本文選題：p53誘導(dǎo)的蛋白磷酸酶1 + 非小細(xì)胞肺癌�。� 參考：《河北醫(yī)科大學(xué)》2016年博士論文

【摘要】：肺癌已經(jīng)成為癌癥相關(guān)病死率最高的惡性腫瘤,2012年赫捷院士報道了中國排名前十位的腫瘤發(fā)病率和死亡率,肺癌無論從發(fā)病率還是死亡率來講,都是名列第一位,其中80%以上病例為非小細(xì)胞肺癌(non-small cell lung cancer,NSCLC),確診為NSCLC時,盡管近來年采用了多種綜合預(yù)防和治療手段,仍然難以顯著降低其發(fā)病率和改善其生存率,肺癌的5年生存率約為15%,因此,系統(tǒng)的研究NSCLC的發(fā)生、發(fā)展機(jī)制,篩選有效的治療靶點(diǎn)和治療藥物,一直是腫瘤研究中面臨的巨大挑戰(zhàn)。作為抑癌基因p53的負(fù)性調(diào)控因子,p53誘導(dǎo)的蛋白磷酸酶1(Wild-type p53-induced phosphatase 1,Wip1)位于人染色體17q23/q24區(qū)域,屬于絲氨酸/蘇氨酸蛋白磷酸酶PP2C(PP2C type protein phosphatase)家族成員,由PPM1D編碼,人的Wip1蛋白分子量約為61k D,由605個氨基酸組成,能夠通過依賴于p53蛋白途徑和非依賴于p53蛋白途徑,促進(jìn)腫瘤進(jìn)展。近年來,肺癌、乳腺癌、胰腺癌、膀胱、肝、腦膜、和神經(jīng)母細(xì)胞瘤細(xì)胞系中發(fā)現(xiàn)了Wip1的擴(kuò)增。此外,許多人類原發(fā)性腫瘤(如神經(jīng)母細(xì)胞瘤、卵巢透明細(xì)胞腺癌、乳腺癌、胰腺腺癌)包含擴(kuò)增的Wip1基因和高表達(dá)的Wip1蛋白質(zhì),并且顯示出與癌癥患者預(yù)后不佳有關(guān)。Naoyuki Satoh等發(fā)現(xiàn)原發(fā)性肺腺癌患者,Wip1在腫瘤上皮細(xì)胞表達(dá)的增加,與腫瘤進(jìn)展和臨床預(yù)后具有重要意義。因此本研究擬觀察Wip1在NSCLC中表達(dá)的臨床病理意義和其判斷預(yù)后的價值,并分析Wip1具體作用機(jī)制,為將其作為一個NSCLC候選治療靶點(diǎn)提供進(jìn)一步的理論和實(shí)驗(yàn)依據(jù)。第一部分p53誘導(dǎo)的蛋白磷酸酶1(Wip1)在非小細(xì)胞肺癌中表達(dá)的臨床病理意義及其預(yù)后價值分析目的:研究Wip1在非小細(xì)胞肺癌中表達(dá)的臨床病理意義,并分析其預(yù)后價值。方法:收集河北省胸科醫(yī)院2001年-2010年期間117例NSCLC患者臨床樣本,均具有完整的隨訪資料,10例來自于支氣管擴(kuò)張等手術(shù)中切除的正常肺組織及癌旁肺組織作為對照組。采用免疫組織化學(xué)方法,檢測Wip1在正常肺組織和非小細(xì)胞肺癌組織中的表達(dá)。采用SPSS 13.0統(tǒng)計(jì)軟件進(jìn)行數(shù)據(jù)分析,應(yīng)用Pearsonχ2檢驗(yàn)和t檢驗(yàn)分析其表達(dá)的臨床病理意義。使用Kaplan-Meier法繪制生存曲線并計(jì)算生存率,單因素分析應(yīng)用Log rank檢驗(yàn)進(jìn)行相關(guān)性判斷,多因素分析使用Cox比例風(fēng)險模型,采用逐步回歸分析進(jìn)行危險因素判斷。以α=0.05為檢驗(yàn)水平,以P0.05為差異具有統(tǒng)計(jì)學(xué)意義。結(jié)果:1 Wip1陽性表達(dá)定位于胞漿和細(xì)胞核,呈淺黃色、棕黃色或黃褐色。在非小細(xì)胞肺癌組織中陽性表達(dá)率為69.2%(81/117),與正常肺組織中Wip1蛋白的陽性表達(dá)率0.00%(0/10)比較具有統(tǒng)計(jì)學(xué)差異(χ2=19.114,P=0.000)。2 Wip1陽性表達(dá)組年齡與對照組比較無統(tǒng)計(jì)學(xué)意義(P=0.268)。非小細(xì)胞肺癌組織Wip1蛋白陽性表達(dá)組中,男性占70.4%(57/81),女性占29.6%(24/81),Wip1蛋白陰性表達(dá)組中,男性占83.3%(30/36),女性占16.7%(6/36),采用χ2檢驗(yàn)差異無統(tǒng)計(jì)學(xué)意義(χ2=2.197,P=0.138)。Wip1在肺腺癌組織中的陽性表達(dá)率為88.7%(47/53),在鱗狀細(xì)胞癌中的表達(dá)率為56.8%(25/44),在其他類型非小細(xì)胞肺癌中的表達(dá)率為45%(9/20),采用χ2檢驗(yàn)進(jìn)行統(tǒng)計(jì),發(fā)現(xiàn)肺腺癌中Wip1表達(dá)高于鱗狀細(xì)胞癌和其他類型非小細(xì)胞肺癌(χ2=18.106,P0.001)在非小細(xì)胞肺癌組織Wip1蛋白陽性表達(dá)組中,病理分化程度高分化組占29.6%(24/81),中低分化組占70.4%(57/81),Wip1蛋白陰性表達(dá)組中,高分化組占19.4%(7/36),中低分化組占80.6%(29/36),采用χ2檢驗(yàn)進(jìn)行統(tǒng)計(jì),非小細(xì)胞肺癌組織中Wip1蛋白表達(dá)與分化程度之間無相關(guān)性,差異無統(tǒng)計(jì)學(xué)意義(χ2=1.328,P=0.249)。Wip1蛋白陽性表達(dá)組中,腫瘤大小≤3 cm病例占14.8%(12/81),腫瘤大小3 cm病例占85.2%(69/81),Wip1蛋白陰性表達(dá)組中,腫瘤大小≤3 cm占38.9%(14/36),腫瘤體積3 cm病例占61.1%(22/36),采用χ2檢驗(yàn)進(jìn)行統(tǒng)計(jì),發(fā)現(xiàn)非小細(xì)胞肺癌組織中Wip1蛋白表達(dá)與腫瘤大小相關(guān),差異有統(tǒng)計(jì)學(xué)意義(χ2=8.357,P=0.004)。Wip1蛋白陽性表達(dá)組中,淋巴結(jié)無轉(zhuǎn)移病例占55.6%(45/81),淋巴結(jié)轉(zhuǎn)移病例占44.4%(36/81),Wip1蛋白陰性表達(dá)組中,淋巴結(jié)無轉(zhuǎn)移病例占69.4%(25/36),淋巴結(jié)轉(zhuǎn)移病例占30.6%(11/36),采用χ2檢驗(yàn)進(jìn)行統(tǒng)計(jì),發(fā)現(xiàn)非小細(xì)胞肺癌組織中Wip1蛋白表達(dá)與淋巴結(jié)轉(zhuǎn)移不相關(guān),差異無統(tǒng)計(jì)學(xué)意義(χ2=2.000,P=0.157)。非小細(xì)胞肺癌Wip1蛋白陽性表達(dá)組織中,臨床分期I-II期占55.6%(45/81),III-IV期占44.4%(36/81),Wip1蛋白陰性表達(dá)組中,臨床分期I-II期占75.0%(27/36),III-IV期占25.0%(9/36),采用χ2檢驗(yàn)進(jìn)行統(tǒng)計(jì),發(fā)現(xiàn)非小細(xì)胞肺癌組織中Wip1蛋白表達(dá)與臨床分期相關(guān),差異有統(tǒng)計(jì)學(xué)意義(χ2=3.98,P=0.046)。3單因素Log-rank檢驗(yàn)分析顯示W(wǎng)ip1表達(dá)與患者預(yù)后差相關(guān),Wip1陽性表達(dá)組總體生存率低于Wip1陰性表達(dá)組。Cox回歸模型分析顯示高Wip1表達(dá)相對危險度為5.096(95%可信區(qū)間=1.501-17.303),臨床分期相對危險度為0.159(95%可信區(qū)間=0.037-0.680),均具有統(tǒng)計(jì)學(xué)差異。小結(jié):1 Wip1在NSCLC組織中高表達(dá)。2 Wip1表達(dá)水平與非小細(xì)胞肺癌病理分型、腫瘤大小、臨床分期關(guān)系密切,而與患者的年齡、性別、組織分化程度、淋巴結(jié)轉(zhuǎn)移無關(guān)。3 Wip1陽性表達(dá)組總體生存期低于Wip1陰性表達(dá)組,其高表達(dá)是預(yù)后不良的高風(fēng)險因子。第二部分Wip1-si RNA對非小細(xì)胞肺癌細(xì)胞增殖的影響目的:研究基因沉默Wip1對NSCLC A549細(xì)胞、NCI-H1299細(xì)胞增殖的抑制作用及其調(diào)節(jié)機(jī)制。方法:研究采用RNA干擾技術(shù)基因沉默Wip1。采用real-time PCR技術(shù)和Western blot技術(shù)從三個設(shè)計(jì)的si RNA中篩選出最有效的si RNA。通過MTT技術(shù)觀察細(xì)胞增殖情況,流式細(xì)胞術(shù)觀察細(xì)胞周期,并應(yīng)用Western blot檢測細(xì)胞內(nèi)增殖細(xì)胞核抗原(proliferating cell nuclear antigen,PCNA)、P21及P27的表達(dá)。結(jié)果:1三種Wip1-si RNA(40 n M)轉(zhuǎn)染A549細(xì)胞、NCI-H1299細(xì)胞株48h,對Wip1的表達(dá)均具有一定的沉默作用,其中Wip1-si RNA-3的沉默效率最高,達(dá)到90%以上;而空白對照組及陰性轉(zhuǎn)染組Wip1 m RNA及蛋白表達(dá)水平無明顯變化。2與陰性轉(zhuǎn)染組細(xì)胞相比,基因沉默Wip1對非小細(xì)胞肺癌細(xì)胞A549、NCI-H1299的細(xì)胞增殖具有顯著的抑制作用,明顯高于Wip1-si RNA轉(zhuǎn)染組,差異具有統(tǒng)計(jì)學(xué)意義(P0.05);而空白對照組及陰性轉(zhuǎn)染組細(xì)胞之間增殖率無明顯差異。3敲低Wip1對非小細(xì)胞肺癌細(xì)胞A549、NCI-H1299的細(xì)胞周期具有顯著作用,表現(xiàn)為S期的細(xì)胞明顯減少,而處于G0/G1期的細(xì)胞顯著增加。4 Wip1-si RNA轉(zhuǎn)染A549、NCI-H1299細(xì)胞48 h后,與Non-Target-si RNA和對照組細(xì)胞相比,PCNA的蛋白表達(dá)明顯下調(diào),而P21、P27的蛋白表達(dá)顯著升高(P0.05)。小結(jié):1設(shè)計(jì)的Wip1-si RNA能夠特異、有效的抑制Wip1 m RNA和蛋白的表達(dá)水平。2 Wip1-si RNA能夠顯著抑制NSCLC細(xì)胞株A549和NCI-H1299細(xì)胞的增殖;3 Wip1-si RNA能夠顯著抑制NSCLC細(xì)胞株A549和NCI-H1299細(xì)胞G1→S的轉(zhuǎn)換;4 Wip1-si RNA能夠顯著抑制NSCLC細(xì)胞株A549和NCI-H1299細(xì)胞PCNA蛋白表達(dá)水平,促進(jìn)抑癌基因p21和p27的蛋白表達(dá)水平。第三部分Wip1-si RNA對與非小細(xì)胞肺癌細(xì)胞遷移、侵襲行為的影響目的:探討Wip-si RNA敲低Wip基因表達(dá)對非小細(xì)胞肺癌細(xì)胞遷移和侵襲能力的影響。方法:本部分研究采用RNA干擾技術(shù)敲低肺腺癌細(xì)胞A549、非小細(xì)胞肺癌NCI-H1299細(xì)胞Wip1的表達(dá),通過細(xì)胞劃痕和Transwell實(shí)驗(yàn)觀察腫瘤細(xì)胞的遷移和侵襲能力,并應(yīng)用Western blot方法檢測基質(zhì)金屬蛋白酶(matrix metalloprotease,MMP)-2、MMP-9和組織金屬蛋白酶抑制劑(tissue inhibitor of metalloproteinase,TIMP)-2蛋白表達(dá)情況。結(jié)果:1 Wip1-si RNA(40 n M)轉(zhuǎn)染A549、NCI-H1299細(xì)胞48 h后,與non-Target-si RNA及對照組相比,其遷移到劃痕區(qū)域的細(xì)胞數(shù)目明顯減少(P0.05)。non-target si RNA組與空白對照組相比,其侵襲率無統(tǒng)計(jì)學(xué)差異(P0.05)。2與non-Target-si RNA組相比,Wip1-si RNA(40 n M)轉(zhuǎn)染A549、NCI-H1299細(xì)胞48 h后,與non-target si RNA及空白對照組相比,Wip1敲低的A549和NCI-H1299細(xì)胞,其侵襲到膜下的細(xì)胞數(shù)目明顯減少(P0.05)。non-Target-si RNA組與對照組相比,其侵襲抑制率無統(tǒng)計(jì)學(xué)差異。3將40 n M的Wip1-si RNA轉(zhuǎn)染A549、NCI-H1299細(xì)胞48 h后,Non-target-si RNA組相比,MMP2、MMP9蛋白表達(dá)明顯下調(diào),而TIMP2蛋白表達(dá)顯著增加,non-Target-si RNA組與對照組相比無明顯差異。小結(jié):1 Wip1敲低顯著抑制A549和NCI-H1299細(xì)胞的遷移能力。2 Wip1敲低顯著抑制A549和NCI-H1299細(xì)胞的侵襲能力。3 A549和NCI-H1299細(xì)胞中敲低Wip1,可以下調(diào)MMP2和MMP9的蛋白表達(dá),促進(jìn)TIMP2的蛋白表達(dá)。結(jié)論:1 Wip1在人非小細(xì)胞肺癌組織中高表達(dá),與腫瘤病理分型、p T分期、臨床分期及預(yù)后相關(guān),可能參與了對NSCLC發(fā)生、發(fā)展的調(diào)控,其可做為判斷NSCLC患者預(yù)后的一個較好的指標(biāo)。2基因沉默Wip1能夠通過下調(diào)PCNA,上調(diào)p21和p27蛋白表達(dá),抑制了G1/S期轉(zhuǎn)換,從而抑制了NSCLC細(xì)胞增殖。3基因沉默Wip1能夠通過下調(diào)MMP2、MMP9,上調(diào)TIMP2的表達(dá),從而抑制了NSCLC細(xì)胞的遷移和侵襲。
[Abstract]:Lung cancer has become the most fatal malignant tumor associated with cancer. In 2012, the academician reported the incidence and mortality of the top ten in China. Lung cancer ranked first in terms of morbidity and mortality, and more than 80% of them were non small cell lung cancer (non-small cell lung cancer, NSCLC), and NSCL was diagnosed as NSCL. C, although a variety of comprehensive prevention and treatment methods have been adopted in recent years, it is still difficult to significantly reduce its incidence and improve its survival rate. The 5 year survival rate of lung cancer is about 15%. Therefore, systematic research on the development of NSCLC, the mechanism of development, the screening of effective therapeutic targets and the treatment of drugs have been a great challenge in cancer research. The negative regulatory factor of the tumor suppressor gene p53, p53 induced protein phosphatase 1 (Wild-type p53-induced phosphatase 1, Wip1), is located in the 17q23/q24 region of the human chromosome, belonging to the serine / threonine protein phosphatase PP2C (PP2C type protein phosphatase) family. In recent years, the amplification of Wip1 has been found in lung, breast, pancreatic, bladder, liver, meningeal, and neuroblastoma cells in lung cancer, breast, liver, and neuroblastoma cell lines. In addition, many human primary swelling tumors (such as neuroblastoma, ovarian clear cell adenocarcinoma, breast cancer, pancreas) Adenocarcinoma) contains the amplified Wip1 gene and the high expression of Wip1 protein, and shows that the expression of primary lung adenocarcinoma in patients with.Naoyuki Satoh is not associated with the prognosis of cancer patients. The increase in the expression of Wip1 in the epithelial cells of the tumor is important to the progression of the tumor and the prognosis of the cancer. Therefore, this study is to observe the expression of Wip1 in NSCLC. The value of clinicopathological significance and its judgement of prognosis, and analysis of the specific mechanism of Wip1 to provide further theoretical and experimental basis for the targeting of NSCLC as a candidate for treatment. The clinical pathological significance and prognostic value of p53 induced protein phosphatase 1 (Wip1) in non small cell lung cancer and its prognostic value: study Wip 1 the clinicopathological significance of expression in non-small cell lung cancer and its prognostic value. Methods: the clinical samples of 117 patients with NSCLC in Hebei thoracic hospital during -2010 2001 were collected, all of which had complete follow-up data, 10 cases of normal lung tissue and paracancerous lung tissue removed from bronchiectasis were used as control group. Immunohistochemical method was used to detect the expression of Wip1 in normal lung tissues and non-small cell lung cancer tissues. The clinical and pathological significance of the expression was analyzed by SPSS 13 statistical software and Pearson chi 2 test and t test. The survival curve was plotted by Kaplan-Meier method and the survival rate was calculated. The single factor analysis was applied to Log rank examination. The Cox proportional hazard model was used to judge the risk factors using the stepwise regression analysis. The level of alpha =0.05 as the test level and the difference of P0.05 were statistically significant. Results: the positive expression of 1 Wip1 was located in the cytoplasm and nucleus, in the light yellow color, brown or yellow brown. The positive expression rate was 69.2% (81/117), and the positive expression rate of Wip1 protein in normal lung tissues was compared with 0% (0/10) (x 2=19.114, P=0.000). The age of.2 Wip1 positive expression group was not statistically significant (P=0.268). 70.4% (57/81) in the positive group of non small cell lung cancer, the male was 70.4% (57/81), female. In the 29.6% (24/81), 83.3% (30/36) and 16.7% (6/36) in the negative expression group of Wip1 protein, the positive rate of.Wip1 in lung adenocarcinoma was 88.7% (47/53), and the expression rate in squamous cell carcinoma was 56.8% (25/44), and the table in other types of non-small cell lung cancer was found to be 88.7% (47/53). The rate of arrival was 45% (9/20), and the statistics showed that the expression of Wip1 in lung adenocarcinoma was higher than that of squamous cell carcinoma and other types of non small cell lung cancer (x 2=18.106, P0.001) in the positive expression group of Wip1 protein in non small cell lung cancer, the high differentiation group was 29.6% (24/81), the middle and low differentiation group was 70.4% (57/81), and the Wip1 protein was negative. In the expression group, the high differentiation group was 19.4% (7/36), the middle and low differentiation group accounted for 80.6% (29/36), and the Wip1 protein expression in the non small cell lung cancer tissues was not correlated with the degree of differentiation, the difference was not statistically significant (x 2=1.328, P=0.249).Wip1 positive expression group, the tumor size less than 3 cm cases accounted for 14.8% (12/81), the tumor was large. 3 cm cases accounted for 85.2% (69/81), Wip1 protein negative expression group, tumor size less than 3 cm accounted for 38.9% (14/36), tumor volume 3 cm cases accounted for 61.1% (22/36). Chi chi 2 test was used to determine the expression of Wip1 protein in non small cell lung tissues related to tumor size, the difference was statistically significant (x 2=8.357, P=0.004).Wip1 protein expression group 55.6% (45/81), 44.4% (36/81) of lymph node metastases, 69.4% (25/36) in Wip1 negative expression group, 30.6% (11/36) in lymph node metastases (11/36), and there was no correlation between the expression of Wip1 protein and lymph node metastasis in non small cell lung cancer. There was no statistical significance (x 2=2.000, P=0.157). In the Wip1 protein positive tissues of non small cell lung cancer, the clinical stage I-II period accounted for 55.6% (45/81), III-IV period accounted for 44.4% (36/81), Wip1 protein negative expression group, clinical stage I-II period 75% (27/36), III-IV phase 25% (9/36), the use of chi 2 test for statistics, found non-small cell lung cancer tissue The expression of P1 protein was correlated with clinical staging. The difference was statistically significant (x 2=3.98, P=0.046).3 single factor Log-rank test analysis showed that the expression of Wip1 was related to the prognosis of patients, and the overall survival rate of Wip1 positive expression group was lower than that of Wip1 negative expression group.Cox regression model analysis showed that the relative risk of high Wip1 expression was 5.096 (95% confidence interval =1.501-17.) 303) the relative risk of clinical staging was 0.159 (95% confidence interval =0.037-0.680), and there were statistical differences. Conclusion: the high expression of.2 Wip1 in NSCLC tissues in 1 Wip1 was closely related to the pathological classification of non-small cell lung cancer, the size of the tumor, and the clinical stage, but it was not related to the age, sex, the degree of differentiation of the tissue and the lymph node metastasis of the patient's.3 Wi. The overall survival time of P1 positive expression group was lower than that of Wip1 negative expression group, and its high expression was a high risk factor for poor prognosis. Second part of the effect of Wip1-si RNA on the proliferation of non-small cell lung cancer cells: the study of the inhibitory effect of gene silencing Wip1 on NSCLC A549 cells and NCI-H1299 cell proliferation and its regulation mechanism. Methods: the study was conducted using RNA dry. Wip1. real-time PCR technology and Western blot technology were used to screen the most effective Si RNA. from three designed Si RNA to observe cell proliferation by MTT technology. Flow cytometry was used to observe cell cycle, and cell proliferation cell nuclear antigen was detected by Western blot. The expression of P21 and P27. Results: 1 three kinds of Wip1-si RNA (40 n M) transfected A549 cells, NCI-H1299 cell line 48h, the expression of Wip1 has a certain silence effect, and Wip1-si RNA-3 has the highest silence efficiency, reaching more than 90%, but there is no significant change in the blank control group and negative transfection group. Compared with the cells, gene silencing Wip1 had a significant inhibitory effect on the proliferation of A549 and NCI-H1299 cells in non small cell lung cancer cells, obviously higher than that of Wip1-si RNA transfection group, the difference was statistically significant (P0.05), but the proliferation rate between the blank control group and the negative transfected group had no significant difference between.3 knockout and low Wip1 against non small cell lung cancer cells A549, NC. The cell cycle of I-H1299 had a significant effect, showing that the cells in the S phase decreased significantly, while the cells in the G0/G1 phase significantly increased the.4 Wip1-si RNA transfection to A549. After NCI-H1299 cells 48 h, the protein expression of PCNA was significantly down compared with Non-Target-si RNA and the control group. Wip1-si RNA can inhibit the proliferation of A549 and NCI-H1299 cells of NSCLC cell lines, which can inhibit the proliferation of NSCLC cell lines A549 and NCI-H1299 cells effectively, and the expression level of Wip1 m RNA and protein can significantly inhibit the proliferation of A549 and NCI-H1299 cells in NSCLC cell lines. The expression level of PCNA protein, promoting the protein expression level of tumor suppressor gene p21 and p27. Third the effect of Wip1-si RNA on the migration and invasion of non small cell lung cancer cells: To explore the effect of Wip-si RNA knocking low Wip gene expression on the migration and invasiveness of non-small cell lung cancer cells. Methods: this part of this study uses RNA interference. The technique knocks low lung adenocarcinoma cell A549 and the expression of Wip1 in non small cell lung cancer NCI-H1299 cells. The migration and invasion ability of tumor cells are observed by cell scratch and Transwell test, and Western blot method is used to detect matrix metalloproteinases (matrix metalloprotease, MMP) -2, MMP-9 and tissue inhibitor of metalloproteinase (tissue) Of metalloproteinase, TIMP) -2 protein expression. Results: 1 Wip1-si RNA (40 n M) transfected A549, NCI-H1299 cells 48 h, compared with non-Target-si and control group, the number of cells migrated to the scratch area significantly decreased. Compared with the arget-si RNA group, Wip1-si RNA (40 n M) transfected A549, NCI-H1299 cells after 48 h, compared with non-target Si RNA and blank control group, the number of cells invaded under the membrane decreased significantly. Ip1-si RNA transfected A549, NCI-H1299 cells 48 h, Non-target-si RNA group compared, MMP2, MMP9 protein expression obviously down, and TIMP2 protein expression significantly increased, non-Target-si RNA group compared with the control group, no significant difference. The invasive ability of 99 cells in.3 A549 and NCI-H1299 cells knocks low Wip1, which can reduce the protein expression of MMP2 and MMP9 and promote the protein expression of TIMP2. Conclusion: the high expression of 1 Wip1 in human non-small cell lung cancer tissues is related to the pathological classification of tumor, P T staging, clinical staging and prognosis, and may be involved in the regulation of NSCLC occurrence and development, which can be done In order to judge the prognosis of NSCLC patients, a better indicator of.2 gene silencing Wip1 can inhibit the G1/S phase conversion by down regulation of PCNA, up regulation of p21 and p27 protein expression, thus inhibiting the.3 gene silencing of NSCLC cells can reduce the expression of MMP2, MMP9, and up-regulation, thus inhibiting the migration and invasion of NSCLC cells.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R734.2

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本文編號：2032431