【摘要】：研究背景及目的:大腸癌是最常見的惡性腫瘤之一,近20年來,在我國發(fā)病率呈迅速增長的趨勢,其死亡率已上升至惡性腫瘤的第三位。2型糖尿病的發(fā)病率,在世界范圍內(nèi)也在不斷增加,預計2030年將上升至4.4%,約4.39億人次。流行病學和臨床研究均顯示2型糖尿病和大腸癌之間有著共同的危險因素,且相互促進。2型糖尿病人群中,大腸癌的發(fā)病及死亡風險增加,且預后差�，F(xiàn)有研究顯示,2型糖尿病時高胰島素、活性氧增加等與大腸癌發(fā)生發(fā)展有關,同時,2型糖尿病時去甲腎上腺素水平增高也是大腸癌發(fā)生風險增高的重要誘因。精氨酸特異性單ADP核糖基轉(zhuǎn)移酶1(ART1)是一種重要的單ADP核糖基轉(zhuǎn)移酶,被認為與多種細胞生物學行為有著密切的關系。課題組前期研究顯示,ART1的表達變化,可以影響大腸癌細胞的增殖、侵襲轉(zhuǎn)移、分化、微血管形成、自噬及凋亡,參與大腸癌的發(fā)生及發(fā)展;ART1與胰島素信號通路肝糖原調(diào)節(jié)的負性調(diào)節(jié)子磷酸化GSK-3β蛋白表達有關,提示ART1可能在糖代謝性疾病中發(fā)揮作用。但ART1對2型糖尿病高NE狀態(tài)下大腸癌生長影響及機制研究,尚未見相關報道。本課題旨在前期研究的基礎上,從三方面入手,首先探討2型糖尿病合并大腸癌患者癌組織ART1的表達變化,其次建立balb/C2型糖尿病小鼠模型,采用課題組前期制備的不同ART1表達水平的CT26細胞,建立小鼠移植瘤模型,此外,以去甲腎上腺素誘導不同ART1表達水平的CT26細胞,從在體及離體兩方面,探討ART1對2型糖尿病高NE狀態(tài)大腸癌生長的影響及其可能的分子機制。為ART1作為治療2型糖尿病合并大腸癌的候選靶點提供實驗依據(jù)。方法:本研究分為三部分進行。1.2型糖尿病合并大腸癌癌組織ART1表達變化采用免疫組化方法,檢測大腸癌組織ART1表達。比較大腸癌合并2型糖尿病(CRCD)組(n=37例)與大腸癌未合并糖尿病(CRCO)組(n=23例)ART1表達強度的變化,并分析ART1表達強度與糖尿病的關系。2.ART1對2型糖尿病高NE狀態(tài)小鼠大腸癌生長的影響(1)離體實驗選用四組CT26細胞:ART1高表達組(GFP-ART1組),空載體組(GFP-Vector組),ART1沉默組(GFP-Sh ART1組),未轉(zhuǎn)染組(Un-transfection組)。1)CCK8法,評估ART1對不同NE濃度誘導CT26細胞增殖活性的影響及ART1對NE不同時間誘導CT26細胞增殖活性影響。2)流式細胞術(shù)評估ART1對NE誘導各組CT26細胞周期的影響。(2)在體實驗1)2型糖尿病小鼠模型的建立采用高脂飼料喂養(yǎng)及腹腔注射1%鏈脲菌素(STZ)的方法建立2型糖尿病Balb/c小鼠模型。對照組Balb/c小鼠腹腔注射等體積生理鹽水。尾靜脈采血檢測小鼠血糖,以確定模型的建立,同時檢測去甲腎上腺素及胰島素水平。2)不同ART1水平2型糖尿病大腸癌移植瘤體積及重量和小鼠荷瘤生存時間檢測以糖尿病Balb/c小鼠為實驗組,非糖尿病Balb/c小鼠為對照組,小鼠右側(cè)腋窩皮下分別接種四組CT26細胞,即ART1高表達CT26細胞(GFP-ART1組)、ART1沉默CT26細胞(GFP-sh ART1組)、未轉(zhuǎn)染CT26細胞(Un-transfection組)和空載體轉(zhuǎn)染CT26細胞(GFP-Vector組),建立Balb/c小鼠大腸癌移植瘤模型。觀測各組小鼠體重變化、移植瘤體積及重量;觀測各組小鼠荷瘤生存時間。3)ART1高表達對2型糖尿病小鼠不同NE水平大腸癌移植瘤生長的影響采用左腎交感神經(jīng)離斷術(shù),建立糖尿病血循環(huán)低NE水平Balb/c小鼠模型。尾靜脈采血檢測小鼠去甲腎上腺素(NE)以確定模型的建立,同時檢測血糖及胰島素水平。在小鼠右側(cè)腋窩皮下接種ART1高表達CT26細胞。以手術(shù)組(LRD組)為實驗組,未手術(shù)組(GFP-ART1組)和假手術(shù)組(LSO組)為對照組,觀測各組小鼠移植瘤體積及重量。3、ART1對2型糖尿病高NE狀態(tài)小鼠大腸癌生長影響的機制(1)離體實驗ART1對高NE誘導的小鼠大腸癌CT26細胞p-AKT、AKT、m TOR、STAT3、Cyclin D1及c-myc蛋白表達影響選用四組CT26細胞:ART1高表達組(GFP-ART1組),空載體組(GFP-Vector組),ART1沉默組(GFP-Sh ART1組),未轉(zhuǎn)染組(Un-transfection組)。以終濃度為1μmmol/l NE誘導各組CT26細胞。采用western blot檢測各組細胞ART1、p-AKT、m TOR、STAT3、Cyclin D1、c-myc蛋白表達變化。(2)在體實驗1)2型糖尿病高NE狀態(tài)小鼠大腸癌移植瘤ART1、P-AKT、m TOR及STAT3表達變化采用Western blot方法,以非糖尿病小鼠移植瘤為對照組,檢測糖尿病小鼠移植瘤組織ART1、p-AKT、AKT、m TOR、STAT3的蛋白表達變2)ART1高表達對2型糖尿病不同NE水平小鼠大腸癌移植瘤組織p-AKT、AKT、m TOR、STAT3蛋白表達影響采用western blot方法,以未手術(shù)組(GFP-ART1組)和假手術(shù)組(LSO組)為對照組,檢測手術(shù)組(LRD組)移植瘤組織ART1、p-AKT、AKT、m TOR、STAT3蛋白表達變化。結(jié)果:1、2型糖尿病合并大腸癌癌組織ART1表達變化(1)免疫組化檢測人大腸癌組織中ART1的表達ART1著色部位主要位于腫瘤細胞胞質(zhì)及胞膜。CRCD組ART1的表達強度明顯高于CRCO組,且有統(tǒng)計學差異(p0.05)。即使對年齡、性別、腫瘤部位、浸潤深度、等因素進行較正后,2型糖尿病仍是ART1表達強度的獨立相關因素。2、ART1對2型糖尿病高NE狀態(tài)小鼠大腸癌生長的影響(1)離體實驗1)ART1對不同NE濃度誘導CT26細胞增殖活性影響CCK8法檢測各組細胞的增殖活性。結(jié)果顯示,隨著NE濃度的增加,GFP-ART1、Un-transfection、GFP-Vector組細胞的增殖活性增加,但GFP-Sh ART1組細胞增殖活性無明顯變化。GFP-ART1組,相較其余三組,細胞增殖活性最高,GFP-Sh ART1組相較其余三組增殖活性最低(p0.05),Un-transfection、GFP-Vector組細胞間則無統(tǒng)計學差異(P0.05)。2)ART1對NE不同時間誘導CT26細胞增殖活性影響CCK8結(jié)果顯示,以終濃度為1μmmol/l NE分別誘導四組CT26細胞,在各誘導處理時間,GFP-ART1組,相較其余三組,細胞增殖活性最高,GFP-Sh ART1組相較其余三組增殖活性最低(p0.05)。且隨誘導時間的延長,GFP-ART1,Un-transfection和GFP-Vector組細胞增殖活性增加(p0.05),但GFP-Sh ART1組細胞增殖活性似乎沒有明顯變化(P0.05)。Un-transfection、GFP-Vector組細胞間則無統(tǒng)計學差異(P0.05)。3)ART1對NE誘導CT26細胞周期影響NE誘導CT26細胞后,未經(jīng)NE誘導的各對照組細胞:(1)ART1高表達組,未轉(zhuǎn)染組及空載體組可見G1期比例明顯減少,S期比例明顯增加,細胞增殖指數(shù)PI明顯增加(p0.05);(2)GFP-sh ART1組,即ART1沉默組,各時期細胞分布及PI無明顯改變(P0.05)。無論各組CT26細胞有無NE誘導,GFP-ART1組,G1期比例最少,S期比例最多,PI增加(p0.05)。Un-transfection、GFP-Vector組細胞間則無統(tǒng)計學差異(P0.05)。(2)在體實驗1)2型糖尿病小鼠模型的建立高脂飲食飼養(yǎng)及腹腔注射1%STZ后,小鼠體型肥胖,體重明顯重于對照組(P0.05);小鼠血糖、胰島素水平明顯高于對照組(P0.01),小鼠NE也明顯高于對照組(P0.01),表明糖尿病動物模型建立成功。2)不同ART1水平2型糖尿病大腸癌移植瘤體積及重量和小鼠荷瘤生存時間變化相同ART1表達水平CT26細胞接種后,與CRCO組比較,CRCD組小鼠移植瘤體積更大,重量更重,荷瘤生存時間更短,差異均具有統(tǒng)計學意義(p0.05)。CRCD組和CRCO組中,接種GFP-ART1 CT26細胞組移植瘤體積均為最大,重量最重,荷瘤生存時間最短,差異均具有統(tǒng)計學意義(p0.05);接種GFP-sh ART1 CT26細胞,移植瘤體積均最小,重量最輕,荷瘤生存時間最長,差異均具有統(tǒng)計學意義(P0.05);未轉(zhuǎn)染組與空載組則均無明顯差異(P0.05)。3)ART1高表達對2型糖尿病小鼠不同NE水平大腸癌移植瘤生長的影響與未手術(shù)組(GFP-ART1組)和假手術(shù)組(LSO組)比較,LRD組小鼠,NE水平,胰島素水平及血糖水平明顯下降(P0.01);移植瘤重量最輕,體積最小,差異具有統(tǒng)計學意義(P0.01)。GFP-ART1組和LSO組間則無統(tǒng)計學意義差異(P0.05)。3、ART1對2型糖尿病高NE狀態(tài)小鼠大腸癌生長影響的機制(1)離體實驗ART1對高NE誘導的小鼠大腸癌CT26細胞p-AKT、m TOR、STAT3、Cyclin D1及c-myc蛋白表達影響1)GFP-ART1組與un-transfection組相比較,ART1、p-AKT、m TOR、STAT3、Cyclin D1、c-myc蛋白表達明顯增加(p0.05)。2)GFP-sh ART1組與GFP-Vector組相比較,ART1、p-AKT、m TOR、STAT3、Cyclin D1、c-myc蛋白表達明顯減少(p0.05)。3)un-transfection組與GFP-Vector組,各蛋白表達無明顯差異(P0.05)。(2)在體實驗1)2型糖尿病高NE狀態(tài)小鼠移植瘤ART1、P-AKT、m TOR及STAT3表達變化Western blot顯示:與CRCO組比較,CRCD移植瘤組織,ART1、m TOR、STAT3、P-AKT蛋白表達明顯增加,(p0.01),AKT的表達,兩組間無明顯差異(P0.05)。2)ART1高表達對2型糖尿病不同NE水平小鼠大腸癌移植瘤組織p-AKT、AKT、m TOR、STAT3蛋白表達影響Western blot顯示:未手術(shù)組(GFP-ART1組)、假手術(shù)組(LSO組)、LRD組,瘤體組織,ART1、AKT蛋白表達三組間無明顯差異(P0.05),GFP-ART1組及LSO組P-AKT,m TOR、STAT3蛋白表達明顯高于LSD組及GFP-ART1組(p0.05)。結(jié)論:1、大腸癌合并2型糖尿病時,癌組織ART1表達明顯增強,且伴淋巴轉(zhuǎn)移組表達強度高于未轉(zhuǎn)移組。ART1表達強度與性別、分化程度及腫瘤部位無關;但對年齡、性別、腫瘤部位、侵潤深度、等因素進行較正后,糖尿病仍是ART1表達強度的獨立相關因素。提示ART1可能在2型糖尿病合并大腸癌時,對腫瘤發(fā)生發(fā)展發(fā)揮了一定作用。2、2型糖尿病小鼠大腸癌移植瘤生長更快,體積更大,重量更重,生存時間更短,且在ART1高表達時,上述現(xiàn)象更明顯;沉默ART1對NE誘導的大腸癌CT26細胞增殖活性具有抑制作用,細胞主要阻滯在G1期。提示ART1對2型糖尿病小鼠大腸癌移植瘤生長具有促進作用。3、糖尿病高NE狀態(tài)下,ART1可通過對AKT調(diào)節(jié),進而影響AKT/m TOR/STAT3信號通路,干預其下游基因cyclin D1、c-myc表達,影響大腸癌細胞的增殖。ART1有望成為糖尿病伴高NE水平時合并大腸癌治療候選靶點。
[Abstract]:Background and purpose: colorectal cancer is one of the most common malignant tumors. In the past 20 years, the incidence of the disease is increasing rapidly in China. The incidence of the third.2 type diabetes which has risen to malignant tumor is increasing in the world. It is expected to rise to 4.4%, about 439 million people in 2030. The bed studies have shown that there is a common risk factor between type 2 diabetes and colorectal cancer and that among people with type.2 diabetes, the risk of colorectal cancer and death is increased and the prognosis is poor. The present study shows that high insulin and active oxygen increase in type 2 diabetes are associated with the development of colorectal cancer, and the normethylene kidney in type 2 diabetes mellitus The increase of the level of the gland is also an important cause of the increased risk of colorectal cancer. Arginine specific single ADP ribonucleotransferase 1 (ART1) is an important single ADP ribonucleotransferase, which is considered to be closely related to a variety of cellular biological behavior. Proliferation, invasion, metastasis, differentiation, microvascular formation, autophagy and apoptosis are involved in the development and development of colorectal cancer; ART1 is associated with the expression of GSK-3 beta protein expression of the negative regulator of liver glycogen regulated by insulin signaling pathway, suggesting that ART1 may play a role in glycometabolic diseases. But ART1 is the growth of colorectal cancer in the high NE state of type 2 diabetes. The study of influence and mechanism has not yet been reported. On the basis of early study, this topic begins with three aspects, first to discuss the changes in the expression of ART1 in the cancer tissue of patients with type 2 diabetes and colorectal cancer, secondly to establish a model of balb/C2 type diabetes in mice, and to establish a small CT26 cell with different ART1 expression levels prepared by the project group. In addition, CT26 cells with different ART1 expression levels were induced by norepinephrine, and the effect of ART1 on the growth of high NE colorectal cancer in type 2 diabetes mellitus and its possible molecular mechanism were investigated from two aspects in vivo and in vitro. This provides an experimental basis for the treatment of ART1 as a candidate target for the treatment of type 2 diabetes with colorectal cancer. The study was divided into three parts, which were divided into three parts. The expression of ART1 expression in the tissues of type.1.2 diabetes and colorectal cancer by immunohistochemical method was used to detect the expression of ART1 in colorectal cancer tissue. The changes in the expression of ART1 in the group of large intestine cancer with type 2 diabetes mellitus (CRCD) and colorectal cancer (CRCO) group (n=23 cases) were compared, and the expression intensity and sugar of ART1 were analyzed. The effect of.2.ART1 on the growth of colorectal cancer in type 2 diabetic mice with high NE status (1) in vitro, four groups of CT26 cells were selected: ART1 high expression group (GFP-ART1 group), GFP-Vector group (group GFP-Vector), ART1 silence group (GFP-Sh ART1 group), non transfection group (Un-transfection group).1) CCK8 method Effect of activity and effect of ART1 on the proliferation of CT26 cells induced by NE at different time.2) flow cytometry was used to evaluate the effect of ART1 on CT26 cell cycle induced by NE. (2) in body experiment 1) the establishment of a model of type 2 diabetic mice by feeding high fat feed and intraperitoneal injection of 1% streptozotocin (STZ) to establish a model of type 2 diabetic Balb/c mice The Balb/c mice in the control group were intraperitoneally injected with equal volume of normal saline. The blood glucose was detected in the tail vein to determine the model, at the same time, the volume and weight of the transplanted tumor and the tumor survival time of the mice with different ART1 levels of type 2 diabetic colorectal cancer were detected at the same level of norepinephrine and insulin level.2). The experimental group of diabetic Balb/c mice was tested. Non diabetic Balb/c mice as control group, four groups of CT26 cells were inoculated subcutaneously in the right armpit of mice, namely, ART1 high expression CT26 cells (group GFP-ART1), ART1 silent CT26 cells (GFP-sh ART1 group), non transfected CT26 cells (Un-transfection group) and empty carrier transfected CT26 cells (Group). The mice model of colorectal carcinoma transplantation tumor was established. The body weight change, the volume and weight of the transplanted tumor, the tumor bearing time of the mice in each group.3) ART1 high expression on the growth of different NE levels of colorectal cancer in type 2 diabetic mice, the left renal sympathetic disconnection was used to establish a Balb/c mouse model with low blood circulation NE level in diabetic mice. Adenin (NE) was used to determine the establishment of the model, and at the same time the blood glucose and insulin levels were detected. ART1 high expression CT26 cells were subcutaneously inoculated in the right armpit of mice. The operation group (group LRD) was the experimental group, the non operation group (group GFP-ART1) and the sham operation group (group LSO) were used as the control group. The volume and weight of the transplanted tumor in each group were observed and.3, and ART1 was highly NE state of type 2 diabetes. The mechanism of the effect of the growth of colorectal cancer in mice (1) in vitro experiment, the effects of ART1 on the expression of p-AKT, AKT, m TOR, STAT3, Cyclin D1 and c-myc protein in CT26 cells induced by high NE in mice were selected as the expression of CT26 cells: the high expression group, the empty body group, the silent group and the untransfected group. CT26 cells were induced with final concentration of 1 mmol/l NE. Western blot was used to detect ART1, p-AKT, m TOR, STAT3, Cyclin D1, and protein expression changes. (2) in body experiment 1) colorectal cancer transplantation tumor of type 2 diabetic mice For the control group, the expression of ART1, p-AKT, AKT, m TOR, STAT3 was 2) in the transplanted tumor tissues of diabetic mice. The high expression of ART1 on the colorectal cancer transplanted tumor tissues of the mice with type 2 diabetes, p-AKT, AKT, m TOR, was used as the control group, and the control group and the sham operation group as the control group. The changes of the expression of ART1, p-AKT, AKT, m TOR, STAT3 protein in the transplanted tumor tissue of the operation group (group LRD). Results: the expression of ART1 expression in the tissues of 1,2 type diabetes combined with colorectal cancer (1) the expression of ART1 stained part of ART1 in human colorectal cancer tissue was mainly located in the cytoplasm and the cell membrane.CRCD group. And there was a statistical difference (P0.05). Even for age, sex, tumor site, depth of infiltration, and other factors, type 2 diabetes was still an independent factor in ART1 expression.2, ART1 had an effect on the growth of colorectal cancer in the high NE state of type 2 diabetes in mice (1) 1 in vitro.) ART1 had an effect on the proliferation of CT26 cells induced by different NE concentrations. The results showed that the proliferation activity of GFP-ART1, Un-transfection, GFP-Vector group increased with the increase of NE concentration, but the proliferation activity of GFP-Sh ART1 group had no obvious changes in.GFP-ART1 group, compared with the other three groups, the cell proliferation activity was the highest, GFP-Sh ART1 group compared with the other three groups, the proliferation activity was the lowest (P). 0.05), there was no statistical difference between Un-transfection and GFP-Vector groups (P0.05).2) ART1 on the proliferation activity of CT26 cells induced by NE at different times, and CCK8 results showed that four groups of CT26 cells were induced at the final concentration of 1 u mmol/l NE respectively. The cell proliferation activity was the highest in the induction time, GFP-ART1 group and the other three groups. The proliferation activity of the other three groups was the lowest (P0.05). And with the prolongation of the induction time, the proliferation activity of GFP-ART1, Un-transfection and GFP-Vector increased (P0.05), but the proliferation activity of GFP-Sh ART1 group did not seem to be significantly changed (P0.05).Un-transfection, and there was no statistical difference between the GFP-Vector groups (P0.05).3) Cell cycle influence NE induced CT26 cells, without NE induced cells: (1) ART1 high expression group, untransfected group and empty body group can obviously decrease the proportion of G1 stage, the proportion of S phase obviously increase, cell proliferation index PI obviously increase (P0.05); (2) GFP-sh ART1 group, that is, ART1 silencing group, cell distribution and PI have no obvious changes at all times. No matter whether the CT26 cells were induced by NE, the proportion of GFP-ART1, the G1 stage was the least, the S stage was the most, PI increased (P0.05).Un-transfection, and there was no statistical difference between the GFP-Vector group (P0.05). (2) in the body experiment 1) the establishment of high fat diet and celiac injection 1%STZ in the model of type 2 diabetes mice was obese and weight was significantly heavier than that in the model of type 2 diabetic mice. Control group (P0.05), mice blood glucose, insulin level was significantly higher than the control group (P0.01), mice NE was also significantly higher than the control group (P0.01), indicating the establishment of diabetic animal model successful.2) different ART1 Level 2 diabetes large intestine cancer transplantation tumor volume and weight and mice bearing tumor survival time changes the same ART1 expression level CT26 cell inoculation, and CRC Compared with group O, the tumor size of the mice in group CRCD was larger, weight was heavier, and the survival time of the tumor was shorter. The difference was statistically significant (P0.05) in group.CRCD and CRCO, the size of the transplanted tumor in the GFP-ART1 CT26 cell group was the largest, the weight was the heaviest, the survival time of the tumor bearing was the shortest, the difference was statistically significant (P0.05); GFP-sh ART1 CT26 was inoculated. Cells, the size of the transplanted tumor was the smallest, the weight was the lightest, the life time of the tumor bearing was the longest, and the difference was statistically significant (P0.05), and there was no significant difference between the untransfected group and the empty group (P0.05).3). The effect of high expression of ART1 on the growth of colorectal cancer in different NE levels of type 2 diabetic mice was compared with that of the unoperated group (group GFP-ART1) and the sham operation group (group LSO). Compared with group LRD, NE level, insulin level and blood glucose level decreased significantly (P0.01), the weight of the transplanted tumor was the lightest, the volume was the smallest, the difference was statistically significant (P0.01), there was no statistical difference between.GFP-ART1 and LSO groups (P0.05).3, ART1 on the growth of colorectal cancer in mice with high NE status of type 2 diabetes mellitus (1) ART1 on high N E induced mouse colorectal cancer CT26 cells p-AKT, m TOR, STAT3, Cyclin D1 and c-myc protein expression influence 1) GFP-ART1 group compared with un-transfection group. There was no significant difference in the expression of protein in group un-transfection and GFP-Vector (P0.05). (2) (2) in body experiment 1) the expression of ART1, P-AKT, m TOR and STAT3 expressed in the high NE state of type 2 diabetes mellitus mice. There was no significant difference between the two groups (P0.05).2) ART1 high expression of p-AKT, AKT, m TOR, and STAT3 protein expression in different NE mice of type 2 diabetes mellitus with the expression of Western blot: the non operative group (GFP-ART1 group), the sham operation group, the tumor body tissue, the tumor tissue, the protein expression of three groups had no significant difference. The expression of P-AKT, m TOR and STAT3 protein in group RT1 and LSO group was significantly higher than that in group LSD and GFP-ART1 group (P0.05). Conclusion: 1, the expression of ART1 in colorectal carcinoma with type 2 diabetes is obviously enhanced, and the expression intensity of the lymph node group is higher than that in the non metastatic group, and the intensity of.ART1 expression is not related to the sex, the degree of differentiation and the tumor site, but the age, sex, and tumor part are not related. Diabetes is still an independent factor in the expression intensity of ART1. It suggests that ART1 may play a role in the development of cancer in type 2 diabetes with colorectal cancer. It may play a role in the development of cancer in type 2 diabetic mice. The growth of the tumor is faster, the volume is greater, the weight is heavier, the survival time is shorter, and the ART1 is higher. At the time of expression, the above phenomenon is more obvious. Silence ART1 can inhibit the proliferation activity of NE induced colorectal CT26 cells, and the cells are mainly blocked at G1 stage. It suggests that ART1 has a promoting effect on the growth of colorectal carcinoma in type 2 diabetic mice, and ART1 can be regulated by AKT under the high NE state of diabetes, and then affects AKT/m TOR/STAT3 signaling pathway. Interfering with the downstream gene cyclin D1, c-myc expression and affecting the proliferation of colorectal cancer cells is expected to be a candidate target for the treatment of colorectal cancer with high NE levels in diabetes.
【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R735.34;R587.1

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