發(fā)布時(shí)間：2018-04-26 17:59

  本文選題：VIP + L　； 參考：《南昌大學(xué)》2016年博士論文

【摘要】：研究背景與目的:胃癌為消化道最常見(jiàn)的惡性腫瘤,在我國(guó)癌癥發(fā)病率及死亡率中排到第2位,較歐美國(guó)家具有極高的發(fā)病率及死亡率。近年來(lái),胃癌發(fā)病率有下降的趨勢(shì),但多數(shù)患者確診時(shí)已屬進(jìn)展期而失去手術(shù)根治機(jī)會(huì)。研究胃癌的免疫調(diào)節(jié)和免疫治療是探索胃癌未來(lái)治療的一個(gè)重要的方向。隨著對(duì)腫瘤的深入研究,發(fā)現(xiàn)腫瘤微環(huán)境在腫瘤的存活、增殖、侵襲和轉(zhuǎn)移的過(guò)程中具有非常重要的作用。腫瘤微環(huán)境中浸潤(rùn)的免疫細(xì)胞是腫瘤間質(zhì)的重要組成部分,這些免疫細(xì)胞參與了腫瘤免疫調(diào)節(jié),而存在于腫瘤微環(huán)境中的巨噬細(xì)胞往往占據(jù)顯著優(yōu)勢(shì),這些巨噬細(xì)胞也被稱為腫瘤相關(guān)性巨噬細(xì)胞(tumor-associated macrophages,TAMs)。巨噬細(xì)胞具有很大的可塑性,在不同微環(huán)境中可極化為M1型和M2型。Ml型巨噬細(xì)胞的活化通過(guò)經(jīng)典的激活途徑,可顯著釋放細(xì)胞炎性因子如TNFα、IL-12等;M2型巨噬細(xì)胞活化則通過(guò)替代途徑激活,信號(hào)機(jī)制復(fù)雜,目前仍不完全清楚。激活的M2型巨噬細(xì)胞可分泌具有免疫抑制的細(xì)胞炎性因子如IL-10等。腫瘤微環(huán)境中的腫瘤細(xì)胞可誘導(dǎo)分化多種浸潤(rùn)的免疫細(xì)胞,使其成為耐受性免疫細(xì)胞,失去對(duì)腫瘤的免疫監(jiān)視功能而促進(jìn)腫瘤的進(jìn)展,如形成腫瘤誘導(dǎo)的腫瘤浸潤(rùn)樹(shù)突細(xì)胞(tumor infiltrating DCs,Ti DCs)、腫瘤誘導(dǎo)的調(diào)節(jié)性T細(xì)胞(regulatory T cells,Tregs)、腫瘤誘導(dǎo)的骨髓來(lái)源的抑制性細(xì)胞(myeloid-derived suppressor cells,MDSCs)和腫瘤誘導(dǎo)的TAMs等。由于在腫瘤間質(zhì)中TAMs往往占據(jù)較大的比例,因此研究TAMs對(duì)腫瘤的免疫逃逸具有十分重要的作用。許多研究發(fā)現(xiàn),TAMs具有M2型巨噬細(xì)胞的表型特征及細(xì)胞功能,可促進(jìn)多數(shù)腫瘤進(jìn)展和轉(zhuǎn)移。血管活性腸肽(Vasoactive intestinal peptide,VIP)是屬于胰泌素/胰高血糖素家族的一種神經(jīng)肽,在機(jī)體廣泛表達(dá),具有許多重要的生理功能,包括擴(kuò)張血管,舒張平滑肌,促進(jìn)胰液的分泌,抑制胃酸及胃泌素的分泌,調(diào)節(jié)胃腸道運(yùn)動(dòng)等。近年研究發(fā)現(xiàn),VIP可以通過(guò)對(duì)免疫細(xì)胞免疫調(diào)節(jié)而維持機(jī)體的生理功能,如VIP可促進(jìn)激活的巨噬細(xì)胞分泌抑制性炎性因子IL-10,而抑制激活的巨噬細(xì)胞的促炎性細(xì)胞因子TNF-α、IL-12等的表達(dá),誘導(dǎo)巨噬細(xì)胞或T細(xì)胞、樹(shù)突細(xì)胞和NK細(xì)胞等其他免疫細(xì)胞的免疫功能而產(chǎn)生免疫耐受。因此,VIP是一種重要的參與免疫抑制、誘導(dǎo)免疫耐受的胃腸肽激素。在機(jī)體的整體調(diào)節(jié)中,神經(jīng)-內(nèi)分泌-免疫調(diào)節(jié)具有特別重要的作用,腫瘤的發(fā)生發(fā)展和人體神經(jīng)壓力的關(guān)系密不可分,許多神經(jīng)遞質(zhì)和激素在對(duì)腫瘤發(fā)生、生長(zhǎng)和轉(zhuǎn)移中起到正性和負(fù)性的調(diào)控作用[1]。研究發(fā)現(xiàn),某些腫瘤細(xì)胞可以分泌VIP,如胃腺癌組織表達(dá)VIP及某些胃癌細(xì)胞系也自分泌VIP,VIP受體在許多腫瘤細(xì)胞上有顯著表達(dá),VIP在調(diào)節(jié)多種腫瘤的生長(zhǎng)過(guò)程中起到重要的作用。因此,在腫瘤免疫調(diào)節(jié)過(guò)程中,VIP可能扮演著重要的角色。VIP為具有免疫抑制功能的胃腸肽激素,能夠抑制巨噬細(xì)胞的免疫功能,具有類似IL-10和TGF-β等抑制性細(xì)胞因子抑制機(jī)體免疫的作用。VIP主要通過(guò)和G蛋白偶聯(lián)受體結(jié)合而啟動(dòng)c AMP依賴和非c AMP依賴信號(hào)通路發(fā)揮對(duì)激活的巨噬細(xì)胞的免疫調(diào)節(jié)作用。由于調(diào)節(jié)巨噬細(xì)胞免疫功能的信號(hào)機(jī)制非常復(fù)雜,VIP是否還能通過(guò)其他信號(hào)途徑調(diào)節(jié)巨噬細(xì)胞的極化改變目前還沒(méi)有發(fā)現(xiàn)。信號(hào)調(diào)節(jié)蛋白α(Signal regulatory proteinα,SIRPα)是SIRPs一個(gè)家族成員。有研究發(fā)現(xiàn),SIRPα能夠調(diào)節(jié)巨噬細(xì)胞的免疫功能,使其出現(xiàn)M2樣極化改變,其顯著特征就是其胞內(nèi)段ITIMs可以發(fā)生酪氨酸磷酸化并募集含有SH2結(jié)構(gòu)域的信號(hào)分子SHP-1和SHP-2,啟動(dòng)相關(guān)信號(hào)機(jī)制,負(fù)性調(diào)節(jié)巨噬細(xì)胞的免疫功能。胃癌組織和一些特定的胃癌細(xì)胞能夠表達(dá)VIP,如SGC-7901細(xì)胞,而胃癌細(xì)胞通過(guò)自分泌VIP調(diào)節(jié)巨噬細(xì)胞的免疫功能,可能與胃癌細(xì)胞的發(fā)生發(fā)展有關(guān)。本研究旨在通過(guò)體內(nèi)和體外細(xì)胞實(shí)驗(yàn)觀察VIP對(duì)巨噬細(xì)胞極化的影響及VIP通過(guò)巨噬細(xì)胞對(duì)胃癌細(xì)胞功能的影響。通過(guò)體外細(xì)胞實(shí)驗(yàn)進(jìn)一步觀察VIP調(diào)節(jié)巨噬細(xì)胞SIRPα表達(dá)及相關(guān)信號(hào)分子的變化,探討上述的結(jié)果是否可能與VIP通過(guò)影響巨噬細(xì)胞SIRPα的信號(hào)機(jī)制對(duì)巨噬細(xì)胞的免疫調(diào)節(jié)作用有關(guān)。為VIP在腫瘤的免疫調(diào)節(jié)和免疫治療中的作用提供理論與實(shí)驗(yàn)依據(jù)。方法:1.收集臨床胃癌患者手術(shù)切除的腫瘤與正常組織樣本,采用免疫組化染色,以CD68為TAMs標(biāo)記,檢測(cè)胃癌組織與正常組織中VIP、CD68、IL-10及IL-12的表達(dá)差異,分析胃癌組織中CD68、VIP與主要臨床病理指標(biāo)的相關(guān)性。進(jìn)一步分析胃癌組織中VIP分別與CD68、IL-10及IL-12之間的相關(guān)性。通過(guò)體內(nèi)實(shí)驗(yàn)探討VIP對(duì)巨噬細(xì)胞極化的影響。2.使用PMA誘導(dǎo)THP-1單核細(xì)胞分化為巨噬細(xì)胞,利用流式細(xì)胞儀檢測(cè)誘導(dǎo)后的THP-1細(xì)胞CD14和CD68的表達(dá)以鑒定巨噬細(xì)胞。采用ELISA和實(shí)時(shí)熒光定量PCR分別檢測(cè)各組巨噬細(xì)胞的相關(guān)炎性細(xì)胞因子及i NOS mRNA、Arg-1 mRNA的表達(dá)。通過(guò)體外細(xì)胞實(shí)驗(yàn)探討VIP對(duì)巨噬細(xì)胞極化的影響。3.采用transwell共培養(yǎng)技術(shù)將巨噬細(xì)胞與SGC-7901細(xì)胞共培養(yǎng),MTT法檢測(cè)各組巨噬細(xì)胞對(duì)胃癌細(xì)胞增殖活性的影響;采用transwell共培養(yǎng)技術(shù)將巨噬細(xì)胞與SGC-7901細(xì)胞共培養(yǎng)后觀察各組巨噬細(xì)胞對(duì)胃癌細(xì)胞侵襲能力的影響。通過(guò)體外細(xì)胞實(shí)驗(yàn)觀察VIP通過(guò)巨噬細(xì)胞對(duì)胃癌細(xì)胞功能的影響。4.采用實(shí)時(shí)熒光定量PCR、Western blot及IP的方法檢測(cè)各組巨噬細(xì)胞SIRPα、p-SIRPα、PI3Kp85、SHP-2、Akt及p-Akt的表達(dá)。通過(guò)體外細(xì)胞實(shí)驗(yàn)進(jìn)一步探討上述的結(jié)果是否與VIP通過(guò)影響巨噬細(xì)胞SIRPα的信號(hào)機(jī)制對(duì)巨噬細(xì)胞的免疫調(diào)節(jié)作用有關(guān)。結(jié)果:1.腫瘤組織CD68陽(yáng)性表達(dá)率及表達(dá)強(qiáng)度顯著高于正常組織的巨噬細(xì)胞(p0.001);腫瘤組織VIP陽(yáng)性表達(dá)率及表達(dá)強(qiáng)度顯著高于正常組織的巨噬細(xì)胞(p0.05,p0.05);腫瘤組織IL-10陽(yáng)性表達(dá)率稍微高于正常組織(p0.05),表達(dá)強(qiáng)度顯著高于正常組織(p0.05);腫瘤組織IL-12陽(yáng)性表達(dá)率低于正常組織(p0.05),表達(dá)強(qiáng)度顯著低于正常組織(p0.01);胃癌組織CD68表達(dá)強(qiáng)度與不同性別、年齡和腫瘤部位等均無(wú)顯著性差異(p0.05),CD68表達(dá)強(qiáng)度與分化程度低、淋巴結(jié)轉(zhuǎn)移陽(yáng)性、TNM高分期有一定的相關(guān)趨勢(shì)(p0.05,p0.01,p0.01);胃癌組織VIP表達(dá)強(qiáng)度與不同性別、年齡和腫瘤部位等均無(wú)顯著性差異(p0.05),VIP表達(dá)強(qiáng)度與分化程度低、淋巴結(jié)轉(zhuǎn)移陽(yáng)性、TNM高分期有一定的相關(guān)趨勢(shì)(p0.05);胃癌組織中VIP與CD68之間的表達(dá)強(qiáng)度呈明顯的正相關(guān)(p0.001),胃癌組織中VIP與IL-10之間的表達(dá)強(qiáng)度呈明顯的正相關(guān)(p0.001),胃癌組織中VIP與IL-12之間的表達(dá)強(qiáng)度呈明顯的負(fù)相關(guān)(p0.001)。2.LPS處理巨噬細(xì)胞后TNF-α、IL-12、IL-6和IL-10表達(dá)均有顯著上升(p0.05);而僅給予VIP對(duì)上述的炎性細(xì)胞因子表達(dá)未見(jiàn)顯著影響(p0.05);VIP對(duì)LPS處理的巨噬細(xì)胞TNF-α、IL-12和IL-6表達(dá)有顯著抑制作用(p0.05),而對(duì)IL-10表達(dá)有顯著促進(jìn)作用(p0.05);LPS處理巨噬細(xì)胞后i NOS mRNA表達(dá)顯著上升(p0.05),僅給予VIPi NOS mRNA表達(dá)未見(jiàn)顯著變化(p0.05);VIP對(duì)LPS處理的巨噬細(xì)胞i NOS mRNA表達(dá)有顯著抑制作用(p0.05);Arg-1mRNA表達(dá)在各組間比較均無(wú)統(tǒng)計(jì)意義(p0.05)。3.LPS處理巨噬細(xì)胞后抑制胃癌細(xì)胞的增殖活性(p0.05),VIP通過(guò)LPS處理的巨噬細(xì)胞促進(jìn)胃癌細(xì)胞的增殖活性(p0.05);LPS處理巨噬細(xì)胞后抑制胃癌細(xì)胞的侵襲力(p0.05),VIP通過(guò)LPS處理的巨噬細(xì)胞促進(jìn)胃癌細(xì)胞的侵襲力(p0.05)。4.LPS處理巨噬細(xì)胞后顯著下調(diào)巨噬細(xì)胞SIRPαmRNA及蛋白水平(p0.05),VIP通過(guò)LPS處理的巨噬細(xì)胞上調(diào)巨噬細(xì)胞SIRPαmRNA及蛋白水平(p0.05);LPS處理巨噬細(xì)胞后上調(diào)巨噬細(xì)胞SIRPα磷酸化水平,VIP通過(guò)LPS處理的巨噬細(xì)胞上調(diào)巨噬細(xì)胞SIRPα磷酸化水平,SIRPα磷酸化后可募集SHP-2及PI3Kp85分子;LPS處理巨噬細(xì)胞后顯著上調(diào)巨噬細(xì)胞Akt磷酸化水平,VIP通過(guò)LPS處理的巨噬細(xì)胞顯著下調(diào)巨噬細(xì)胞Akt磷酸化水平(p0.05),各組Akt蛋白比較無(wú)顯著性差異(p0.05)。結(jié)論:1.通過(guò)體內(nèi)實(shí)驗(yàn)證實(shí)了VIP促進(jìn)了巨噬細(xì)胞M2樣極化改變,VIP與胃癌的免疫逃逸相關(guān)。2.通過(guò)體外細(xì)胞實(shí)驗(yàn)進(jìn)一步驗(yàn)證了VIP促進(jìn)巨噬細(xì)胞M2樣極化改變,從而促進(jìn)胃癌細(xì)胞的增殖和侵襲能力。3.上述過(guò)程可能與VIP通過(guò)上調(diào)巨噬細(xì)胞SIRPα蛋白及促進(jìn)SIRPα磷酸化,進(jìn)而與SHP-2結(jié)合,競(jìng)爭(zhēng)性抑制NF-κB及PI3K-Akt信號(hào)的激活,負(fù)性調(diào)節(jié)巨噬細(xì)胞免疫功能的機(jī)制有關(guān)。
[Abstract]:Background and objective: gastric cancer is the most common malignant tumor in the digestive tract. It ranks second in the incidence and mortality of cancer in China. It has a very high incidence and mortality compared with the European and American countries. In recent years, the incidence of gastric cancer has declined, but most of the patients have lost the chance of radical operation at the time of diagnosis. Immunotherapy is an important direction for the exploration of the future treatment of gastric cancer. With the in-depth study of the tumor, it is found that the tumor microenvironment plays an important role in the survival, proliferation, invasion and metastasis of the tumor. The immune cells infiltrated in the tumor microenvironment are an important part of the tumor interstitium. These immune cells are immune to the tumor. Cells are involved in tumor immunomodulation, and macrophages, which exist in tumor microenvironments, often occupy significant advantages. These macrophages are also called tumor-associated macrophages (TAMs). Macrophages have great plasticity. In different microenvironments, the macrophages can be polarized to type M1 and M2 type.Ml macrophages. Activation through classical activation pathways can significantly release inflammatory cytokines such as TNF alpha, IL-12, etc. the activation of M2 type macrophages is activated by alternative pathways, and the signal mechanism is complex and is still not completely clear. Activated M2 macrophages can secrete inflammatory cytokines such as IL-10, such as IL-10. Tumor microenvironment tumors are fine. Cells can induce a variety of infiltrating immune cells, making it a tolerant immune cell, losing the immune surveillance of the tumor and promoting the progress of the tumor, such as the formation of tumor induced tumor infiltrating dendritic cells (tumor infiltrating DCs, Ti DCs), tumor induced T cells (regulatory T cells, Tregs), tumor induced bone Myeloid-derived suppressor cells (MDSCs) and tumor induced TAMs and so on. Because TAMs often occupies a large proportion in the tumor interstitium, the study of TAMs plays an important role in the immune escape of the tumor. Many studies have found that TAMs has the phenotypic characteristics and cell functions of the M2 type macrophages. Vasoactive intestinal peptide (VIP), a neuropeptide belonging to the secretin / glucagon family, is widely expressed in the body and has many important physiological functions, including dilating blood vessels, relaxing smooth muscle, promoting secretion of pancreatic juice, inhibiting the secretion of gastric acid and gastrin, and regulating the secretion of gastric acid and gastrin. Recent studies have found that VIP can maintain the physiological function of the body by immunoregulation of immune cells, such as VIP can promote the secretion of inhibitory inflammatory factor IL-10 by activated macrophages, and inhibit the expression of inflammatory cytokines, TNF- a, IL-12 and so on, and induce macrophage or T cells, and the dendrite is fine. The immune tolerance of other immune cells, such as cell and NK cells, is produced. Therefore, VIP is an important gastrointestinal peptide hormone involved in immunosuppression and induction of immune tolerance. In the overall regulation of the body, neuroendocrine immunoregulation is of special importance. The relationship between the development of tumor and the pressure of human body is closely related. Many neurotransmitters and hormones play a positive and negative regulatory role in the occurrence, growth and metastasis of tumors. [1]. studies have found that some tumor cells can secrete VIP, such as gastric adenocarcinoma tissue expression VIP and some gastric cancer cell lines that also secrete VIP, VIP receptors are expressed in many tumor cells, VIP is regulating a variety of tumors. In the process of growth, VIP may play an important role in the process of immunomodulating,.VIP, a gastrointestinal peptide hormone with immunosuppressive function, which inhibits the immune function of macrophages, and has the effect of inhibiting the immune function, such as IL-10 and TGF- beta, and the effect of.VIP mainly through and G Protein coupled receptors bind to activate C AMP dependent and non C AMP dependent signaling pathways for the immunoregulation of activated macrophages. As the signal mechanism for regulating macrophage immunity is very complex, it is not yet found that VIP can regulate the change of macrophage polarity through other signaling pathways. White alpha (Signal regulatory protein alpha, SIRP a) is a member of a family of SIRPs. Some studies have found that SIRP alpha can regulate the immune function of macrophages and make it M2 like polarization change. Its significant feature is that its intracellular segment ITIMs can produce tyrosine phosphorylation and raise the signal molecules containing SH2 domains, SHP-1 and SHP-2, to initiate related letters. The immune function of macrophages is negatively regulated. Gastric cancer tissue and some specific gastric cancer cells can express VIP, such as SGC-7901 cells, and gastric cancer cells regulate the immune function of macrophages by autocrine VIP, which may be related to the occurrence and development of gastric cancer cells. This study aims to observe the giant VIP by in vivo and in vitro cell experiments. The effect of macrophage polarization and the effect of VIP through macrophage on the function of gastric cancer cells. Through in vitro cell experiment, we further observe the changes in the expression of SIRP alpha in macrophages and the related signal molecules by VIP, and explore whether the above results may be related to the immunoregulation of VIP through the signal mechanism affecting macrophage SIRP alpha. To provide theoretical and experimental basis for the role of VIP in the immunomodulatory and immunotherapy of tumor. Methods: 1. the tumor and normal tissue samples of the patients with gastric cancer were collected and the immunohistochemical staining was used to detect the difference in the expression of VIP, CD68, IL-10 and IL-12 in the gastric cancer tissue and the normal group with the CD68 TAMs markers. The correlation between CD68, VIP and main clinicopathological indexes in gastric cancer tissue. Further analysis of the correlation between VIP and CD68, IL-10 and IL-12 in gastric cancer tissue. The effect of VIP on the polarization of macrophages through the experiment in vivo:.2. using PMA induced THP-1 mononuclear cells to differentiate into macrophages, and the detection of the induced THP- by flow cytometry. 1 cells CD14 and CD68 were expressed to identify macrophages. ELISA and real-time fluorescence quantitative PCR were used to detect the inflammatory cytokines, I NOS mRNA, and the expression of Arg-1 mRNA, respectively. The effect of VIP on the polarization of macrophages in vitro was studied.3. by Transwell co culture technique. The effect of macrophages on the proliferation of gastric cancer cells was detected by MTT method. The influence of macrophages and SGC-7901 cells on the invasion ability of gastric cancer cells was observed by co culture of macrophages and SGC-7901 cells by Transwell co culture technique. The effect of macrophage on the function of gastric cancer cells through macrophage in vitro was observed. .4. used real-time fluorescent quantitative PCR, Western blot and IP to detect the expression of SIRP alpha, p-SIRP a, PI3Kp85, SHP-2, Akt and p-Akt in each group. The results of the in vitro cell test were further explored whether the above results were related to the immunoregulation effect of VIP through the signaling mechanism affecting macrophages. Results: 1. The positive expression rate and expression intensity of CD68 in tumor tissues were significantly higher than those of normal tissue macrophages (p0.001), and the positive expression rate and expression intensity of VIP in tumor tissues were significantly higher than those of normal tissue macrophages (P0.05, P0.05), and the positive rate of IL-10 in tumor tissues was slightly higher than that of normal tissue (P0.05), and the expression intensity was significantly higher than that of normal tissue (P0.05). The positive expression rate of IL-12 in tumor tissue was lower than that of normal tissue (P0.05), and the expression intensity was significantly lower than that of normal tissue (P0.01). The expression intensity of CD68 in gastric cancer tissues was not significantly different from that of different sex, age and tumor site (P0.05), CD68 expression intensity and differentiation degree were low, lymph node metastasis was positive, and TNM high stage had a certain correlation trend (P0.05, P0.01, P0.01); there was no significant difference in the expression intensity of VIP in gastric cancer tissue with different sex, age and tumor site (P0.05), VIP expression intensity and differentiation degree, lymph node metastasis positive, TNM high staging (P0.05); the expression intensity between VIP and CD68 in gastric cancer tissues was positively correlated (p0.001), gastric cancer tissue The expression intensity of VIP and IL-10 was positively correlated (p0.001). The expression intensity of VIP and IL-12 in gastric cancer tissues was negatively correlated (p0.001).2.LPS treated macrophages, TNF- a, IL-12, IL-6 and IL-10 were significantly increased (P0.05). 5); VIP had a significant inhibitory effect on the expression of TNF- alpha, IL-12 and IL-6 in the macrophages treated by LPS (P0.05), but significantly promoted the expression of IL-10 (P0.05). The expression of I NOS mRNA was significantly higher than that of LPS treated macrophages. Inhibition effect (P0.05); Arg-1mRNA expression in each group had no statistically significant (P0.05).3.LPS treatment of macrophages to inhibit the proliferation activity of gastric cancer cells (P0.05), VIP through LPS treated macrophages to promote the proliferation activity of gastric cancer cells (P0.05); LPS treated macrophages to inhibit the invasion of gastric cancer cells (P0.05), VIP through LPS Macrophages promoted the invasion of gastric cancer cells (P0.05).4.LPS to significantly reduce macrophage SIRP alpha mRNA and protein level (P0.05), VIP through LPS treated macrophages up regulation of macrophage SIRP alpha mRNA and protein level (P0.05); LPS treatment of macrophage after macrophage activation of macrophage SIRP alpha phosphorylation level. LPS treated macrophages raised the level of SIRP alpha phosphorylation of macrophages, and SIRP alpha could raise SHP-2 and PI3Kp85 molecules after phosphorylation. LPS treated macrophages significantly up-regulated the level of phosphorylation of Akt in macrophages. VIP through LPS treated macrophages significantly lowered the level of phosphorylation of Akt of macrophage Akt (P0.05). There was no significant difference in Akt protein in each group. Difference (P0.05). Conclusion: 1. in vivo experiments confirmed that VIP promoted the M2 like polarization change of macrophages and the immune escape related.2. of VIP and gastric cancer further verified that VIP promoted M2 like polarization change of macrophages, thus promoting the proliferation and invasion of gastric cancer cells, which may be associated with VIP through up regulation of macrophages. The cell SIRP alpha protein and the promotion of SIRP alpha phosphorylation, then combined with SHP-2, competitively inhibit the activation of NF- kappa B and PI3K-Akt signals, and the mechanism of negative regulation of macrophage immune function.

【學(xué)位授予單位】：南昌大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R735.2

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