不同部位和海拔胃癌预后分析及EPAS-1参与胃癌耐药研究
发布时间：2018-09-05 13:49
【摘要】：背景及目的:贲门癌是起源于胃食管结合部的腺癌。虽然世界范围内非贲门癌发病有下降趋势,但近年来包括中国在内的一些地区,尤其是西方国家,贲门癌发病率有增长趋势。贲门癌具有与非贲门癌不同的一些特殊的病因和临床病理特征。目前有关接受R0术后贲门癌患者预后因素研究很少,而且接受R0术后贲门癌患者与非贲门癌患者预后差异的研究也很少,且结论不一致。因此,R0术后贲门癌患者临床病理特征及预后仍不完全清楚,尤其是相同分期贲门癌与非贲门癌预后有无差异目前研究极少,需要进一步明确。本研究旨在比较R0术后贲门癌与非贲门癌临床病理特征及预后的差异。方法:连续收集自2009年12月至2011年12月在国内4家医院经组织学确诊为胃癌,且经R0切除(即显微镜下无肿瘤细胞)的患者。分析患者临床病理特征包括年龄、性别、民族、手术时间、解剖学位置、组织学类型、pTNM分期、手术方式、脉管及神经侵犯、(新)辅助化疗、(新)辅助放疗和复发时间。分析生存数据包括术后无病生存期(Disease-freesurvival,DFS)和总生存期(Overallsurvival,OS)。将患者分为贲门癌和非贲门癌2组,分析2组患者临床病理特征及长期生存的差异。结果:共有1633名患者纳入研究,其中贲门癌组581例,非贲门癌组1052例。比较贲门癌及非贲癌临床病理特征发现:民族及神经侵犯在两组间分布相似,但贲门癌组患者确诊时年龄更大(P0.001),男性比例更高(P0.001),pT3及pT4期病例更多(P0.001),淋巴结阳性比例更高(P = 0.003),病理分期Ⅱ-Ⅲ期更多(P0.001),病理学中分化更多(P0.001),脉管侵犯比例更高(P = 0.035)。治疗方面,接受淋巴结清扫(P=0.088),新辅助化疗(P=0.489),新辅助放疗(P=1.000)或辅助化疗(P = 0.068)比例在两组间并无显著差异,但是贲门癌患者较非贲门癌患者接受更多的辅助放化疗(P = 0.006)。比较2组DFS,贲门癌患者5年DFS较非贲门癌患者低(50.84 vs.59.22%,P0.001)。但是根据每一个病理分期分析DFS时,除了Ⅰ期贲门癌患者5年DFS更低(77.88 vs.86.92%,P=0.038)外,病理分期为Ⅱ期及Ⅲ期患者5年DFS并无差异。对于总体pTNM分期而言,5年疾病相关生存率贲门癌组(55.57%)低于非贲门癌组(62.38%;P=0.005)。然而,当根据每个pTNM分期分别分析OS时,贲门癌组和非贲门癌两组间无显著性差异(P均0.05)。根据每个pT分期或pN分期分别分析OS时,2组也没有显著差异性(P均0.05)。单因素生存分析显示年龄、病理分期、肿瘤分级、脉管侵犯及神经侵犯与贲门癌OS具有相关性。COX多因素回归分析发现病理分期Ⅲ期是一个独立的预后危险因素(P0.001),而病理分期Ⅱ期统计学分析处于具有显著性差异的临界值(P=0.054)。结论:与非贲门癌相比,贲门癌患者具有诊断时年龄更大,男性比例较多,明显不同的临床病理特征和术后pTNM病理分期较晚等特点。全部R0术后胃癌患者人群中,与非贲门癌患者相比,贲门癌患者5年DFS较低。然而,相同pTNM分期的贲门癌和非贲门癌中的总生存差异并没有显著性(至少在Ⅱ-Ⅲ期如此)。病理分期是影响贲门癌总生存的独立预后因素。在这项研究中的中国贲门癌术后患者病理分期更晚。研究提示只要患者能够及时进行检查作出早期诊断并接受合适的治疗,贲门癌患者可以获得与非贲门癌患者相似的预后。背景及目的:环境原因中除了幽门螺旋杆菌(Helicobacter pylori,HP)这一主要因素外,地理因素也在胃癌的发生和预后中起着重要作用。GLOBOCAN2012数据显示东亚是世界上胃癌发病率最高的地区。高原是一个特殊的低氧环境,也与胃癌发生存在相关性。虽然已有一些研究报道高原地区胃癌发病率和死亡率均较高,但目前仍然没有关于高原地区和平原地区胃癌临床病理特征及预后差异的研究。我们开展这项多中心研究比较了中国高原和平原地区R0术后胃癌临床病理特征及预后的差异。方法:从2009年12月至2011年12月,收集四个中国高原地区和平原地区中心胃癌术后病例并进行回顾性分析。所有患者均在青海大学附属医院、青海省人民医院、青海省红十字医院或中国医学科学院肿瘤医院经组织学诊断为原发性胃癌并接受R0切除。所有患者均长期居住在高原或者平原地区。按居住海拔将患者分为2组,海拔大于2200m者为高原组,低于1000m者为平原组。采集临床病理特征包括患者年龄、性别、民族、手术方式、肿瘤位置、组织学分级、pTNM分期、(新)辅助化疗、(新)辅助放疗和随访等参数。分析2组患者临床病理特征及长期生存的差异。COX比例风险模型评估高原因素对胃癌预后的影响。结果:共纳入高原地区251例患者和1382例平原患者。分析2组间病理特征和预后差异,与平原地区患者比较,在高原地区患者患病年龄更小,而且这种年龄差异仅存在于非贲门胃癌,而不存在于贲门癌患者;少数民族更多;非贲门胃癌比例更高;病理学中-高分化比例更高而低-中分化比例较少;接受新辅助化疗和辅助放疗的患者更少。生存分析发现,高原地区3年肿瘤相关生存率与平原地区差异无显著性(70.35%,72.22%,P=0.172)。而且,按不同部位分析,高原地区贲门癌患者3年肿瘤相关生存率(72.09%)与平原地区(67.38%)差异也无显著性(P = 0.987)。然而,非贲门患者3年肿瘤相关生存率(69.94%)低于平原地区(75.23%)(log-rank test:P = 0.033)。通过多变量Cox比例风险模型分析,高原被确定为非贲门胃癌的重要预后因素(HR:高原地区vs平原地区:1.50,95%CI:1.14-1.97,P= 0.004),且独立于其它所有预后因素。结论:高原地区R0术后胃癌患者患病年龄较平原地区更小,而且这种年龄差异仅存在于非贲门癌;非贲门癌比例高;病理分期与性别无差异。高原地区非贲门术后患者预后较平原地区差。高原被确定为非贲门胃癌的重要预后因素,且独立于其它所有预后因素。高原可能在非贲门癌发病及发展中起一定作用。需要重视和提高对高原地区胃癌患者的诊治。背景及目的:由于肿瘤细胞快速增值、血管异常及贫血等原因,实体瘤内低氧是其常见特征。研究表明低氧与实体瘤发生发展密切相关。实体瘤独特的低氧微环境除了参与肿瘤代谢、血管生成和转移等以外,目前普遍认为其还与肿瘤细胞的放化疗抵抗有关。通过调节低氧诱导因子家族成员EPAS-1/HIF-2(Endotheial PAS domain-containing protein 1,EPAS-1;Hypoxia-inducible factor-2,HIF-2)是低氧参与肿瘤发展的重要作用方式之一。近年有越来越多的研究表明EPAS-1也在实体瘤耐药中起着重要作用。有诸多机制参与EPAS-1介导的耐药,对同一个病例而言,还可能有多种机制同时参与EPAS-1调节的耐药过程。而且,药物耐药网络机制复杂,在不同肿瘤都会不同,甚至药物耐药会随着肿瘤发展而发生变化。目前报道的EPAS-1参与肿瘤耐药的机制包括调节细胞增殖、增加DNA修复能力、增强药物外排、调控细胞代谢、调节干细胞以及影响信号传导通路等。另外,胃癌仍然是威胁人类健康的常见肿瘤之一,化疗药物是晚期胃癌的重要治疗手段之一。虽然研发了很多化疗药物,但晚期胃癌患者预后仍然很差,几乎所有患者最后都出现耐药,迫切需要进一步研究胃癌多药耐药机制。EPAS-1表达于包括胃癌在内的多种肿瘤中。推测EPAS-1也参与胃癌耐药,但其在胃癌中耐药机制尚未见报道。而且,虽然目前已有许多研究表明EPAS-1可以促进肿瘤增值、迁移和侵袭等,但其具体机制仍然不完全明确。本研究旨在明确EPAS-1与胃癌的关系及其参与胃癌耐药的机制。方法:通过免疫组化检测胃癌配对组织中EPAS-1的表达,明确其与胃癌病理特征及预后的关系;ELISA检测EPAS-1在胃癌患者和健康对照组血清中的表达,明确其与对照组表达差异;以免疫共沉淀(Co-immunoprecipitation)和GSTpulldown实验确定EPAS-1和核受体Pregnane X Receptor(PXR)蛋白相互作用;以染色质免疫沉淀(Chromatin immuno-precipitation,ChIP)明确 EPAS-1、PXR 及其靶基因 CYP 3A4 的关系;以亚细胞分离实验(Subcellular fractionation assays)定位 PXR 和 EPAS-1;以软琼脂实验观察细胞增长;以流式细胞仪检测细胞周期及凋亡;Trans-well实验检测细胞侵袭;裸鼠成瘤实验检测EPAS-1体内成瘤能力;胃癌细胞系过表达EPAS-1或沉默EPAS-1表达,检测EPAS-1在胃癌增殖和对丝裂霉素(Mitomycin C,MMC)及紫杉醇(Paclitaxel,PTX)作用效果的影响。结果:EPAS-1在胃癌高表达并与胃癌预后不良相关,胃癌患者血清EPAS-1升高。EPAS-1/可以促进BGC-823胃癌细胞生长,并且EPAS-1可以与PXR相互作用,后者可以调节多个参与多药耐药(Multi-drugs resistance,MDR)基因的转录。以免疫共沉淀和GST pull down实验确定EPAS-1蛋白可以与PXR蛋白相互作用,EPAS-1募集PXR到它的反应元件—CYP3 A4的启动子/增强子,而后者是PXR的靶基因。过表达EPAS-1可以增加PXR反应基因的表达,促进BGC-823细胞增值,导致BGC-823细胞对MMC和PTX等细胞毒化疗药物耐药;而通过siRNA下调EPAS-1表达则可以抑制BGC-823细胞增值,并增强BGC-823细胞对化疗药物MMC和PTX的敏感性。而且,EPAS-1促进胃癌细胞裸鼠体内成瘤。结论:EPAS-1在胃癌增值、生存及预后和MDR方面均起着重要作用。EPAS-1与PXR可以共同作用,参与胃癌发展尤其是MDR过程。这些发现有可能为探索更加有效的胃癌靶向治疗药物提供新的方向。
[Abstract]:BACKGROUND AND OBJECTIVE: Cardiac cancer is an adenocarcinoma originating from the gastroesophageal junction. Although the incidence of non-cardiac cancer has been declining worldwide, the incidence of cardiac cancer has been increasing in some regions including China, especially in western countries in recent years. Cardiac cancer has some special etiology and Clinicopathology different from non-cardiac cancer. The prognostic factors of patients with cardiac cancer after R0 operation are seldom studied, and the prognostic differences between patients with cardiac cancer after R0 operation and those without cardiac cancer after R0 operation are few and inconsistent. The purpose of this study was to compare the clinicopathological characteristics and prognosis of cardiac cancer and non-cardiac cancer after R0 surgery. Methods: A series of patients with gastric cancer diagnosed histologically from December 2009 to December 2011 were collected from 4 hospitals in China, who underwent R0 resection (that is, no tumor cells under microscope). Patient. The clinicopathological features of the patients were analyzed, including age, sex, ethnicity, operative time, anatomical degree, histological type, pTNM stage, surgical procedure, vascular and nerve invasion, neoadjuvant chemotherapy, neoadjuvant radiotherapy, and recurrence time. Results: A total of 1633 patients were included in the study, including 581 patients with cardiac cancer and 1052 patients with non-cardiac cancer. Similarly, patients with cardiac cancer were older at diagnosis (P 0.001), more males (P 0.001), more pT3 and pT4 (P 0.001), more lymph node positive (P = 0.003), more pathological stages II-III (P 0.001), more differentiated (P 0.001), and more vascular invasion (P = 0.035). For treatment, patients received lymph node dissection (P = 0.035). 088, neoadjuvant chemotherapy (P = 0.489), neoadjuvant radiotherapy (P = 1.000) or adjuvant chemotherapy (P = 0.068) were not significantly different between the two groups, but patients with cardiac cancer received more adjuvant radiotherapy and chemotherapy than patients without cardiac cancer (P = 0.006). Compared with the two groups, patients with cardiac cancer had lower 5-year DFS (50.84 vs. 59.22%, P 0.001). The 5-year disease-related survival rate (55.57%) was lower in cardiac cancer group (62.38%) than in non-cardiac cancer group (62.38%; P = 0.005) according to the overall pTNM stage. There was no significant difference between the two groups in OS staging (P 0.05). There was no significant difference between the two groups in OS staging (P 0.05). Univariate survival analysis showed that age, pathological stage, tumor grade, vascular invasion and nerve invasion were associated with OS. Multivariate regression analysis showed that pathological stage III was an independent prognostic risk factor (P 0.001), while the statistical analysis of pathological stage II was at a critical value with significant difference (P = 0.054). Conclusion: Compared with non-cardiac cancer, patients with cardiac cancer had older age at diagnosis, more males and significantly different clinicopathological characteristics. Five-year DFS was lower in all patients with gastric cancer after R0 than in non-cardiac cancer. However, there was no significant difference in overall survival between cardiac cancer and non-cardiac cancer at the same pTNM stage (at least in stage II-III). Pathological stage was an independent factor affecting the overall survival of cardiac cancer. Prognostic factors. Pathological staging was later in this study in patients with cardiac cancer after surgery in China. The study suggests that patients with cardiac cancer can achieve similar prognosis as non-cardiac cancer patients if they are able to make early diagnosis and receive appropriate treatment promptly. Background and objective: Environmental causes other than Helicobacter pylori (Helicobacter pylori) Geographical factors also play an important role in the occurrence and prognosis of gastric cancer. GLOBOCAN 2012 data show that East Asia has the highest incidence of gastric cancer in the world. We conducted a multicenter study to compare the clinicopathological characteristics and prognosis of gastric cancer after R0 surgery in Plateau and plain areas in China. METHODS: From December 2009 to December 2011, four cases were collected. All patients were histologically diagnosed as primary gastric cancer and underwent R0 resection in the Affiliated Hospital of Qinghai University, Qinghai People's Hospital, Qinghai Red Cross Hospital or Cancer Hospital of the Chinese Academy of Medical Sciences. The patients were divided into two groups according to their living altitude, the plateau group was higher than 2200m, and the plain group was lower than 1000m. Results: A total of 251 patients in plateau area and 1382 patients in plain area were included. Pathological characteristics and prognosis differences between the two groups were analyzed. Patients in plateau area were younger and worse than those in plain area. Differentiation exists only in non-cardiac gastric cancer, not in cardiac cancer patients; more ethnic minorities; a higher proportion of non-cardiac gastric cancer; a higher and lower-to-moderate pathological differentiation rate; fewer patients received neoadjuvant chemotherapy and adjuvant radiotherapy. Survival analysis found that the 3-year tumor-related survival rate in plateau areas was worse than in plain areas. There was no significant difference (70.35%, 72.22%, P = 0.172). Moreover, there was no significant difference in 3-year tumor-related survival rate (72.09%) between Plateau and plain areas (67.38%) according to the location analysis. However, the 3-year tumor-related survival rate (69.94%) in non-cardiac patients was lower than that in plain areas (75.23%) (log-rank test: P = 0.033). Multivariate Cox proportional hazard model analysis showed that plateau was identified as an important prognostic factor for non-cardiac gastric cancer (HR: plateau vs plain area: 1.50, 95% CI: 1.14-1.97, P = 0.004), independent of all other prognostic factors. Conclusion: Patients with gastric cancer after R0 operation in plateau area were younger than those in plain area, and this age difference existed only in Plateau area. The prognosis of non-cardiac cancer patients in plateau area was worse than that in plain area. Plateau was identified as an important prognostic factor of non-cardiac cancer and independent of all other prognostic factors. Plateau may play a role in the pathogenesis and development of non-cardiac cancer. BACKGROUND AND OBJECTIVE: Hypoxia in solid tumors is a common feature of gastric cancer at high altitude due to rapid proliferation of tumor cells, vascular abnormalities and anemia. Studies have shown that hypoxia is closely related to the occurrence and development of solid tumors. Hypoxia-inducible factor-2 (HIF-2), a member of the hypoxia-inducible factor family EPAS-1/HIF-2 (Endothelial PAS domain-containing protein-1, EPAS-1), is one of the most important mechanisms of hypoxia-inducible factor-2 (HIF-2) in tumor development. There are many mechanisms involved in EPAS-1-mediated drug resistance. In the same case, there may be many mechanisms involved in the regulation of EPAS-1 at the same time. Moreover, drug resistance network mechanism is complex, different tumors will be different, and even drug resistance will change with the development of tumors. The reported mechanisms of EPAS-1 involved in tumor resistance include regulating cell proliferation, increasing DNA repair capacity, enhancing drug efflux, regulating cell metabolism, regulating stem cells, and affecting signal transduction pathways. Many chemotherapeutic drugs have been developed, but the prognosis of advanced gastric cancer patients is still poor. Almost all patients eventually develop drug resistance. Further study on the mechanism of multidrug resistance of gastric cancer is urgently needed. EPAS-1 is expressed in a variety of tumors including gastric cancer. Although many studies have shown that EPAS-1 can promote tumor proliferation, migration and invasion, the specific mechanism is still not clear. The purpose of this study is to clarify the relationship between EPAS-1 and gastric cancer and its mechanism involved in drug resistance in gastric cancer. The expression of EPAS-1 in serum of gastric cancer patients and healthy control group was detected by ELISA, and the difference between EPAS-1 and control group was clarified. The relationship between EPAS-1, PXR and its target gene CYP 3A4 was clarified by precipitation, subcellular fractionation assays were used to localize PXR and EPAS-1, soft agar assay was used to observe cell growth, flow cytometry was used to detect cell cycle and apoptosis, trans-well assay was used to detect cell invasion, and nude mice tumorigenesis assay was used to detect EPAS-1. The proliferation of gastric cancer and the effect of mitomycin C (MMC) and paclitaxel (PTX) on the proliferation of gastric cancer were detected by overexpression of EPAS-1 or silence of EPAS-1 expression in gastric cancer cell lines. 823 gastric cancer cells grew, and EPAS-1 could interact with PXR, which could regulate the transcription of multiple genes involved in multidrug resistance (MDR). Overexpression of EPAS-1 can increase the expression of PXR-responsive gene and promote the proliferation of BGC-823 cells, resulting in resistance of BGC-823 cells to cytotoxic chemotherapeutics such as MMC and PTX. Downregulation of EPAS-1 expression by siRNA can inhibit the proliferation of BGC-823 cells and enhance the sensitivity of BGC-823 cells to MMC and PTX. Conclusion: EPAS-1 plays an important role in the proliferation, survival, prognosis and MDR of gastric cancer. EPAS-1 and PXR can play a joint role in the development of gastric cancer, especially in the MDR process.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R735.2
本文编号：2224463
[Abstract]:BACKGROUND AND OBJECTIVE: Cardiac cancer is an adenocarcinoma originating from the gastroesophageal junction. Although the incidence of non-cardiac cancer has been declining worldwide, the incidence of cardiac cancer has been increasing in some regions including China, especially in western countries in recent years. Cardiac cancer has some special etiology and Clinicopathology different from non-cardiac cancer. The prognostic factors of patients with cardiac cancer after R0 operation are seldom studied, and the prognostic differences between patients with cardiac cancer after R0 operation and those without cardiac cancer after R0 operation are few and inconsistent. The purpose of this study was to compare the clinicopathological characteristics and prognosis of cardiac cancer and non-cardiac cancer after R0 surgery. Methods: A series of patients with gastric cancer diagnosed histologically from December 2009 to December 2011 were collected from 4 hospitals in China, who underwent R0 resection (that is, no tumor cells under microscope). Patient. The clinicopathological features of the patients were analyzed, including age, sex, ethnicity, operative time, anatomical degree, histological type, pTNM stage, surgical procedure, vascular and nerve invasion, neoadjuvant chemotherapy, neoadjuvant radiotherapy, and recurrence time. Results: A total of 1633 patients were included in the study, including 581 patients with cardiac cancer and 1052 patients with non-cardiac cancer. Similarly, patients with cardiac cancer were older at diagnosis (P 0.001), more males (P 0.001), more pT3 and pT4 (P 0.001), more lymph node positive (P = 0.003), more pathological stages II-III (P 0.001), more differentiated (P 0.001), and more vascular invasion (P = 0.035). For treatment, patients received lymph node dissection (P = 0.035). 088, neoadjuvant chemotherapy (P = 0.489), neoadjuvant radiotherapy (P = 1.000) or adjuvant chemotherapy (P = 0.068) were not significantly different between the two groups, but patients with cardiac cancer received more adjuvant radiotherapy and chemotherapy than patients without cardiac cancer (P = 0.006). Compared with the two groups, patients with cardiac cancer had lower 5-year DFS (50.84 vs. 59.22%, P 0.001). The 5-year disease-related survival rate (55.57%) was lower in cardiac cancer group (62.38%) than in non-cardiac cancer group (62.38%; P = 0.005) according to the overall pTNM stage. There was no significant difference between the two groups in OS staging (P 0.05). There was no significant difference between the two groups in OS staging (P 0.05). Univariate survival analysis showed that age, pathological stage, tumor grade, vascular invasion and nerve invasion were associated with OS. Multivariate regression analysis showed that pathological stage III was an independent prognostic risk factor (P 0.001), while the statistical analysis of pathological stage II was at a critical value with significant difference (P = 0.054). Conclusion: Compared with non-cardiac cancer, patients with cardiac cancer had older age at diagnosis, more males and significantly different clinicopathological characteristics. Five-year DFS was lower in all patients with gastric cancer after R0 than in non-cardiac cancer. However, there was no significant difference in overall survival between cardiac cancer and non-cardiac cancer at the same pTNM stage (at least in stage II-III). Pathological stage was an independent factor affecting the overall survival of cardiac cancer. Prognostic factors. Pathological staging was later in this study in patients with cardiac cancer after surgery in China. The study suggests that patients with cardiac cancer can achieve similar prognosis as non-cardiac cancer patients if they are able to make early diagnosis and receive appropriate treatment promptly. Background and objective: Environmental causes other than Helicobacter pylori (Helicobacter pylori) Geographical factors also play an important role in the occurrence and prognosis of gastric cancer. GLOBOCAN 2012 data show that East Asia has the highest incidence of gastric cancer in the world. We conducted a multicenter study to compare the clinicopathological characteristics and prognosis of gastric cancer after R0 surgery in Plateau and plain areas in China. METHODS: From December 2009 to December 2011, four cases were collected. All patients were histologically diagnosed as primary gastric cancer and underwent R0 resection in the Affiliated Hospital of Qinghai University, Qinghai People's Hospital, Qinghai Red Cross Hospital or Cancer Hospital of the Chinese Academy of Medical Sciences. The patients were divided into two groups according to their living altitude, the plateau group was higher than 2200m, and the plain group was lower than 1000m. Results: A total of 251 patients in plateau area and 1382 patients in plain area were included. Pathological characteristics and prognosis differences between the two groups were analyzed. Patients in plateau area were younger and worse than those in plain area. Differentiation exists only in non-cardiac gastric cancer, not in cardiac cancer patients; more ethnic minorities; a higher proportion of non-cardiac gastric cancer; a higher and lower-to-moderate pathological differentiation rate; fewer patients received neoadjuvant chemotherapy and adjuvant radiotherapy. Survival analysis found that the 3-year tumor-related survival rate in plateau areas was worse than in plain areas. There was no significant difference (70.35%, 72.22%, P = 0.172). Moreover, there was no significant difference in 3-year tumor-related survival rate (72.09%) between Plateau and plain areas (67.38%) according to the location analysis. However, the 3-year tumor-related survival rate (69.94%) in non-cardiac patients was lower than that in plain areas (75.23%) (log-rank test: P = 0.033). Multivariate Cox proportional hazard model analysis showed that plateau was identified as an important prognostic factor for non-cardiac gastric cancer (HR: plateau vs plain area: 1.50, 95% CI: 1.14-1.97, P = 0.004), independent of all other prognostic factors. Conclusion: Patients with gastric cancer after R0 operation in plateau area were younger than those in plain area, and this age difference existed only in Plateau area. The prognosis of non-cardiac cancer patients in plateau area was worse than that in plain area. Plateau was identified as an important prognostic factor of non-cardiac cancer and independent of all other prognostic factors. Plateau may play a role in the pathogenesis and development of non-cardiac cancer. BACKGROUND AND OBJECTIVE: Hypoxia in solid tumors is a common feature of gastric cancer at high altitude due to rapid proliferation of tumor cells, vascular abnormalities and anemia. Studies have shown that hypoxia is closely related to the occurrence and development of solid tumors. Hypoxia-inducible factor-2 (HIF-2), a member of the hypoxia-inducible factor family EPAS-1/HIF-2 (Endothelial PAS domain-containing protein-1, EPAS-1), is one of the most important mechanisms of hypoxia-inducible factor-2 (HIF-2) in tumor development. There are many mechanisms involved in EPAS-1-mediated drug resistance. In the same case, there may be many mechanisms involved in the regulation of EPAS-1 at the same time. Moreover, drug resistance network mechanism is complex, different tumors will be different, and even drug resistance will change with the development of tumors. The reported mechanisms of EPAS-1 involved in tumor resistance include regulating cell proliferation, increasing DNA repair capacity, enhancing drug efflux, regulating cell metabolism, regulating stem cells, and affecting signal transduction pathways. Many chemotherapeutic drugs have been developed, but the prognosis of advanced gastric cancer patients is still poor. Almost all patients eventually develop drug resistance. Further study on the mechanism of multidrug resistance of gastric cancer is urgently needed. EPAS-1 is expressed in a variety of tumors including gastric cancer. Although many studies have shown that EPAS-1 can promote tumor proliferation, migration and invasion, the specific mechanism is still not clear. The purpose of this study is to clarify the relationship between EPAS-1 and gastric cancer and its mechanism involved in drug resistance in gastric cancer. The expression of EPAS-1 in serum of gastric cancer patients and healthy control group was detected by ELISA, and the difference between EPAS-1 and control group was clarified. The relationship between EPAS-1, PXR and its target gene CYP 3A4 was clarified by precipitation, subcellular fractionation assays were used to localize PXR and EPAS-1, soft agar assay was used to observe cell growth, flow cytometry was used to detect cell cycle and apoptosis, trans-well assay was used to detect cell invasion, and nude mice tumorigenesis assay was used to detect EPAS-1. The proliferation of gastric cancer and the effect of mitomycin C (MMC) and paclitaxel (PTX) on the proliferation of gastric cancer were detected by overexpression of EPAS-1 or silence of EPAS-1 expression in gastric cancer cell lines. 823 gastric cancer cells grew, and EPAS-1 could interact with PXR, which could regulate the transcription of multiple genes involved in multidrug resistance (MDR). Overexpression of EPAS-1 can increase the expression of PXR-responsive gene and promote the proliferation of BGC-823 cells, resulting in resistance of BGC-823 cells to cytotoxic chemotherapeutics such as MMC and PTX. Downregulation of EPAS-1 expression by siRNA can inhibit the proliferation of BGC-823 cells and enhance the sensitivity of BGC-823 cells to MMC and PTX. Conclusion: EPAS-1 plays an important role in the proliferation, survival, prognosis and MDR of gastric cancer. EPAS-1 and PXR can play a joint role in the development of gastric cancer, especially in the MDR process.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R735.2
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1 赵久达;不同部位和海拔胃癌预后分析及EPAS-1参与胃癌耐药研究[D];北京协和医学院;2017年
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