示,喉鱗癌RKIP表達(dá)水平較正常喉黏膜組織明顯降低,差異有統(tǒng)計(jì)學(xué)意義(P=0.012)。41例喉鱗癌中,有轉(zhuǎn)移的喉癌中表達(dá)陽(yáng)性率低于無(wú)轉(zhuǎn)移的喉癌,RKIP表達(dá)存在顯著差異(P=0.016)。有轉(zhuǎn)移的10例中,原發(fā)灶與轉(zhuǎn)移灶相比,RKIP表達(dá)無(wú)顯著差異。RKIP的表達(dá)與性別、年齡、腫瘤發(fā)病部位、T分期、臨床分期等臨床病理因素沒(méi)有直接關(guān)系。 2 P-ERK的表達(dá) 部分正常黏膜組織中,P-ERK集中分布于基底層和靠近基底層的棘細(xì)胞層中。在喉癌中多呈陽(yáng)性或強(qiáng)陽(yáng)性表達(dá)。 3 RKIP與P-ERK相關(guān)性分析 在41例喉癌原發(fā)灶標(biāo)本中,RKIP與P-ERK的表達(dá)情況作Spearman秩相關(guān)分析,結(jié)果P=0.003,r=0.456,有統(tǒng)計(jì)學(xué)意義,可以認(rèn)為兩者呈正相關(guān)性。 結(jié)論: 1與正常喉黏膜組織相比,喉鱗癌RKIP表達(dá)明顯降低。 2 RKIP低表達(dá)的喉癌更容易發(fā)生轉(zhuǎn)移。 3 RKIP的表達(dá)與性別、年齡、腫瘤發(fā)病部位、T分期、臨床分期等臨床病理因素沒(méi)有直接關(guān)系。 4除了通過(guò)調(diào)節(jié)MAPK通路外,RKIP可能通過(guò)執(zhí)行其它未知功能來(lái)抑制喉癌轉(zhuǎn)移的發(fā)生。
[Abstract]:Objective: Laryngeal cer is a malignant tumor derived from the epithelial tissue of the laryngeal mucosa. It is a common malignant tumor of the head and neck. The etiology may be related to smoking, drinking, air pollution, occupational factors, viral infections, radiation, and the like. In recent years, the incidence of laryngeal cancer is increasing. The treatment of laryngeal carcinoma mainly includes operation, radiotherapy and so on, the treatment effect of the early laryngeal carcinoma is good, and the curative effect of the advanced laryngeal carcinoma is poor. The metastasis of the laryngeal carcinoma is the main cause of the death and failure of the patient. Raf-1 kinase inhibitor protein (RKIP) is widely present in many tissues of human body, such as testis, adrenal gland, liver, kidney, etc. The members of the RKIP family have a high degree of similarity in the sequence and play an important and conservative biological function in the human body. Recently, in the study of prostate cancer, colorectal cancer, breast cancer, and malignant melanoma, it is found that RKIP can inhibit the metastasis of tumor cells, so it is considered to be a tumor metastasis suppressor gene, which plays an important role in the development and prognosis of malignant tumors. The mechanism of RKIP to inhibit tumor metastasis is not clear, and in vivo, RKIP plays an important role in the regulation of many signal pathways. RKIP can inhibit the activity of mitogen-activated protein kinase (MAPK) signaling pathway by interacting with Raf-1. We know that MAPK signaling pathway is involved in the regulation of many major functions of the cell, such as proliferation, differentiation and apoptosis. This pathway changes in 30% of the tumors and plays an important role in the carcinogenicity transition, invasion and metastasis. The pathway is a function of the cascade of three kinases of the extracellular signal-regulated kinase (ERK) through the Raf-1/ MAPK kinase/ extracellular signal-regulated kinase (ERK), and after the phosphorylation of Raf-1, the MAPK kinase is activated, and the ERK is further activated after the phosphorylation of the MAPK kinase, and the ERK at the last stage plays a role. The expression and clinical significance of Raf-1 kinase inhibitor in laryngeal squamous cell carcinoma, lymph node metastasis and normal laryngeal squamous epithelium were discussed in this study. Phosphorylated ERK (P-ERK) was also used to verify the role of RKIP in laryngeal carcinoma to inhibit the metastasis of laryngeal carcinoma. Methods: The materials were from the Bethune International Peace Hospital from January 2007 to February 2009. The expression of RKIP in laryngeal squamous cell carcinoma, lymph node metastasis and normal laryngeal mucosa in 41 patients with laryngeal carcinoma was detected by immunohistochemical method (PV method). Expression of P-ERK in laryngeal squamous cell carcinoma, lymph node metastasis and normal laryngeal mucosa in 41 patients with laryngeal carcinoma by immunohistochemistry (SP method) expression condition The expression of 1. 1 RKIP was 1. 1 in the squamous epithelium of normal laryngeal mucosa, RKIP was mainly distributed in the spine. In high-differentiated tumors, RKIP is mainly distributed in the cell-like and granular-like cells. in tumor cell, and in basal cell-like cells The results showed that the expression of RKIP in laryngeal squamous cell carcinoma was significantly lower than that of normal laryngeal mucosa (P = 0.012). In 41 cases of laryngeal squamous cell carcinoma, the positive rate of expression in laryngeal squamous cell carcinoma was lower than that of non-metastatic laryngeal carcinoma. There was a significant difference between the expression of RKIP and the expression of RKIP (P = 0.016). In the case, there was no significant difference in the expression of RKIP compared with the metastatic focus. The expression of RKIP was related to sex, age, and tumor. Site, T staging, clinical the clinical and pathological factors such as stage were not directly related. The expression of P-ERK P-ERK set in normal mucosal tissue a fine band distributed in the base layer and adjacent to the base layer The expression of RKIP and P-ERK in laryngeal carcinoma was analyzed in 41 patients with laryngeal carcinoma, and the expression of RKIP and P-ERK was used as the expression of Spearm. an縐，

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