【摘要】：第一部分CK2抑制劑CX-4945逆轉(zhuǎn)胃癌耐藥細(xì)胞放射抗性的作用機(jī)制在我國,胃癌的發(fā)病與死亡處于惡性腫瘤第三位。據(jù)統(tǒng)計(jì),2012年全國胃癌發(fā)病數(shù)約40萬,死亡數(shù)約32萬,胃癌病人五年生存率不足20%。手術(shù)、化療、放療是治療胃癌的主要手段。早期胃癌可通過手術(shù)方式切除局部腫瘤病灶,晚期胃癌由于發(fā)生廣泛浸潤和轉(zhuǎn)移,失去手術(shù)機(jī)會(huì),則以放化療聯(lián)合治療方案為主。腫瘤細(xì)胞對各種放化療措施的耐受性往往導(dǎo)致放化療失敗。順鉑是胃癌化療一線用藥,主要通過誘導(dǎo)DNA交聯(lián)—雙鏈斷裂損傷殺傷腫瘤細(xì)胞。腫瘤細(xì)胞可以通過發(fā)展多種耐藥機(jī)制抵抗順鉑誘導(dǎo)的細(xì)胞凋亡,其中DNA損傷修復(fù)能力增強(qiáng)是最主要的機(jī)制。而放療主要靶向DNA,通過誘導(dǎo)DNA雙鏈斷裂損傷抑制細(xì)胞增殖,引發(fā)細(xì)胞凋亡。對順鉑耐受的腫瘤細(xì)胞同時(shí)也會(huì)對放療產(chǎn)生交叉耐受性。因此,研發(fā)針對放化療交叉耐受關(guān)鍵分子的干預(yù)措施,對于有效逆轉(zhuǎn)放化療交叉耐受和提高胃癌治療效果,具有十分重要的科學(xué)意義,也是目前臨床腫瘤治療急需解決的重大科學(xué)問題。酪蛋白激酶2(Casein Kinase 2,CK2),是一個(gè)多效的絲氨酸/蘇氨酸蛋白激酶。CK2在細(xì)胞生理活動(dòng)的調(diào)節(jié)中處于中心地位,廣泛參與細(xì)胞增殖、分化、死亡等過程,CK2表達(dá)及功能的異常往往導(dǎo)致腫瘤發(fā)生發(fā)展。CX-4945是近年來研發(fā)的特異性針對CK2的抑制劑,體內(nèi)外研究發(fā)現(xiàn)CX-4945通過抑制CK2活性發(fā)揮抗腫瘤作用,可提高化療效果,而CX-4945能否提高胃癌放療效果,逆轉(zhuǎn)胃癌細(xì)胞放療抗性則未見報(bào)道。本實(shí)驗(yàn)室前期用濃度梯度法誘導(dǎo)建立了胃癌順鉑耐藥細(xì)胞模型,發(fā)現(xiàn)DNA修復(fù)蛋白XRCC1表達(dá)異常升高介導(dǎo)順鉑所致DNA損傷修復(fù)過程是導(dǎo)致胃癌細(xì)胞產(chǎn)生順鉑耐受性的重要原因。進(jìn)一步研究發(fā)現(xiàn),順鉑耐藥細(xì)胞中CK2表達(dá)升高是導(dǎo)致XRCC1高表達(dá)的重要機(jī)制,采用CX-4945能有效殺傷耐藥細(xì)胞,提高其對順鉑敏感性。XRCC1是參與修復(fù)放射誘導(dǎo)的DNA損傷的重要分子,提示胃癌順鉑耐藥細(xì)胞可能對放療具有交叉耐受,而通過抑制CK2可逆轉(zhuǎn)順鉑耐藥細(xì)胞的放療耐受。目的:研究胃癌順鉑耐藥細(xì)胞放射抗性產(chǎn)生及逆轉(zhuǎn)的分子基礎(chǔ)。方法:在已經(jīng)成功構(gòu)建的胃癌順鉑耐藥細(xì)胞株中采用細(xì)胞分子生物學(xué)技術(shù)比較耐藥細(xì)胞與敏感細(xì)胞對輻射損傷修復(fù)能力的差異、XRCC1表達(dá)差異,探討CK2、XRCC1等分子表達(dá)與胃癌順鉑耐藥細(xì)胞放射抗性關(guān)系及其分子機(jī)制。結(jié)果:1.XRCC1介導(dǎo)胃癌順鉑耐藥細(xì)胞放射抗性。在用濃度梯度法構(gòu)建的兩株耐藥細(xì)胞BGC823/DDP、SGC7901/DDP及其敏感性親本株中采用高能X-射線處理,結(jié)果顯示DNA損傷程度顯著低于相同劑量處理的敏感細(xì)胞。而胃癌順鉑耐藥細(xì)胞中P-XRCC1水平顯著高于敏感細(xì)胞。在敏感細(xì)胞中轉(zhuǎn)染GFP-XRCC1表達(dá)質(zhì)粒上調(diào)XRCC1表達(dá)可以顯著抑制高能X-射線引起的DNA損傷;在耐藥細(xì)胞中轉(zhuǎn)染XRCC1 siRNA抑制XRCC1表達(dá)可以顯著增加高能X-射線引起的DNA損傷。2.CK2抑制劑CX-4945通過抑制XRCC1增加X-射線誘導(dǎo)的DNA損傷。耐藥細(xì)胞對CX-4945保持敏感性,CX-4945可抑制P-XRCC1水平,從而提高X-射線誘導(dǎo)的DNA損傷程度。3.CX-4945逆轉(zhuǎn)順鉑耐藥細(xì)胞對放射的抗性。克隆形成實(shí)驗(yàn)表明,順鉑耐藥細(xì)胞對X-射線引發(fā)的細(xì)胞死亡具有顯著的抵抗能力。而采用CX-4945可以提高X-射線誘導(dǎo)的順鉑耐藥細(xì)胞死亡率。4.CX-4945逆轉(zhuǎn)胃癌順鉑耐藥細(xì)胞對于紫外UVB輻射的抗性。胃癌順鉑耐藥細(xì)胞對于紫外UVB輻射引起的DNA損傷修復(fù)能力也顯著增強(qiáng),抵抗輻射誘導(dǎo)的細(xì)胞凋亡;當(dāng)CK2抑制劑聯(lián)合紫外UVB輻射后可以抑制XRCC1磷酸化使細(xì)胞不能修復(fù)紫外UVB誘導(dǎo)的DNA損傷,促進(jìn)其損傷加重及凋亡。結(jié)論:本研究首次發(fā)現(xiàn)胃癌順鉑耐藥細(xì)胞對放療及紫外UVB輻射具有交叉耐受,闡明了 XRCC1在胃癌順鉑耐藥細(xì)胞內(nèi)修復(fù)放療及紫外UVB引起DNA損傷的作用,首次提出通過抑制胃癌耐藥細(xì)胞中CK2的表達(dá),可以逆轉(zhuǎn)其放射抗性。第二部分胃賁門癌組織CK2α的表達(dá)與放療療效的關(guān)系目的:采用免疫組化(immunohistochemistry,IHC)檢測胃賁門癌單純放療患者胃鏡活檢組織中CK2和XRCC1的表達(dá),探討二者相關(guān)性以及和胃賁門癌放射治療效果及與病人臨床指標(biāo)及預(yù)后生存的關(guān)系。明確以CK2為靶點(diǎn),判斷胃賁門癌患者放療敏感度,作為個(gè)體化放療的依據(jù)。方法:1.本研究所用資料來自中國人民解放軍第八二醫(yī)院腫瘤中心2010年1月至2013年12月收治的有手術(shù)禁忌或本人拒絕等原因未經(jīng)手術(shù)治療的首診、無放療禁忌癥,年齡50歲以上、KPS評分大于70分并且病例資料完備的胃責(zé)門癌病人。46例患者都具備胃鏡下活檢病理診斷支持。患者中有36例男性,10例女性,年齡平均71.8±10.23歲,中位數(shù)71.2歲。分期選擇我國目前普遍使用的非手術(shù)患者臨床病理分期,Ⅰ期0例,Ⅱ期22例,Ⅲ期18例,Ⅳ期6例(其中肝轉(zhuǎn)移4例,左鎖骨上淋巴結(jié)轉(zhuǎn)移2例)。2.應(yīng)用免疫組織化學(xué)方法(SP法),檢測46例胃賁門癌組織蠟塊中CK2和XRCC1的表達(dá)情況,分析二者相關(guān)性以及和胃賁門癌放射治療效果及與病人臨床一般資料的關(guān)系。3.采用PASW Statistics 18統(tǒng)計(jì)軟件包進(jìn)行數(shù)據(jù)錄入和分析,計(jì)數(shù)數(shù)據(jù)采用X2檢驗(yàn)。采用X2檢驗(yàn)分析CK2及XRCC1表達(dá)與臨床資料參數(shù)間關(guān)系;采用單因素分析Kaplan-Meier法進(jìn)行生存分析研究胃賁門癌患者預(yù)后影響因素。P0.05差異有統(tǒng)計(jì)學(xué)意義。結(jié)果:1.賁門癌組織中CK2的表達(dá)水平與臨床病理指標(biāo)的關(guān)系賁門癌組織中CK2高表達(dá)定位于細(xì)胞漿,陽性表達(dá)率為45.7%(21/46)�？ǚ綑z驗(yàn)結(jié)果,CK2陽性表達(dá)和患者胃癌家族史、淋巴結(jié)轉(zhuǎn)移、臨床分期有關(guān),存在統(tǒng)計(jì)學(xué)差異(P0.05)。CK2在有胃癌家族史人群中陽性表達(dá)率為75.0%(9/12);有淋巴結(jié)轉(zhuǎn)移組陽性率為56.3%(18/32)、無淋巴結(jié)轉(zhuǎn)移組陽性率為21.4%(3/14);病例中無Ⅰ期患者,CK2陽性表達(dá)率Ⅱ期27.3%(6/22)、Ⅲ期66.7%(12/18)、ⅣV期50.0%(3/6)。CK2陽性表達(dá)和病人性別、年齡、KPS評分、慢性胃病史、主要癥狀表現(xiàn)、血紅蛋白濃度、腺癌分化級別、遠(yuǎn)處轉(zhuǎn)移沒有關(guān)系,無統(tǒng)計(jì)學(xué)差異(P0.05)。2.責(zé)門癌組織中XRCC1的表達(dá)水平與臨床病理指標(biāo)的關(guān)系責(zé)門癌組織中XRCC1高表達(dá)定位在細(xì)胞核,陽性表達(dá)率為65.2%(30/46)。卡方檢驗(yàn)結(jié)果,XRCC1陽性表達(dá)和患者淋巴結(jié)轉(zhuǎn)移、臨床分期有關(guān),存在統(tǒng)計(jì)學(xué)差異(P0,05)。XRCC1在有淋巴結(jié)轉(zhuǎn)移組陽性率為78.1%(25/32)、無淋巴結(jié)轉(zhuǎn)移組陽性率為35.7%(5/14);病例中無Ⅰ期患者,XRCC1陽性表達(dá)率Ⅱ 期 45.5%(10/22)、Ⅲ 期 88.9%(16/18)、Ⅳ 期 66.7%(4/6)。XRCC1 陽性表達(dá)和病人性別、年齡、KPS評分、慢性胃病史、胃癌家族史、主要癥狀表現(xiàn)、血紅蛋白濃度、腺癌分化級別、遠(yuǎn)處轉(zhuǎn)移沒有關(guān)系,無統(tǒng)計(jì)學(xué)差異(P0.05)。3.賁門癌組織中CK2與XRCC1表達(dá)水平存在相關(guān)性CK2在46例胃癌患者中的表達(dá)21例,XRCC1在46例胃癌患者中的表達(dá)30例,卡方檢驗(yàn)顯示,兩者表達(dá)有相關(guān)性(x2=4.267,P0.05)。4.CK2和XRCC1的表達(dá)與胃癌放療療效的及預(yù)后的關(guān)系46例胃賁門癌患者中,CK2表達(dá)陽性者21例,放射治療后復(fù)查影像學(xué)指標(biāo)評價(jià)療效5例CR,2例PR,有效緩解率RR(CR+PR)為33.3%(7/21);CK2表達(dá)陰性者25例,復(fù)查療效評價(jià)12例CR,8例PR,有效緩解率RR(CR+PR)為80.0%(20/25),有統(tǒng)計(jì)學(xué)差異(P0.05),說明CK2表達(dá)與放療后近期療效相關(guān),CK2表達(dá)較低者放療有效率較高(x2=10.252,P0.05)。XRCC1表達(dá)陽性者30例,放射治療后復(fù)查影像學(xué)指標(biāo)評價(jià)療效9例CR,4例PR,有效緩解率RR(CR+PR)為43.3%(13/30);XRCC1表達(dá)陰性者16例,復(fù)查療效評價(jià)8例CR,6例PR,有效緩解率RR(CR+PR)為87.5%(14/16),有統(tǒng)計(jì)學(xué)差異(P0.05),說明XRCC1表達(dá)與放療后近期療效也相關(guān),XRCC1表達(dá)較低者放療有效率較高(x2=8.396,P0.05)。CK2高表達(dá)組和低表達(dá)組1、2年生存率分別為 33.3%(7/21)、14.3%(3/21)和 68.0%(17/25)、48.0%(12/25);XRCC1高表達(dá)組和低表達(dá)組1、2年生存率分別為40.0%(12/30)、23.3%(7/30)和 75.0%(12/16)、50.0%(8/16)。Kaplan-Meier 曲線生存分析結(jié)果,CK2 與XRCC1的表達(dá)水平和預(yù)后生存相關(guān),二者表達(dá)陽性者生存期較短,表達(dá)陰性者生存期較長(P0.05)。而且,CK2與XRCC1兩個(gè)分子聯(lián)合起來判斷胃癌預(yù)后表現(xiàn)出比單個(gè)分子更大的預(yù)測效能。結(jié)論:1.CK2和XRCC1在胃賁門癌組織中表達(dá)均較高,并且有相關(guān)性;CK2與XRCC1的表達(dá)和淋巴結(jié)轉(zhuǎn)移、臨床病理分期相關(guān),提示期別越晚,二者陽性越高�？赡芘c胃癌家族史有關(guān)。與患者性別、年齡、KPS評分、慢性胃病史、臨床主要癥狀(上腹痛、吞咽困難、消瘦)、血紅蛋白濃度、分化級別、遠(yuǎn)處轉(zhuǎn)移沒有關(guān)系。2.CK2及XRCC1高表達(dá)患者放療有效率顯著低于低表達(dá)患者,CK2和XRCC1高表達(dá)者1年、2年生存率顯著低于低表達(dá)者。本研究通過CK2蛋白在體內(nèi)表達(dá)程度的差異和臨床放療及預(yù)后的關(guān)系,說明CK2作為胃癌患者個(gè)體化放療分子標(biāo)志物的潛在價(jià)值以及CK2作為胃癌放化療交叉耐受逆轉(zhuǎn)治療的新靶點(diǎn),為CK2抑制劑CX-4945應(yīng)用于胃癌臨床放療增敏提供了理論依據(jù)。
[Abstract]:In the first part, the mechanism of CK2 inhibitor CX-4945 reverses the radiation resistance of gastric cancer resistant cells in China. The incidence and death of gastric cancer are in third malignant tumors. According to the statistics, the number of gastric cancer in China is about 400 thousand in 2012, the number of deaths is about 320 thousand. The five year survival rate of gastric cancer patients is less than 20%. operation, chemotherapy and radiotherapy are the main means for the treatment of gastric cancer. Early gastric cancer can excision local tumor by surgical procedure. Advanced gastric cancer has extensive infiltration and metastasis and loss of operation opportunity. The combination of radiotherapy and chemotherapy is the main method. The tolerance of tumor cells to various chemoradiotherapy often leads to the failure of radiotherapy and chemotherapy. Cisplatin is the first line of chemotherapy for gastric cancer, mainly by inducing DNA delivery. The tumor cells can kill tumor cells. The tumor cells can resist cisplatin induced apoptosis by developing a variety of resistance mechanisms. The enhancement of DNA damage repair ability is the most important mechanism. Radiotherapy is mainly targeted to DNA, which induces cell proliferation by inducing DNA double strand breakage and induces apoptosis. The tumor cells also have cross tolerance to radiotherapy. Therefore, it is of great scientific significance for the effective reversal of the cross tolerance of chemoradiotherapy and the improvement of the therapeutic effect of gastric cancer. It is also a major scientific problem to be solved urgently in clinical cancer treatment. Casein stimulated by the intervention measures of key molecules of cross tolerance of radiotherapy and chemotherapy. Enzyme 2 (Casein Kinase 2, CK2), a multipotent serine / threonine protein kinase.CK2, is in a central position in the regulation of cell physiological activity, and is widely involved in cell proliferation, differentiation, and death. The abnormal expression of CK2 and the abnormal function of CK2 often lead to the development of.CX-4945 as a specific inhibitor for CK2. Internal and external studies have found that CX-4945 can improve the effect of chemotherapy by inhibiting the activity of CK2, and can improve the effect of chemotherapy, but whether CX-4945 can improve the radiotherapy effect of gastric cancer and reverse the radiation resistance of gastric cancer cells has not been reported. In the early stage of the laboratory, the cisplatin resistance fine cell model of gastric cancer was induced by concentration gradient method, and the abnormal expression of DNA repair protein XRCC1 was found to be abnormal. The increase of DNA damage repair induced by cisplatin is an important cause of the tolerance to cisplatin induced by gastric cancer cells. Further studies have found that the increase of CK2 expression in cisplatin resistant cells is an important mechanism for the high expression of XRCC1. The use of CX-4945 to effectively kill drug resistant cells and to improve the sensitivity of.XRCC1 to cisplatin is involved in the repair of radiation induced by cisplatin. The important molecules of DNA damage suggest that cisplatin resistant cells may have cross tolerance to radiotherapy, and by inhibiting CK2 can reverse the radiotherapy tolerance of cisplatin resistant cells. Objective: To study the molecular basis of radiation resistance production and reversal of cisplatin resistant cells in gastric cancer. Methods: in the successful construction of cisplatin resistant cell lines of cisplatin, a successful cell line of cisplatin resistance in gastric cancer Cell molecular biology technique was used to compare the difference of radiation damage repair ability between drug resistant and sensitive cells, the difference of XRCC1 expression and the relationship between CK2, XRCC1 and other molecular mechanisms of cisplatin resistant cells in gastric cancer and its molecular mechanism. Results: 1.XRCC1 mediated radiation resistance of cisplatin resistant cells in gastric cancer. Two strains of resistant cells BGC823/DDP, SGC7901/DDP and their sensitive parent strains were treated with high energy X- ray. The results showed that the degree of DNA damage was significantly lower than that of the same dose treated sensitive cells. The P-XRCC1 level of cisplatin resistant cells in gastric cancer was significantly higher than that of the sensitive cells. The GFP-XRCC1 expression plasmid was transfected in the sensitive cells to up regulate the XRCC1 table. The DNA damage caused by high energy X- ray can be significantly inhibited, and the conversion of XRCC1 siRNA to XRCC1 expression in the drug resistant cells can significantly increase the DNA damage of DNA damage caused by high energy X- ray, CX-4945 by inhibiting XRCC1 to increase X- ray induced DNA damage. The increase of X- ray induced DNA damage.3.CX-4945 reverses the radiation resistance of cisplatin resistant cells. Cloning and formation experiments showed that cisplatin resistant cells had significant resistance to X- ray induced cell death. The use of CX-4945 could improve the X- ray induced cisplatin resistance cell mortality.4.CX-4945 to reverse cisplatin in gastric cancer. Resistance cells are resistant to ultraviolet UVB radiation. The ability to repair DNA damage caused by UVB radiation from cisplatin is also significantly enhanced to resist radiation induced apoptosis. When CK2 inhibitors combined with UV UVB radiation, XRCC1 phosphorylation can inhibit the cell failure to repair DNA damage induced by ultraviolet UVB and promote its damage. Conclusion: the cross tolerance of cisplatin resistant cells to radiotherapy and ultraviolet UVB radiation was first found in this study, and the effect of XRCC1 on the repair of cisplatin resistant cells in gastric cancer and DNA damage caused by ultraviolet UVB was first proposed. The first proposed to reverse the expression of CK2 in gastric cancer resistant cells could reverse its radiation resistance. The relationship between the expression of CK2 alpha and the effect of radiotherapy in the two part of gastric cardia carcinoma: immunohistochemistry (IHC) was used to detect the expression of CK2 and XRCC1 in the gastric biopsies of gastric cardia cancer patients. The correlation between the gastric cardia cancer and gastric cardia cancer patients was examined and the effects of radiotherapy on the gastric cardia cancer and the clinical indicators and survival of the patients were discussed. CK2 as a target to determine the sensitivity of radiotherapy for gastric cardia cancer patients as a basis for individualized radiotherapy. Methods: 1. the data from the No.82 Hospital of PLA tumor center from January 2010 to December 2013 were treated with surgical taboos or refusal of the first diagnosis of untreated surgery, and no contraindications of radiotherapy. Patients with age over 50 years old, KPS score greater than 70 points and.46 patients with complete case data have a pathological diagnosis support for endoscopic biopsy. There are 36 males and 10 females with an average age of 71.8 + 10.23 years, with a median of 71.2 years. 0 cases, 22 cases in stage II, 18 cases in stage III, 6 cases in stage IV (4 cases of hepatic metastases and 2 cases of left supraclavicular lymph node metastasis).2. application immuno histochemical method (SP) to detect the expression of CK2 and XRCC1 in 46 cases of gastric cardia cancer tissue, analyze the correlation between two and the effect of radiotherapy for gastric cardia cancer and the general clinical data of the patients. .3. using PASW Statistics 18 statistical software package for data entry and analysis, counting data using X2 test. X2 test was used to analyze the relationship between the expression of CK2 and XRCC1 and the parameters of clinical data, and the survival analysis of gastric cardia cancer patients by the single factor analysis Kaplan-Meier method was statistically significant. Results: the expression level of CK2 in 1. cardiac carcinoma tissues was related to the clinicopathological index. The high expression of CK2 was located in the cytoplasm and the positive expression rate was 45.7% (21/46). The result of chi square test was that the positive expression of CK2 was related to the family history of gastric cancer, lymph node metastasis and clinical stage, and there was a statistical difference (P0.05).CK2 in the family history of gastric cancer The positive rate in the population was 75% (9/12), the positive rate in the lymph node metastasis group was 56.3% (18/32), the positive rate in the non lymph node metastasis group was 21.4% (3/14). There were no stage I patients, CK2 positive expression stage II 27.3% (6/22), stage III 66.7% (12/18), 50% (3/6).CK2 positive expression in stage IV V and patients' sex, age, KPS score, and chronic stomach disease history. Symptoms, hemoglobin concentration, grade of differentiation of adenocarcinoma, distant metastasis, no statistical difference (P0.05) the relationship between the expression level of XRCC1 and the clinicopathological index in.2. imputation carcinoma tissue, the high expression of XRCC1 in the cell carcinoma tissue is located in the nucleus, the positive expression rate is 65.2% (30/46). The result of chi square test, the positive expression of XRCC1 and the patient Lymph node metastasis, clinical staging, statistical difference (P0,05).XRCC1 in lymph node metastasis group positive rate was 78.1% (25/32), no lymph node metastasis group positive rate was 35.7% (5/14); no stage I patients, XRCC1 positive expression stage II 45.5% (10/22), stage III 88.9% (16/18), stage IV 66.7% (4/6).XRCC1 positive expression and patient sex No, age, KPS score, history of chronic stomach disease, family history of gastric cancer, main symptoms, hemoglobin concentration, grade of adenocarcinoma differentiation, distant metastasis, no statistical difference (P0.05), there is a correlation between CK2 and XRCC1 expression in.3. cardiac cancer tissue, CK2 in 46 patients with gastric cancer, and XRCC1 in 46 cases of gastric cancer 30 The relationship between the expression of x2=4.267, P0.05,.4.CK2 and XRCC1 and the relationship between the expression of.4.CK2 and XRCC1 and the prognosis and prognosis of gastric cancer were 46 cases of gastric cardia cancer, 21 cases of CK2 expression positive, 5 cases of CR, 2 PR, 33.3% (7/21) effective remission rate RR (CR+PR), CK2 expression 2. 5 cases, 12 cases of CR and 8 cases of PR, effective remission rate RR (CR+PR) was 80% (20/25), and there were statistical differences (P0.05), indicating that the expression of CK2 was related to the short-term effect after radiotherapy, 30 cases with higher efficiency of radiotherapy (x2=10.252, P0.05).XRCC1 expression in the lower CK2 expression. 9 cases of CR and 4 cases were evaluated after radiological treatment. There were 4 cases. The remission rate of RR (CR+PR) was 43.3% (13/30) and 16 cases with negative XRCC1 expression, 8 cases of CR and 6 cases of PR were rechecked. The effective remission rate RR (CR+PR) was 87.5% (14/16), and there was a statistical difference (P0.05), indicating that XRCC1 expression was also related to the short-term effect after radiotherapy, and the high expression and low expression of radiotherapy were higher in the lower XRCC1 table. The survival rate of group 1,2 was 33.3% (7/21), 14.3% (3/21) and 68% (17/25), 48% (12/25), and the survival rate of 1,2 year in XRCC1 high expression group and low expression group was 40% (12/30), 23.3% (7/30) and 75% (12/16), 50% (8/16).Kaplan-Meier curve survival analysis. The survival rate was related to the expression level and the prognosis of the prognosis, and the two expressed positive. The survival period was shorter and the expression negative person had a longer life period (P0.05). Moreover, CK2 and XRCC1 were combined to judge the prognosis of gastric cancer to be more predictive than single molecule. Conclusion: the expression of 1.CK2 and XRCC1 in gastric cardia cancer tissues were higher and correlated, and the expression of CK2 and XRCC1, lymph node metastasis, and clinicopathological stages Close, the more late the period, the more positive of the two. It may be related to the family history of gastric cancer. Sex, age, KPS score, history of chronic gastropathy, clinical major symptoms (upper abdominal pain, dysphagia, emaciation), hemoglobin concentration, differentiation grade, and distant metastasis are not related to.2.CK2 and XRCC1 high expression, the effective rate of radiotherapy is significantly lower than that of low expression patients. The 2 year survival rate of the high expression of CK2 and XRCC1 was significantly lower than that of low expression in 1 years. This study demonstrated the potential value of CK2 as a molecular marker of individualized radiotherapy for gastric cancer patients and the new target of CK2 as a cross tolerance reversal therapy for gastric cancer and chemotherapy through the relationship between the difference in the expression of CK2 protein in the body and the relationship between the clinical radiotherapy and prognosis. 2 inhibitor CX-4945 provides a theoretical basis for clinical radiotherapy sensitization of gastric cancer.
【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R735.2

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