發(fā)布時(shí)間：2018-04-24 05:24

  本文選題：宮頸癌 + 細(xì)胞自噬��； 參考：《鄭州大學(xué)》2015年博士論文

【摘要】：研究背景宮頸癌發(fā)病率及死亡率居全球女性惡性腫瘤的第二位,在我國(guó)則居于女性生殖系統(tǒng)惡性腫瘤的第一位,因此,如何采取有效措施降低宮頸癌的發(fā)病率與死亡率,已經(jīng)成為重要的社會(huì)公共健康問(wèn)題。細(xì)胞自噬是實(shí)現(xiàn)細(xì)胞的代謝和細(xì)胞器的新舊交替,維持細(xì)胞自身穩(wěn)定的生物學(xué)過(guò)程。自噬及相關(guān)蛋白的表達(dá)情況,與多種疾病特別是惡性腫瘤的發(fā)生、發(fā)展密切相關(guān)。Beclin1是自噬體在形成過(guò)程中的一個(gè)重要蛋白,它可以促進(jìn)自噬前體的形成,調(diào)控自噬體的形成和成熟過(guò)程;p62是一種選擇性自噬受體,主要參與細(xì)胞內(nèi)膜膜流、DNA修復(fù)、介導(dǎo)泛素化蛋白等自噬降解過(guò)程,是反映自噬活性的標(biāo)記性蛋白;LC-3由LC-3-Ⅰ和LC-3-II組成,主要參與自噬體的形成。由于LC-3-II的含量與自噬小泡的數(shù)量成正比,因此LC-3(主要是LC-3-II)常作為評(píng)價(jià)自噬活性的重要指標(biāo)。進(jìn)行自噬相關(guān)蛋白表達(dá)如Beclin1、p62及LC-3蛋白表達(dá)與宮頸癌的相關(guān)性研究,可以進(jìn)一步揭示宮頸癌發(fā)生和發(fā)展機(jī)制,為宮頸癌的預(yù)后判斷、有效預(yù)防及尋找宮頸癌治療新靶點(diǎn)提供依據(jù)。擴(kuò)散加權(quán)成像(DWI)是目前唯一能夠在體外測(cè)定活體組織內(nèi)水分子擴(kuò)散情況的影像學(xué)檢查技術(shù),通過(guò)對(duì)宮頸癌DWI圖像表觀擴(kuò)散系數(shù)(ADC)值的定量分析,可以較為準(zhǔn)確地反映有關(guān)宮頸癌腫瘤的功能性改變,但能否用于對(duì)宮頸癌預(yù)后的預(yù)測(cè)和評(píng)價(jià)方面,尚缺乏相關(guān)的研究性證據(jù)。本研究采用免疫組化方法探討自噬相關(guān)蛋白Beclin1、p62和LC-3在正常子宮頸組織、宮頸上皮內(nèi)瘤變(CIN)、子宮頸鱗狀細(xì)胞癌組織中的陽(yáng)性表達(dá)情況,分析上述三種蛋白與宮頸癌臨床病理因素之間的關(guān)系,以及對(duì)宮頸癌生存和預(yù)后的影響。同時(shí)利用磁共振擴(kuò)散加權(quán)成像(DWI)對(duì)不同分化程度子宮頸鱗狀細(xì)胞癌的ADC值進(jìn)行測(cè)定,探討自噬相關(guān)蛋白與功能磁共振定量參數(shù)間的關(guān)系,為宮頸癌的轉(zhuǎn)化醫(yī)學(xué)研究提供新的思路和方法。目的觀察beclin1、p62及l(fā)c-3在正常子宮頸、cin和宮頸癌中的陽(yáng)性表達(dá)情況,分析上述三種自噬相關(guān)蛋白的表達(dá)與宮頸癌臨床病理因素之間的關(guān)系,以及對(duì)宮頸癌生存和預(yù)后的影響。測(cè)定高、中、低分化子宮頸鱗狀細(xì)胞癌患者的adc值并進(jìn)行分析比較,同時(shí)研究宮頸癌自噬相關(guān)蛋白表達(dá)與adc值間的相關(guān)性。由此探討擴(kuò)散加權(quán)成像及自噬相關(guān)蛋白表達(dá)在宮頸癌中的價(jià)值。材料與方法采用免疫組化sp法對(duì)宮頸癌組(子宮頸鱗狀細(xì)胞癌)標(biāo)本191例、cin組標(biāo)本63例和正常子宮頸組標(biāo)本32例進(jìn)行beclin1、p62及l(fā)c-3蛋白陽(yáng)性表達(dá)的標(biāo)記和半定量評(píng)分比較,分析上述三種蛋白表達(dá)與患者臨床病理因素之間的關(guān)系,以及對(duì)宮頸癌組患者總生存時(shí)間和無(wú)進(jìn)展生存時(shí)間的影響。同時(shí)將宮頸癌組患者dwi影像資料后處理所得adc值與自噬相關(guān)蛋白表達(dá)進(jìn)行分析比較。結(jié)果1.beclin1蛋白定位于細(xì)胞膜及細(xì)胞質(zhì)中,在正常子宮頸組、cin組及宮頸癌組的陽(yáng)性表達(dá)率分別為31.3%、36.5%和19.4%,具有統(tǒng)計(jì)學(xué)差異(x2=19.323,p=0.000)。beclin1蛋白在宮頸癌組陽(yáng)性表達(dá)的評(píng)分值低于正常子宮頸組及cin組(p0.01,p0.001),而且陽(yáng)性表達(dá)與患者的年齡、腫瘤分化、figo分期、sccag值、腫瘤直徑、肌層浸潤(rùn)深度、手術(shù)切緣、死亡無(wú)統(tǒng)計(jì)學(xué)差異(p值均0.05),與淋巴結(jié)轉(zhuǎn)移和復(fù)發(fā)有統(tǒng)計(jì)學(xué)差異(p值均0.05)。2.p62蛋白定位于細(xì)胞質(zhì)和細(xì)胞核中,在正常子宮頸組、cin組及宮頸癌組的陽(yáng)性表達(dá)率分別為65.6%、65.1%、73.8%,具有統(tǒng)計(jì)學(xué)差異(x2=9.617,p0.01)。p62蛋白在宮頸癌組陽(yáng)性表達(dá)的評(píng)分值高于正常子宮頸組與cin組(p值均0.01),并且陽(yáng)性表達(dá)與患者的年齡、腫瘤分化、figo分期、腫瘤直徑、肌層浸潤(rùn)深度、手術(shù)切緣、死亡無(wú)統(tǒng)計(jì)學(xué)差異(p值均0.05),與sccag值、淋巴結(jié)轉(zhuǎn)移和復(fù)發(fā)有統(tǒng)計(jì)學(xué)差異(p值均0.05)。3.lc-3蛋白定位于細(xì)胞質(zhì)和細(xì)胞核中,在正常子宮頸組、cin組及宮頸癌組的陽(yáng)性表達(dá)率分別為84.4%、73.0%、50.3%,具有統(tǒng)計(jì)學(xué)差異(x2=36.291,p=0.000)。lc-3蛋白在宮頸癌組陽(yáng)性表達(dá)的評(píng)分值低于正常子宮頸組及cin組(P0.001,P0.01),而且與患者的年齡、FIGO分期、SCCAg值、腫瘤直徑、手術(shù)切緣、死亡無(wú)統(tǒng)計(jì)學(xué)差異(P值均0.05),與腫瘤分化、淋巴結(jié)轉(zhuǎn)移、肌層浸潤(rùn)深度及復(fù)發(fā)有統(tǒng)計(jì)學(xué)差異(P值均0.05)。4.腫瘤分化、淋巴結(jié)轉(zhuǎn)移、LC-3表達(dá)是影響總生存時(shí)間的危險(xiǎn)因素(P值均0.05),年齡、FIGO分期、SCCAg值、腫瘤直徑、肌層浸潤(rùn)深度、手術(shù)切緣、Beclin1表達(dá)和p62表達(dá)與總生存時(shí)間無(wú)統(tǒng)計(jì)學(xué)差異(P值均0.05);SCCAg值、淋巴結(jié)轉(zhuǎn)移、Beclin1表達(dá)、p62表達(dá)和LC-3表達(dá)是影響宮頸癌組患者無(wú)進(jìn)展生存時(shí)間的危險(xiǎn)因素(P值均0.05);年齡、腫瘤分化、FIGO分期、腫瘤直徑、肌層浸潤(rùn)深度和手術(shù)切緣與無(wú)進(jìn)展生存時(shí)間無(wú)統(tǒng)計(jì)學(xué)差異(P值均0.05)。5.宮頸癌組患者中高分化宮頸癌患者的平均ADC值中分化宮頸癌患者的平均ADC值低分化宮頸癌患者的平均ADC值(P0.05)。6.在宮頸癌組中,高分化患者的LC-3陽(yáng)性表達(dá)與ADC值無(wú)統(tǒng)計(jì)學(xué)差異,中、低分化患者中LC-3陽(yáng)性表達(dá)與ADC值間有統(tǒng)計(jì)學(xué)差異(P0.05)。結(jié)論1.Beclin1蛋白在子宮頸鱗狀細(xì)胞癌組織中呈現(xiàn)低表達(dá),與腫瘤的淋巴結(jié)轉(zhuǎn)移和復(fù)發(fā)具有統(tǒng)計(jì)學(xué)差異,且是影響無(wú)進(jìn)展生存時(shí)間的危險(xiǎn)因素,說(shuō)明Beclin1蛋白可能與宮頸癌的發(fā)生及發(fā)展密切相關(guān)。2.p62蛋白在子宮頸鱗狀細(xì)胞癌組織中呈現(xiàn)高表達(dá),與腫瘤的淋巴結(jié)轉(zhuǎn)移、SCCAg值和腫瘤的復(fù)發(fā)具有統(tǒng)計(jì)學(xué)差異,且是影響無(wú)進(jìn)展生存時(shí)間的危險(xiǎn)因素,說(shuō)明p62蛋白可能與宮頸癌的發(fā)展及預(yù)后相關(guān)。3.LC-3蛋白在子宮頸鱗狀細(xì)胞癌組織中呈現(xiàn)低表達(dá),與腫瘤的分化、淋巴結(jié)轉(zhuǎn)移、肌層浸潤(rùn)深度和復(fù)發(fā)具有統(tǒng)計(jì)學(xué)差異,且是影響總生存時(shí)間及無(wú)進(jìn)展生存時(shí)間的危險(xiǎn)因素,說(shuō)明LC-3蛋白與宮頸癌的發(fā)生、發(fā)展及預(yù)后密切相關(guān)。4.ADC值測(cè)定不僅可用于判斷子宮頸鱗狀細(xì)胞癌的分化程度,而且與LC結(jié)合可能可以用于宮頸癌的預(yù)后評(píng)估。
[Abstract]:Background the incidence and mortality of cervical cancer are the second most malignant tumors in the world. In our country, it is the first of the female reproductive system malignant tumors. Therefore, how to take effective measures to reduce the incidence and mortality of cervical cancer has become an important social public health problem. Cell autophagy is the realization of cell metabolism and the development of cell autophagy. The new and old alternation of organelles, the biological process of maintaining cell self stability. The expression of autophagy and related proteins, and the development of.Beclin1 is an important protein in the formation of autophagic bodies, which can promote the formation of autophagic precursors and regulate the formation and maturation of autophagic bodies. Process; p62 is a selective autophagy receptor, which is mainly involved in the cell membrane flow, DNA repair, and ubiquitination protein, which is a marker protein reflecting autophagic activity; LC-3 is composed of LC-3- I and LC-3-II and is mainly involved in the formation of autophagic. As the content of LC-3-II is proportional to the number of autophagic vesicles, LC-3 (principal) If LC-3-II) is often used as an important indicator of autophagic activity, the correlation between the expression of autophagy related protein, such as Beclin1, p62 and LC-3 protein expression and cervical cancer, can further reveal the mechanism of cervical cancer development and development, and provide a basis for the prognosis of cervical cancer, the effective prevention and search for new targets for cervical cancer treatment. Right imaging (DWI) is the only imaging technique that can determine the diffusion of water molecules in living tissues in vitro. By quantitative analysis of the apparent diffusion coefficient (ADC) value of the DWI image of cervical cancer, the functional alteration of cervical cancer can be accurately reflected, but it can be used to predict and evaluate the prognosis of cervical cancer. In this study, there is still a lack of relevant research evidence. In this study, the immunohistochemical method was used to investigate the positive expression of autophagy related protein Beclin1, p62 and LC-3 in normal cervical tissue, cervical intraepithelial neoplasia (CIN), cervical squamous cell carcinoma, and analysis of the relationship between the three proteins and the clinicopathological factors of cervical cancer, and the relationship between these proteins and the clinicopathological factors of cervical cancer, and The effects on the survival and prognosis of cervical cancer. At the same time, the ADC value of cervical squamous cell carcinoma with different degree of differentiation was measured by magnetic resonance diffusion weighted imaging (DWI). The relationship between autophagy related proteins and quantitative parameters of functional magnetic resonance (fMRI) was explored to provide new ideas and methods for the research of the transformation medicine of cervical cancer. The purpose of this study was to observe Beclin1, p62 And the positive expression of LC-3 in normal cervix, CIN and cervical cancer. The relationship between the expression of the three autophagy related proteins and the clinicopathological factors of cervical cancer, and the influence on the survival and prognosis of cervical cancer. The ADC value of the patients with high, medium and low differentiated cervical squamous cell carcinoma was analyzed and compared, and the study of the uterus was also studied. The correlation between the expression of autophagy related protein and the value of ADC in cervical cancer. The value of DWI and autophagy related protein expression in cervical cancer was discussed. Materials and methods were treated by immunohistochemical SP method in 191 specimens of cervical cancer group (cervical squamous cell carcinoma), 63 cases in group CIN and 32 cases of normal cervix group for Beclin1, p62 and l C-3 protein positive expression and semi quantitative comparison were used to analyze the relationship between the three protein expressions and the patients' clinicopathological factors, as well as the total survival time and the progression free survival time of the patients with cervical cancer group. At the same time, the ADC value of the DWI image data in the cervical cancer group was expressed with the autophagy related protein. Results 1.beclin1 protein was located in the cell membrane and cytoplasm. The positive expression rate in the normal cervical group, the CIN group and the cervical cancer group were 31.3%, 36.5% and 19.4% respectively. The statistical difference (x2=19.323, p=0.000) was lower than the normal cervix group and the CIN group (P0.01, p0.00) in the cervical cancer group. 1) and positive expression with the patient's age, tumor differentiation, FIGO staging, SCCAg value, tumor diameter, myometrium infiltration depth, surgical margin, death without statistical difference (P value is 0.05), and lymph node metastasis and recurrence (both P 0.05).2.p62 protein located in the cytoplasm and nucleus, in the normal cervix group, CIN group and cervix. The positive expression rates of the cancer group were 65.6%, 65.1% and 73.8% respectively. The positive expression of.P62 protein in the cervical cancer group was higher than that of the normal cervical group and the CIN group (P value of 0.01), and the positive expression was with the age of the patients, the tumor differentiation, the FIGO stage, the tumor diameter, the depth of the myometrium infiltration, the surgical margin and death. Statistical difference (P value was 0.05), and SCCAg value, lymph node metastasis and recurrence were statistically different (P value was 0.05).3.lc-3 protein located in cytoplasm and nucleus, in normal cervical group, CIN group and cervical cancer group positive expression rate was 84.4%, 73%, 50.3%, with statistical difference (x2=36.291, p=0.000).Lc-3 protein in cervical cancer group The score of positive expression was lower than that of normal cervix group and CIN group (P0.001, P0.01), and there was no statistical difference between the patients' age, FIGO staging, SCCAg value, tumor diameter, surgical margin and death (P value was 0.05). There were statistical differences with tumor differentiation, lymph node metastasis, myometrium infiltration depth and recurrence (P value was 0.05).4. tumor differentiation, lymph node turn. LC-3 expression was a dangerous factor affecting the total survival time (P value was 0.05). Age, FIGO staging, SCCAg value, tumor diameter, myometrium infiltration depth, surgical margin, Beclin1 expression, p62 expression and total survival time were not statistically different (P value was 0.05); SCCAg, lymph node metastasis, Beclin1 expression, p62 expression and LC-3 expression were affected by cervical cancer. The risk factors of non progressive survival time (P value was 0.05); age, tumor differentiation, FIGO staging, tumor diameter, myometrium infiltration depth, surgical margin and non progressive survival time (P value of all 0.05). The average ADC value of highly differentiated cervical cancer patients in the.5. cervical cancer patients was lower than the average ADC value of differentiation of cervical cancer patients. The average ADC value (P0.05).6. of cervical cancer patients was in the cervical cancer group. There was no statistical difference between the positive expression of LC-3 and the value of ADC in the highly differentiated patients. In the patients with low differentiation, there was a statistical difference between the positive expression of LC-3 and the ADC value (P0.05). Conclusion the expression of 1.Beclin1 protein in the squamous cell carcinoma of the cervix is low, with the lymph node metastasis of the tumor and the metastasis of the tumor. The recurrence has statistical difference, and it is a risk factor that affects the time of no progress. It is suggested that Beclin1 protein may be closely related to the occurrence and development of cervical cancer and the high expression of.2.p62 protein in cervical squamous cell carcinoma tissue, and the lymph node metastasis of tumor, SCCAg value and tumor recurrence have statistical difference, and it has no effect on the recurrence of tumor. The risk factors for the development of the survival time indicate that the p62 protein may be associated with the development and prognosis of cervical cancer and the low expression of.3.LC-3 protein in the squamous cell carcinoma of the cervix, which is statistically different from the tumor differentiation, lymph node metastasis, the depth and recurrence of the myometrium, and is a danger to the total survival time and the progression free survival time. The risk factor indicates that LC-3 protein is closely related to the occurrence, development and prognosis of cervical cancer, and the determination of.4.ADC value can not only be used to judge the degree of differentiation of cervical squamous cell carcinoma, but also with LC may be used to evaluate the prognosis of cervical cancer.

【學(xué)位授予單位】：鄭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類(lèi)號(hào)】：R737.33;R445.2

【參考文獻(xiàn)】

相關(guān)期刊論文 前2條

1 王寵;張萍;朱衛(wèi)國(guó);;細(xì)胞自噬與腫瘤發(fā)生的關(guān)系[J];中國(guó)生物化學(xué)與分子生物學(xué)報(bào);2010年11期

2 郭德玉;孫慧勤;;自噬及其與腫瘤關(guān)系的研究進(jìn)展[J];現(xiàn)代腫瘤醫(yī)學(xué);2010年06期

，

本文編號(hào)：1795343