本文關(guān)鍵詞： 胃癌 microRNA-138-5p 順鉑耐藥 核苷酸切除修復(fù) 低鈉血癥　出處：《安徽醫(yī)科大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：研究背景:胃癌是世界范圍內(nèi)常見的惡性腫瘤之一,我國是胃癌高發(fā)國家。雖然近年來胃癌的診療技術(shù)已經(jīng)取得了一些進步,但由于腫瘤早期癥狀表現(xiàn)無特異性,及高侵襲性和轉(zhuǎn)移率,使得胃癌總體預(yù)后欠佳。晚期胃癌治療以姑息性化療為主,鉑類作為胃癌化療的基石類藥物,大部分含鉑方案的有效率均不超過50%,存在鉑類原發(fā)或繼發(fā)耐藥現(xiàn)象限制了其在臨床應(yīng)用。近年來研究發(fā)現(xiàn)microRNAs(miRNAs)的表達異常與腫瘤化療敏感性密切相關(guān)。miR-138-5p在肺癌化療耐藥中的作用已經(jīng)得以證實,可通過負性調(diào)控ERCC1表達影響DNA損傷修復(fù)能力減少順鉑耐藥。但迄今為止,關(guān)于miR-138-5p是否能調(diào)節(jié)胃癌細胞化療耐藥及其機制尚未明確,是否能真正用于指導(dǎo)胃癌患者臨床治療亦未明確。因此,本課題擬探討miR-138-5p能否調(diào)控胃癌細胞株(SGC7901)對順鉑治療敏感性,及其可能的作用機制。并進一步探討晚期胃癌患者癌組織中及血漿中miR-138-5p的表達水平及其與一線含鉑方案化療療效的相關(guān)性。以期更好的指導(dǎo)晚期胃癌患者臨床個體化治療。本研究在前期的臨床病例資料收集過程中發(fā)現(xiàn)晚期胃癌伴有低鈉血癥患者預(yù)后明顯變差,提示低鈉血癥為胃癌負性療效預(yù)測因子。而目前關(guān)注晚期胃癌與低鈉血癥關(guān)系的研究較少,因此本研究探討了晚期胃癌患者合并低鈉血癥發(fā)生情況對其一線治療療效、預(yù)后的影響,并進一步探討低鈉血癥影響晚期胃癌患者化療療效及預(yù)后的原因,是否與miR-138-5p表達相關(guān)。以期將患者的實驗室檢驗與miRNA檢測結(jié)果相結(jié)合更好的指導(dǎo)臨床個體化治療。本研究共分三部分。第一部分:miR-138-5p在胃癌順鉑耐藥細胞中的作用及機制研究目的:研究miR-138-5p在胃癌順鉑耐藥細胞中表達情況及其介導(dǎo)順鉑耐藥的可能機制。方法:采用基因芯片技術(shù)分析胃癌耐順鉑細胞SGC7901/DDP和親本細胞SGC7901中表達差異miRNAs。生物信息學(xué)軟件預(yù)測miR-138-5p作用靶點。采用qRT-PCR及Western blot分別檢測胃癌耐順鉑細胞SGC7901/DDP和親本細胞SGC7901中miR-138-5p及ERCC1、ERCC4的表達水平;利用包含干擾miR-138-5p表達的目的基因的慢病毒液及陰性對照negative control RNA(NC)轉(zhuǎn)染至SGC7901細胞下調(diào)miR-138-5p表達,轉(zhuǎn)染至SGC7901/DDP細胞上調(diào)miR-138-5p表達;熒光顯微鏡觀察轉(zhuǎn)染結(jié)果,qRT-PCR技術(shù)驗證轉(zhuǎn)染后miR-138-5p表達;Western blot驗證轉(zhuǎn)染后ERCC1,ERCC4的表達情況;MTT法檢測細胞對順鉑治療的敏感性;結(jié)果:1.基因芯片檢測結(jié)果表明miR-138-5p在SGC7901/DDP細胞內(nèi)的表達是SGC7901中的0.2686倍。進一步采用qRT-PCR方法驗證miR-138-5p在SGC7901中的表達量是SGC7901/DDP的5.006倍,差異有統(tǒng)計學(xué)意義(P0.01)。兩者結(jié)果一致,表明其在胃癌耐藥細胞株(SGC7901/DDP)中表達明顯下調(diào);2.生物信息學(xué)軟件預(yù)測miR-138-5p作用靶點為核苷酸切除修復(fù)通路中的ERCC1、ERCC4蛋白。Western blot結(jié)果表明ERCC1和ERCC4在SGC7901/DDP中表達較SGC7901細胞中明顯升高,差異有統(tǒng)計學(xué)意義(P0.01);3.轉(zhuǎn)染攜帶目的基因片段慢病毒液調(diào)節(jié)miR-138-5p的表達,在SGC7901細胞中下調(diào)miR-138-5p的表達,在SGC7901/DDP細胞中上調(diào)miR-138-5p的表達。熒光顯微鏡觀察轉(zhuǎn)染后SGC7901細胞呈現(xiàn)紅色為表達下調(diào),SGC7901/DDP細胞呈現(xiàn)綠色為表達上調(diào)。采用qRT-PCR方法檢測慢病毒轉(zhuǎn)染后miR-138-5p表達水平,結(jié)果證實其在SGC7901-LV-miR-138-5p-KD組中的表達下調(diào),分別是SGC7901和NC-KD組的0.209倍和0.211倍,差異具有統(tǒng)計學(xué)意義(P0.05)。在SGC7901/DDP-LV-miR138-5p-OE中表達上調(diào),分別是SGC-7901/DDP和SGC7901/DDP-LV-NC-OE組4.17和4.36倍,差異有統(tǒng)計學(xué)意義(P0.05);4.Western blot結(jié)果表明ERCC1、ERCC4在SGC7901-LV-miR138-5p-KD(miR-138-5p表達下調(diào)細胞)內(nèi)的表達明顯升高,在SGC7901/DDP-LV-miR138-5p-OE(miR-138-5p表達上調(diào)細胞)內(nèi)的表達明顯減少,差異有統(tǒng)計學(xué)意義(P0.01);5.MTT法結(jié)果表明SGC7901/DDP-LV-miR138-5p-OE組細胞,miR-138-5p表達上調(diào)后對順鉑的敏感性較SGC7901/DDP和SGC7901/DDP-LV-NC-OE增加,IC50分別是:3.14±0.32、6.81±0.12、6.89±0.14,差異有統(tǒng)計學(xué)意義(P0.01)。SGC7901-LV-miR138-5p-KD組細胞,miR-138-5p表達下調(diào)后對順鉑的耐藥性增強,其IC50較SGC7901和SGC7901-LV-NC-KD細胞升高,IC50分別為:0.39±0.04、0.20±0.01、0.25±0.05差異有統(tǒng)計學(xué)意義(P0.01)。結(jié)論:miR-138-5p在胃癌耐藥細胞株(SGC7901/DDP)中低表達,通過慢病毒轉(zhuǎn)染使得miR-138-5p表達上調(diào)后,SGC7901/DDP細胞中ERCC1、ERCC4表達明顯減少,核苷酸切除修復(fù)缺陷,增強胃癌耐藥細胞株SGC7901/DDP對順鉑治療的敏感性,起化療增敏作用。下調(diào)miR-138-5p表達,SSGC7901細胞中ERCC1、ERCC4表達明顯增加,核苷酸切除修復(fù)增加,導(dǎo)致胃癌細胞株SGC7901對順鉑耐藥。推測其可能的作用機制為通過負性調(diào)控ERCC1、ERCC4表達干擾DNA損傷修復(fù)調(diào)節(jié)對順鉑治療的敏感性。第二部分:miR-138-5p表達水平與晚期胃癌含鉑方案化療療效的相關(guān)性研究目的:探討晚期胃癌患者癌組織中及血漿中miR-138-5p的表達水平與一線含鉑方案化療療效的相關(guān)性。方法:采用qRT-PCR方法檢測51例晚期胃癌患者癌組織及血漿中miR-138-5p的表達水平,同時選取相匹配的癌旁組織標本20例及健康志愿者血漿20例作為實驗對照。所有患者均接受含鉑方案一線化療,并評價其近期療效及一線化療后無進展生存時間、總生存。結(jié)果:胃癌組織中miR-138-5p的表達水平低于癌旁組織(t=4.30,P㩳0.01),胃癌患者血漿中miR-138-5p的表達水平低于健康對照組(t=3.04,P㩳0.01)。晚期胃癌患者癌組織中及血漿中miR-138-5p的表達水平與患者性別、年齡、轉(zhuǎn)移部位、轉(zhuǎn)移器官數(shù)目、ECOG評分、癌組織分化程度等均無相關(guān)性(P0.05)。51例患者均可評價近期療效,其中11例PR、23例SD、17例PD,ORR率為21.6%,DCR率為66.7%。癌組織及血漿中miR-138-5p的相對表達量均與化療近期療效呈正相關(guān)(P㩳0.05)。采用ROC曲線判斷miR-138-5p表達水平預(yù)測化療有效率的最佳截斷值,取癌組織中miR-138-5p表達量0.104為截點,AUC值為0.907,預(yù)測含鉑方案化療后疾病控制的靈敏度為90.91%,特異度為75%。超過0.104為高表達組,低于0.104為低表達組。取血漿中miR-138-5p表達量0.091為截點,AUC值為0.973,預(yù)測含鉑方案化療后疾病控制的靈敏度為100%,特異度為85%。超過0.091為高表達組,低于0.091為低表達組。51例患者中位PFS時間為4.0月(95%CI:3.7~4.3月),中位OS為9.9月(95%CI:9.2~10.6月)。胃癌組織中miR-138-5p高表達與低表達組的中位PFS分別為5.5月(95%CI:3.5~7.5月)及3.2月(95%CI:1.7~4.7月)(P0.05);中位OS分別為11.2月(95%CI:10.9~11.5月)及9.2月(95%CI:8.7~9.7月),采用Log-rank檢驗,差異均有統(tǒng)計學(xué)意義(P0.01)。血漿中miR-138-5p高表達與低表達組的中位PFS分別為5.5月(95%CI:3.0~8.1月)及3.5月(95%CI:1.5~5.5月)(P0.05)。中位OS分別為11.4月(95%CI:11.0~11.8月)及9.5月(95%CI:8.6~10.4月),采用Log-rank檢驗,差異均有統(tǒng)計學(xué)意義(P0.01)。線性相關(guān)分析表明,胃癌腫瘤組織與血漿中miR-138-5p的表達具有正相關(guān)性(r=0.899,P0.05)。結(jié)論:胃癌組織及血漿中miR-138-5p的表達水平具有正相關(guān)性,且癌組織及血漿中miR-138-5p表達水平高低與晚期胃癌患者一線含鉑化療方案的近期療效、一線PFS、OS具有一定的正相關(guān)性。第三部分:低鈉血癥與晚期胃癌化療療效及miR-138-5p表達水平的相關(guān)性研究目的:探討晚期胃癌合并低鈉血癥患者的臨床特點及預(yù)后分析,及低鈉血癥發(fā)生與miR-138-5p表達水平的相關(guān)性;方法:收集2009/06/01-2015/12/31期間在安徽醫(yī)科大學(xué)第一附屬醫(yī)院住院的胃癌合并低鈉血癥患者信息,從中篩選出44例晚期胃癌伴有低鈉血癥并接受一線化療患者,并將45例晚期胃癌血鈉正�；颊咦鳛閷φ战M,進行回顧性對照分析。收集這些患者一線化療的近期療效,一線PFS及毒副反應(yīng)信息。采用qRT-PCR方法檢測了低鈉組共5例、對照組共10例患者組織中miR-138-5p表達水平。結(jié)果:晚期、女性、肝臟及腹膜轉(zhuǎn)移、ECOG評分低的胃癌患者更易合并低鈉血癥。低鈉組及對照組一線化療的ORR率分別為:25%(11/44)和40.0%(18/45)(P=0.131);DCR率分別為40.9%(18/44)和73.3%(33/45)(P=0.002),疾病控制率的差異具有統(tǒng)計學(xué)意義。低鈉組一線化療中位PFS為3.0個月(95%CI:2.8~3.7月),對照組一線化療中位PFS為4.5個月(95%CI:4.3~6.2月),(χ2=14.618,P0.001),兩組差異具有統(tǒng)計學(xué)意義。低鈉血癥糾正者一線化療PFS優(yōu)于低鈉血癥持續(xù)存在患者,差異具有統(tǒng)計學(xué)意義。低鈉組一線化療后貧血、惡心、嘔吐、乏力、納差的發(fā)生率更高,差異具有統(tǒng)計學(xué)意義。低鈉組胃癌組織中miR-138-5p表達水平低于對照組,但差異并無統(tǒng)計學(xué)意義。結(jié)論:低鈉血癥可作為晚期胃癌患者不良的化療療效預(yù)測因素之一,可結(jié)合miR-138-5p表達水平共同預(yù)測晚期胃癌鉑類化療療效及判斷預(yù)后。
[Abstract]:Background: gastric cancer is one of the most common malignant tumors in the world, China is a country with high incidence of gastric cancer. Although in recent years, the technology of diagnosis and treatment of gastric cancer has made some progress, but because the early symptoms of cancer are nonspecific, and high invasion and metastasis of gastric cancer, the prognosis is poor overall in palliative treatment of advanced gastric cancer. Chemotherapy, platinum drugs as a cornerstone of gastric cancer chemotherapy, the effective rate of most platinum containing regimens was less than 50%, there are platinum primary or secondary drug resistance limit its clinical application. Recent studies have found that microRNAs (miRNAs) effect are closely related to the abnormal expression and chemosensitivity of.MiR-138-5p in lung cancer chemotherapy in has been confirmed through the negative regulation of ERCC1 ability to repair DNA damage effects of decreased expression of cisplatin resistance. But so far, about whether miR-138-5p can regulate the gastric cancer Cell resistance to chemotherapy and its mechanism is not yet clear whether can really be used to guide the clinical treatment of patients with gastric cancer is not clear. Therefore, this thesis intends to explore whether miR-138-5p can regulate the gastric cancer cell line (SGC7901) on cisplatin sensitivity and its possible mechanism. And to further explore the correlation between the expression of miR-138-5p in tumor tissues of patients with advanced gastric cancer and in plasma and the efficacy of first-line platinum based chemotherapy. In order to better guide clinical individualized treatment for patients with advanced gastric cancer. The prognosis of patients with advanced gastric cancer found hyponatremia was significantly worse on the pre clinical data collection process, suggesting that hyponatremia is the negative effect of gastric cancer predictors. At present, paying attention to relationship advanced gastric cancer with hyponatremia research, this study of the advanced gastric cancer patients with hyponatremia in the first-line treatment The curative effect and prognosis, and to further explore the causes of hyponatremia in patients with gastric cancer undergoing chemotherapy efficacy and prognosis of advanced, is associated with expression of miR-138-5p. In order to make the laboratory test and miRNA test results were combined with the clinical individual treatment better. This research is divided into three parts. The first part: To study in the cisplatin resistant cell in gastric cancer: effect and mechanism of miR-138-5p expression and its mechanism may be mediated by cisplatin resistance of miR-138-5p in gastric cancer cells resistant to cisplatin resistant human gastric cancer. Methods: analysis of differentially expressed miRNAs. were predicted by bioinformatics software miR-138-5p target cells SGC7901/DDP and cisplatin SGC7901 parental cells by gene chip technology. Using qRT-PCR and Western blot was used to detect the miR-138-5p and ERCC1 of cisplatin resistant human gastric cancer cell SGC7901/DDP and its parental cell line SGC7901, the expression level of ERCC4; Using lentiviral solution and negative expression of miR-138-5p gene contains interference control of negative control RNA (NC) was transfected into SGC7901 cells by down regulating the expression of miR-138-5p was transfected into SGC7901/DDP cells by upregulation of miR-138-5p expression; transfection results by fluorescence microscopy, the expression of miR-138-5p qRT-PCR Western blot to verify the verification after transfection; ERCC1 after transfection, the expression of ERCC4 MTT; method to detect the sensitivity of cells to cisplatin therapy; results: the testing results showed that the expression of miR-138-5p 1. gene chip in SGC7901/DDP cells is 0.2686 times of SGC7901. A qRT-PCR method was used to verify the expression of miR-138-5p in SGC7901 was 5.006 times of SGC7901/DDP, the difference was statistically significant (P0.01). The two results are consistent, that the resistant gastric cancer cell lines (SGC7901/DDP) in gene expression was significantly decreased; 2. were predicted by bioinformatics software miR-138-5p targets As the nucleotide excision repair pathway of ERCC1, ERCC4 protein.Western blot results showed that the expression of ERCC1 and ERCC4 in SGC7901/DDP was significantly higher than that in SGC7901 cells, the difference was statistically significant (P0.01); 3. GFP gene fragment lentiviral solution regulating miR-138-5p expression, down-regulation of miR-138-5p expression in SGC7901 cells, upregulation of miR-138-5p the expression in SGC7901/DDP cells. After transfection, SGC7901 cells showed expression of red fluorescence microscopy, SGC7901/DDP cells showed green expression. The expression of miR-138-5p was detected by qRT-PCR lentiviral transfection results confirmed the down-regulation of its expression in the SGC7901-LV-miR-138-5p-KD group, SGC7901 and NC-KD were 0.209 times and 0.211 times group, with statistically significant difference (P0.05). The expression of SGC7901/DDP-LV-miR138-5p-OE, SGC-7901/DDP and SGC790 respectively. Group 1/DDP-LV-NC-OE was 4.17 and 4.36 times, the difference was statistically significant (P0.05); 4.Western blot ERCC1 ERCC4 in SGC7901-LV-miR138-5p-KD showed that, (the down-regulation of miR-138-5p expression in cells) was significantly increased in SGC7901/DDP-LV-miR138-5p-OE (upregulation of miR-138-5p expression in the cells) decreased significantly, the difference was statistically significant (P0.01); 5.MTT assay results showed that SGC7901/DDP-LV-miR138-5p-OE group cells, miR-138-5p expression after sensitivity to cisplatin than SGC7901/DDP and SGC7901/DDP-LV-NC-OE, IC50 respectively is: 3.14 + 0.32,6.81 + 0.12,6.89 + 0.14, the difference was statistically significant (P0.01) cells in.SGC7901-LV-miR138-5p-KD group, miR-138-5p expression was down regulated after cisplatin resistance increased, the IC50 compared with SGC7901 and SGC7901-LV-NC-KD cells increased, IC50 were statistically 0.39 + 0.04,0.20 + 0.01,0.25 + 0.05 difference (P0.01). Conclusion: miR- 138-5p in gastric cancer multidrug resistance cell line (SGC7901/DDP) low expression, makes the expression of miR-138-5p by lentivirus transfected ERCC1 SGC7901/DDP cells, the expression of ERCC4 was significantly reduced, nucleotide excision repair defects, enhance the sensitivity of gastric cancer SGC7901/DDP cells to cisplatin treatment, chemotherapy sensitization. Expression of miR-138-5p ERCC1 in SSGC7901 cells. The expression of ERCC4 increased obviously, nucleotide excision repair, leading to gastric cancer cell line SGC7901 to cisplatin resistance. Its possible mechanism was speculated through negative regulation of ERCC1 expression, ERCC4 interference DNA damage repair regulation on sensitivity of cisplatin treatment. The second part: the expression level of miR-138-5p and the efficacy of chemotherapy for advanced gastric cancer platinum correlation study the expression level of miR-138-5p and the first: To investigate the effect of advanced gastric cancer tissues and plasma in the treatment with platinum based chemotherapy Methods: using the qRT-PCR method. Correlation between the expression level of miR-138-5p in tumor tissues of patients with advanced gastric cancer and 51 cases of plasma detection, and selected matched noncancerous tissues and 20 cases of healthy volunteers plasma in 20 cases as the control. All the patients were treated with platinum based first-line chemotherapy, and to evaluate its efficacy and after first-line chemotherapy progression free survival and overall survival. Results: the expression of miR-138-5p in gastric cancer tissue than that of adjacent tissues (t=4.30, P? 0.01), the expression level of miR-138-5p in plasma of gastric cancer patients were lower than the healthy control group (t=3.04, P? 0.01). The expression level of miR-138-5p in tumor tissues of patients with advanced gastric cancer and plasma in patients with gender, age, metastasis, number of metastatic organs, ECOG scores, there was no correlation between cancer tissue differentiation degree (P0.05) of.51 patients were evaluable for efficacy, including 11 cases of PR, 23 cases SD, 17 cases PD, ORR rate was 21. 6%, the DCR rate of miR-138-5p 66.7%. in cancer tissue and plasma relative expression were positively associated with the recent curative effect of chemotherapy (P? 0.05). Using ROC curve to determine the expression of miR-138-5p optimal truncation level prediction of chemotherapy efficiency value, miR-138-5p expression of the 0.104 cutoff point in cancer tissue, AUC value was 0.907, the sensitivity of the forecasts the disease control of platinum based chemotherapy was 90.91%, the specificity was 75%. more than 0.104 high expression group and low expression group were less than 0.104. The expression of miR-138-5p in 0.091 as the cut-off point in plasma, the AUC value is 0.973, the prediction of disease control sensitivity of platinum based chemotherapy was 100%, the specificity was more than 0.091 85%. for high expression group and low expression group was less than 0.091.51 PFS patients the median time was 4 months (95%CI:3.7~4.3 months), the median OS was 9.9 months (95%CI:9.2~10.6 months). The high expression of miR-138-5p in gastric cancer tissues respectively with a median of PFS low expression group was 5.5 months (9 5%CI:3.5~7.5 months) and 3.2 months (95%CI:1.7~4.7 months) (P0.05); the median OS was 11.2 months (95%CI:10.9~11.5 months) and 9.2 months (95%CI:8.7~9.7 months), the Log-rank test, the differences were statistically significant (P0.01). Plasma miR-138-5p high expression and low PFS expression respectively in the group was 5.5 months (95%CI:3.0~8.1 months) and 3.5 months (95%CI:1.5~5.5 months) (P0.05). The median OS was 11.4 months (95%CI:11.0~11.8 months) and 9.5 months (95%CI:8.6~10.4 months), the Log-rank test, the differences were statistically significant (P0.01). The correlation analysis of linear table Ming, the expression of miR-138-5p in tumor tissue and plasma in gastric cancer with a positive correlation (r=0.899, P0.05). Conclusion: the expression of miR-138-5p in gastric cancer tissue and plasma in a positive correlation, and miR-138-5p expression in cancer tissue and plasma level of efficacy, and late first-line platinum based chemotherapy in patients with gastric cancer line PFS, OS has a The positive correlation between the objective. The third part: the relationship between hyponatremia and advanced gastric cancer chemotherapy and the expression level of miR-138-5p: To investigate the clinical characteristics and prognostic analysis of hyponatremia in patients with advanced gastric cancer complicated with hyponatremia and the level of correlation with the expression of miR-138-5p; methods: in the First Affiliated Hospital of Medical University Of Anhui were collected during 2009/06/01-2015/12/31 gastric cancer complicated with hyponatremia, screened from 44 patients with advanced gastric cancer patients with hyponatremia and received first-line chemotherapy, and 45 cases of advanced gastric cancer patients with normal serum sodium as control group, were analyzed retrospectively. These patients collected short-term efficacy of first-line chemotherapy, and toxicity of first-line PFS information detection of the low sodium group. A total of 5 cases with qRT-PCR method, the expression level of miR-138-5p in control group of 10 patients in tissues. Results: the late female, liver and Peritoneal metastasis, low ECOG score of patients with gastric cancer more easily hyponatremia. Low sodium group and control group in the first-line chemotherapy ORR rate was 25% (11/44) and 40% (18/45) (P=0.131); the DCR rate was 40.9% (18/44) and 73.3% (33/45) (P=0.002), the difference was statistically significant the disease control rate. Low sodium group first-line chemotherapy, the median PFS was 3 months (95%CI:2.8~3.7 months), the control group first-line chemotherapy. The median PFS was 4.5 months (95%CI:4.3~6.2 months), (2=14.618, P0.001), statistically significant differences between the two groups. Hyponatremia corrected first-line chemotherapy is better than low sodium PFS persist in patients, the difference was statistically significant. Anemia, low sodium group after first-line chemotherapy nausea, vomiting, fatigue, anorexia, the incidence is higher, the difference was statistically significant. The level of miR-138-5p expression in gastric cancer tissues than in the control group low sodium group, but the difference was not statistically significant. Conclusion: Hyponatremia can As one of the predictors of poor chemotherapy efficacy in advanced gastric cancer, it can be combined with miR-138-5p expression level to predict prognosis and prognosis of platinum based chemotherapy for advanced gastric cancer.

【學(xué)位授予單位】：安徽醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R735.2

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