本文選題：肝再生磷酸酶-3 + 基質(zhì)金屬蛋白酶-14��； 參考：《鄭州大學(xué)》2011年碩士論文

【摘要】：喉鱗狀細(xì)胞癌是頭頸部最常見的惡性腫瘤之一,95%-98%的喉部惡性腫瘤為鱗狀細(xì)胞癌,目前其主要的治療手段是以根治性手術(shù)輔以放療或精確的放療為主,在早期患者可以獲得比較好的局部控制率,但不能預(yù)防或減少遠(yuǎn)處轉(zhuǎn)移,對于中晚期患者常規(guī)治療的療效不盡人意,大概局部復(fù)發(fā)率27-61%、遠(yuǎn)處轉(zhuǎn)移率18-21%、五年生存率27-34%,隨著腫瘤生物學(xué)的發(fā)展許多生物學(xué)治療的新技術(shù)運(yùn)用到臨床,實(shí)際運(yùn)用中許多現(xiàn)象和結(jié)果至今都無法解釋。 頭頸部腫瘤的浸潤和轉(zhuǎn)移是影響患者生存率的主要原因,但腫瘤由原發(fā)灶向周邊組織浸潤以致發(fā)生遠(yuǎn)處轉(zhuǎn)移的機(jī)制目前尚未清楚,癌細(xì)胞是如何獲得浸潤能力的尚不清楚!探索新的、特異性高的腫瘤標(biāo)志物,對提高喉癌患者的預(yù)后和進(jìn)一步明確喉癌由原發(fā)灶向周邊組織浸潤以致發(fā)生遠(yuǎn)處轉(zhuǎn)移的機(jī)制有重要意義。 肝再生磷酸酶-3(PhosPhatase of regenerating liver-3, PRL-3)是新近發(fā)現(xiàn)的蛋白酪氨酸磷酸酶,其通過蛋白去磷酸化實(shí)現(xiàn)調(diào)節(jié)蛋白功能,參與各種細(xì)胞的生命活動,研究表明,PRL-3通過促進(jìn)細(xì)胞增殖、遷移、侵襲、粘附及血管生成等途徑參與了多種腫瘤的發(fā)生,浸潤及轉(zhuǎn)移。 基質(zhì)金屬蛋白酶-14(Matrix metailo Proteinase-14, MMP-14)屬膜型基質(zhì)金屬蛋白酶類,存在于細(xì)胞膜上,是一種跨膜蛋白,具有降解細(xì)胞外基質(zhì)的能力,這是惡性腫瘤形成的必須條件之一。 CD105又名endoglin,是一種糖蛋白,CD105陽性染色主要定位于新生血管內(nèi)皮細(xì)胞的細(xì)胞膜和細(xì)胞質(zhì),在大血管內(nèi)皮細(xì)胞中不表達(dá),是理想的血管內(nèi)皮細(xì)胞標(biāo)記物,是計(jì)數(shù)腫瘤微血管密度(MVD)的金標(biāo)準(zhǔn)即CD105-MVD。 目前,國內(nèi)外關(guān)于PRL-3的研究主要集中在腺癌方面,其在鱗癌方面的研究尚少,在喉鱗癌方面的研究國內(nèi)外還未見報(bào)道。PRL-3參與腫瘤浸潤和轉(zhuǎn)移的機(jī)制尚不清楚,有文獻(xiàn)報(bào)道PRL-3可能通過基質(zhì)金屬蛋白酶和血管生成途徑參與腫瘤的浸潤和轉(zhuǎn)移,但PRL-3、MMP-14及CD105在喉鱗癌中的表達(dá)及相關(guān)性尚未見報(bào)道。本課題應(yīng)用HE染色和免疫組化法對人喉鱗癌中的PRL-3、MMP-14蛋白的表達(dá)進(jìn)行檢測,并用CD105標(biāo)記腫瘤組織的微血管密度(CD105-MVD),旨在探索其與人喉癌的發(fā)生、浸潤和轉(zhuǎn)移的關(guān)系,尋找可能預(yù)測喉癌浸潤和轉(zhuǎn)移的腫瘤標(biāo)志物,為喉鱗癌患者的預(yù)后提供有益的觀測指標(biāo),并為進(jìn)一步的機(jī)制研究提供理論依據(jù)。 目的 檢測PRL-3、MMP-14在人喉鱗癌、相應(yīng)癌旁組織和正常喉黏膜組織中的表達(dá),并用CD105標(biāo)記微血管密度(CD105-MVD),探討PRL-3、MMP-14和CD105-MVD在喉鱗狀細(xì)胞癌各臨床病理因素中的作用及相關(guān)性,旨在探索其與人喉癌的發(fā)生、浸潤及轉(zhuǎn)移的關(guān)系,尋找可能預(yù)測喉癌浸潤和轉(zhuǎn)移的腫瘤標(biāo)志物,為喉鱗癌患者的預(yù)后提供有益的觀測指標(biāo),并為進(jìn)一步的機(jī)制研究提供理論依據(jù)。 材料與方法 1、研究對象 選擇鄭州大學(xué)第一附屬醫(yī)院2006年1月～2008年12月收治的69例喉鱗狀細(xì)胞癌患者的癌組織蠟塊標(biāo)本,其中高分化鱗狀細(xì)胞癌28例,中-低分化鱗狀細(xì)胞癌41例(低分化癌病例較少,與中分化病例合為中-低分化組)。伴淋巴結(jié)轉(zhuǎn)移陽性者25例,淋巴結(jié)轉(zhuǎn)移陰性者44例。按國際抗癌協(xié)會(UICC) TNM分類標(biāo)準(zhǔn)(2002)分期：Ⅰ期11例,Ⅱ期15例,Ⅲ期27例,Ⅳ期16例。病人年齡在40歲至84歲之間(平均62歲),男67例,女2例,所有患者臨床資料完整,術(shù)前均未作放療、化療及任何免疫治療。另取35例同批患者的癌旁組織,32例正常喉黏膜組織作對照,癌旁組織取自肉眼觀察距腫瘤邊緣1.0 cm以外的喉黏膜組織,均經(jīng)病理證實(shí)為鱗狀上皮不典型增生,未發(fā)現(xiàn)癌細(xì)胞。 2、實(shí)驗(yàn)方法 采用免疫組織化學(xué)方法檢測69例人喉鱗狀細(xì)胞癌組織、35例相應(yīng)癌旁組織和32例正常喉黏膜組織中PRL-3和MMP-14的表達(dá)情況,并用CD105作為血管內(nèi)皮標(biāo)記物對喉癌組織的MVD進(jìn)行標(biāo)記,結(jié)合臨床病理因素分析。 3、統(tǒng)計(jì)學(xué)處理 采用SPSS18.0軟件包進(jìn)行統(tǒng)計(jì)分析,樣本率的比較采用x檢驗(yàn),計(jì)量資料用x±s表示,均數(shù)比較采用t驗(yàn),PRL-3、MMP-14與CD105-MVD相關(guān)性采用Spearman等級相關(guān)分析,以a=0.05為檢驗(yàn)水準(zhǔn)。 結(jié)果 1、PRL-3在喉鱗癌組織中的陽性表達(dá)率(65.22%)高于癌旁組織(17.14%)和正常喉黏膜組織(15.63%),差異有統(tǒng)計(jì)學(xué)意義(P0.01)。淋巴結(jié)轉(zhuǎn)移組的PRL-3陽性表達(dá)率明顯高于無淋巴結(jié)轉(zhuǎn)移組,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。PRL-3的表達(dá)與病理分期、組織分化程度及淋巴結(jié)轉(zhuǎn)移相關(guān),與腫瘤原發(fā)部位、性別及年齡無關(guān)。 2、MMP-14在喉鱗癌組織中的陽性表達(dá)率(76.81%)高于癌旁組織(31.43%)和正常喉黏膜組織(25.00%),差異顯著,有統(tǒng)計(jì)學(xué)意義(P0.01)。淋巴結(jié)轉(zhuǎn)移陽性組的MMP-14蛋白陽性表達(dá)率明顯高于淋巴結(jié)轉(zhuǎn)移陰性組,差異顯著,具有統(tǒng)計(jì)學(xué)意義(P0.05)。MMP-14的表達(dá)與病理分期、組織分化程度和淋巴結(jié)轉(zhuǎn)移相關(guān),與腫瘤原發(fā)部位、性別及年齡無關(guān)。 3、臨床病理分期較晚的Ⅲ～Ⅳ的CD105-MVD (12.7907±4.16080)明顯高于Ⅰ～Ⅱ期(9.8846±4.13112),淋巴結(jié)轉(zhuǎn)移陽性組的CD105-MVD(13.4000±4.36845)高于無淋巴結(jié)轉(zhuǎn)移組(10.7273±4.08835),差異均有統(tǒng)計(jì)學(xué)意義(P0.05或P0.01)。CD105-MVD值與分化程度、原發(fā)部位、年齡及性別無關(guān),比較差異無統(tǒng)計(jì)學(xué)意義(P0.05)。 4、PRL-3表達(dá)與CD105-MVD呈正相關(guān)(γs=0.811,P0.01)；MMP-14表達(dá)與CD105-MVD呈正相關(guān)(r=0.867,P0.01)； 5、PRL-3蛋白與MMP-14蛋白的陽性表達(dá)率差異無統(tǒng)計(jì)學(xué)意義(P0.05),但PRL-3蛋白的表達(dá)與MMP-14的表達(dá)呈正相關(guān)(r=0.367,P0.01)。 1、PRL-3、MMP-14參與了喉鱗狀細(xì)胞癌的發(fā)生、浸潤及轉(zhuǎn)移,對喉鱗癌的診斷有重要參考價(jià)值； 2、PRL-3與MMP-14的表達(dá)呈正相關(guān),二者可能促進(jìn)喉癌的浸潤和轉(zhuǎn)移,可聯(lián)合作為喉鱗癌標(biāo)志物,對臨床治療方案的選擇及評估預(yù)后有一定的參考價(jià)值； 3、CD105是理想的腫瘤新生血管標(biāo)記物,CD105-MVD可作為預(yù)測喉癌轉(zhuǎn)移及評估預(yù)后的重要指標(biāo)； 4、PRL-3、MMP-14與腫瘤血管的形成密切相關(guān),在喉鱗狀細(xì)胞癌形成中起重要作用。
[Abstract]:Laryngeal squamous cell carcinoma (laryngeal squamous cell carcinoma) is one of the most common malignant tumors in the head and neck. The malignant tumor of the larynx of 95%-98% is squamous cell carcinoma. At present, the main means of treatment are radical surgery supplemented by radiotherapy or precise radiotherapy, and a better local control rate can be obtained in early patients, but it can not prevent or reduce distant metastasis. The curative effect of conventional treatment in advanced patients is not satisfactory, the local recurrence rate is 27-61%, the distant metastasis rate is 18-21%, the five year survival rate is 27-34%. With the development of tumor biology, many new techniques of biological treatment are applied to the clinic. Many phenomena and results are not explained so far in practical application.
The invasion and metastasis of the head and neck tumors are the main factors that affect the survival rate of the patients. However, the mechanism of tumor invasion from the primary tissue to the peripheral tissue and the distant metastasis is not yet clear. It is not clear how the cancer cells can obtain the infiltration capacity. Explore new, high specific tumor markers to improve the prognosis and advance of the patients with larynx cancer. One step is to clarify the mechanism of laryngeal cancer infiltrating from the primary to the surrounding tissues, leading to distant metastasis.
The liver regenerative phosphatase -3 (PhosPhatase of regenerating liver-3, PRL-3) is a newly discovered protein tyrosine phosphatase, which regulates protein function through protein dephosphorylation and participates in the life activities of various cells. The study shows that PRL-3 has been involved in many swells by promoting cell proliferation, migration, invasion, adhesion and angiogenesis. The occurrence, infiltration and metastasis of the tumor.
Matrix metalloproteinase -14 (Matrix metailo Proteinase-14 (MMP-14)) is a membrane type matrix metalloproteinase, which exists on the cell membrane. It is a transmembrane protein and has the ability to degrade the extracellular matrix, which is one of the necessary conditions for the formation of malignant tumors.
CD105, also known as endoglin, is a kind of glycoprotein. CD105 positive staining is mainly located in the cell membrane and cytoplasm of the neovascular endothelial cells. It is not expressed in the large vascular endothelial cells. It is an ideal vascular endothelial cell marker. It is the golden standard for counting the tumor microvascular density (MVD), that is, CD105-MVD.
At present, domestic and foreign research on PRL-3 mainly focuses on adenocarcinoma, and its research on squamous cell carcinoma is few. There is no report on the mechanism of.PRL-3 involvement in tumor invasion and metastasis at home and abroad. It is reported that PRL-3 may be involved in tumor infiltration through matrix metalloproteinase and angiogenesis pathway. The expression and correlation of PRL-3, MMP-14 and CD105 in laryngeal squamous cell carcinoma have not yet been reported. The purpose of this study was to detect the expression of PRL-3, MMP-14 protein in human laryngeal squamous cell carcinoma by HE staining and immunohistochemical method, and to mark the microvascular density (CD105-MVD) of the tumor tissue with CD105 in order to explore the occurrence, infiltration and metastasis of human larynx cancer. The relationship is to find the tumor markers that may predict the invasion and metastasis of laryngeal carcinoma, providing useful observations for the prognosis of the patients with laryngeal squamous cell carcinoma and providing a theoretical basis for further mechanism research.
objective
The expression of PRL-3 and MMP-14 in human laryngeal squamous cell carcinoma, corresponding paracancerous tissue and normal laryngeal mucosa, and CD105 labeled microvascular density (CD105-MVD) were used to explore the role and correlation of PRL-3, MMP-14 and CD105-MVD in the various clinicopathological factors of laryngeal squamous cell carcinoma, in order to explore the relationship with the occurrence, infiltration and metastasis of human larynx cancer. The tumor markers that may predict the invasion and metastasis of laryngeal carcinoma provide useful observations for the prognosis of the patients with laryngeal squamous cell carcinoma and provide a theoretical basis for further mechanism research.
Materials and methods
1, the object of research
69 cases of squamous cell carcinoma of the larynx were selected from the First Affiliated Hospital of Zhengzhou University from January 2006 to December 2008, including 28 cases of highly differentiated squamous cell carcinoma, 41 cases of medium low differentiated squamous cell carcinoma (low differentiated carcinoma cases, middle and low differentiation with middle differentiation cases). 25 cases with lymph node metastasis were found. According to the international anticancer association (UICC) TNM classification standard (UICC) classification standard (2002) stage: 11 cases, 15 cases in stage II, 27 cases in stage III, 16 cases in stage IV. The patients were aged from 40 to 84 years (average 62 years old), 67 men and 2 cases, all patients were complete with clinical data, no preoperative radiotherapy, chemotherapy and any immunotherapy. And 35 cases of the same batch In the para cancerous tissue, 32 normal laryngeal mucosa tissues were compared. The para cancerous tissue was taken from the naked eye to observe the laryngeal mucosa outside the tumor margin 1 cm from the tumor. All of them were proved to be atypical hyperplasia of squamous epithelium by pathology, and no cancer cells were found.
2, experimental method
The expression of PRL-3 and MMP-14 in 69 cases of human laryngeal squamous cell carcinoma (laryngeal squamous cell carcinoma), 35 cases of corresponding para cancerous tissue and 32 normal laryngeal mucosa tissues were detected by immunohistochemistry. The MVD of laryngeal carcinoma tissue was labeled with CD105 as vascular endothelial marker, combined with clinicopathological analysis.
3, statistical treatment
The SPSS18.0 software package was used for statistical analysis. The comparison of sample rate was compared with X test. The measurement data was expressed in X + s. The average number was compared to t, PRL-3, MMP-14 and CD105-MVD, and a=0.05 was used as the test level.
Result
1, the positive expression rate of PRL-3 in laryngeal squamous cell carcinoma (65.22%) was higher than that of paracancerous tissue (17.14%) and normal laryngeal mucosa (15.63%). The difference was statistically significant (P0.01). The positive rate of PRL-3 in the lymph node metastasis group was significantly higher than that in the non lymph node metastasis group, and the difference was statistically significant (P0.05).PRL-3 expression and pathological stage, tissue differentiation. The degree and lymph node metastasis were not related to the primary location, sex and age of the tumor.
2, the positive expression rate of MMP-14 in the laryngeal squamous cell carcinoma (76.81%) was higher than that of the paracancerous tissue (31.43%) and normal laryngeal mucosa (25%). The difference was significant (P0.01). The positive rate of MMP-14 protein in the lymph node metastasis positive group was significantly higher than that of the lymph node metastasis negative group, and the difference was significant (P0.05).MMP-14 table It was related to pathological stage, histological differentiation and lymph node metastasis, and was not related to the primary location, sex and age of the tumor.
3, CD105-MVD (12.7907 + 4.16080) of late stage of clinicopathological stage (12.7907 + 4.16080) was significantly higher than that of stage I to II (9.8846 + 4.13112), CD105-MVD (13.4000 + 4.36845) of lymph node metastasis positive group was higher than that of no lymph node metastasis group (10.7273 + 4.08835). The difference was statistically significant (P0.05 or P0.01).CD105-MVD value and differentiation degree, primary site, year Age and sex were not related, the difference was not statistically significant (P0.05).
4, PRL-3 expression was positively correlated with CD105-MVD (gamma s=0.811, P0.01); MMP-14 expression was positively correlated with CD105-MVD (r=0.867, P0.01).
5, there was no significant difference in the positive expression rate of PRL-3 protein and MMP-14 protein (P0.05), but the expression of PRL-3 protein was positively correlated with the expression of MMP-14 (r=0.367, P0.01).
1, PRL-3 and MMP-14 participate in the occurrence, invasion and metastasis of laryngeal squamous cell carcinoma, and have important reference value for the diagnosis of laryngeal squamous cell carcinoma.
2, the expression of PRL-3 is positively correlated with the expression of MMP-14. The two may promote the invasion and metastasis of larynx cancer, and can be combined as a marker of laryngeal squamous cell carcinoma, which has a certain reference value for the selection of clinical treatment scheme and evaluation of prognosis.
3, CD105 is an ideal marker for tumor angiogenesis. CD105-MVD can be used as an important indicator for predicting metastasis and evaluating prognosis of laryngeal carcinoma.
4, PRL-3 and MMP-14 are closely related to tumor angiogenesis and play an important role in the formation of laryngeal squamous cell carcinoma.
【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2011
【分類號】：R739.65

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