促肾上腺皮质激素释放因子2型受体在肿瘤生长中的作用及其机制的研究
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摘要
促肾上腺皮质素释放因子(corticotropin-releasing factor,CRF)家族由CRF、urocortin 1 (UCN 1)、UCN 2和UCN 3组成。它们是大约40个氨基酸的神经肽,能与它们的两个受体,CRF受体1和CRF受体2结合。这两种受体是G蛋白偶联受体,它们的激活能通过诱导蛋白激酶信号通路产生效应。两种CRF受体在中枢和外周都有分布,但有着不同的药理学特征。大量报道证实CRF通路参与了一系列生理和病理生理学过程,而且,CRF通路是被认为是一种非常有希望的临床治疗靶点。Reubi等人报道许多人肿瘤组织中有CRF受体1和CRF受体2的表达。CRF/UCN也被发现在许多不同种类的肿瘤中有分布,比如垂体腺瘤、前列腺癌和子宫内膜癌。而且,一系列文献报道CRF/UCN通过CRF受体1产生抗肿瘤作用。尽管关于CRF受体2和肿瘤关系的报道还比较少,但是CRF受体2在肿瘤发生发展中的作用逐渐受到人们的重视。
本论文主要研究CRF受体2在人类肿瘤中的作用及其机制。不同种类的人肿瘤组织被用来筛查是否表达CRF受体。人小细胞肺癌组织被发现只有CRF受体2的表达。因此,小细胞肺癌细胞被用来研究CRF受体2对于肿瘤细胞的直接作用。由于CRF受体2被认为是一种强烈的血管生成抑制因子,而且由于肝细胞癌是一种高血管密度的肿瘤,且目前没有有效的化疗手段,所以我们利用人肝细胞癌来研究CRF受体2在肿瘤血管生成中的作用。
在论文的第一部分,我们探讨了CRF受体2在人小细胞肺癌细胞中的直接作用。CRF受体2也被发现表达于人小细胞肺癌组织和细胞系(NCI-H446和NCI-H1688)中。因此,我们利用CRF受体2的激动剂UCN 1和UCN 2来研究CRF受体2对于人小细胞肺癌的直接作用。根据我们的研究发现,UCNs能剂量依赖性的抑制小细胞肺癌细胞NCI-H446和NCI-H1688的增殖,同时,UCNs也能促进小细胞肺癌细胞的凋亡。预先给予CRF受体2阻断剂anti-sauvagine-30 (anti-Svg-30)能取消它的抗增殖和促凋亡作用。这些结果说明UCNs能抑制小细胞肺癌的生长,而且这一作用是通过激活CRF受体2来介导的。有趣的是,在人小细胞肺癌细胞中给予UCNs能抑制p38和AKT的磷酸化,然而对ERK1/2和JNK1/2则没有影响。这提示CRF受体2对于小细胞肺癌细胞的作用也许通过抑制p38和AKT磷酸化实现,而不是ERK1/2或JNK1/2来介导。此外,我们也测量了小细胞肺癌细胞分泌血管内皮生长因子(vascular endothelial growth factor, VEGF)的水平,通过给予UCNs激活CRF受体2能显著降低VEGF的表达水平,但是预先给予p38激动剂anisomysin或AKT激动剂PIP2能拮抗UCNs抑制VEGF分泌的作用。总而言之,UCNs激活CRF受体2抑制p38和AKT的磷酸化,使得VEGF分泌下调,最终抑制人小细胞肺癌细胞的生长。因此,我们推断CRF受体2是一种潜在的小细胞肺癌抗肿瘤靶点。此外,它的配体有可能成为一种针对内分泌小细胞肺癌的新型内分泌生物反应调节剂。
有报道指出CRF受体2的激活能强烈抑制血管生成和血管重构,UCN也能通过CRF受体2来抑制血管平滑肌细胞的增殖。我们以前的数据也显示UCN能降低大鼠血管平滑肌细胞的生存率。而且,VEGF作为内皮细胞源性的分裂原和一种主要的病理血管生成的介导子,通过给予UCN激活CRF受体2能降低大鼠血管平滑肌细胞中的VEGF水平。这些报道强烈提示CRF受体2可能在肿瘤血管生成中产生一种抑制作用,进而通过针对肿瘤中的内皮细胞产生抑制肿瘤的作用。在本文的第二部分,我们研究了CRF受体2在肿瘤血管生成中的潜在作用。由于肝细胞癌以高血管生成为特点,而且没有有效的化疗方法,因此我们利用肝细胞癌作为模型研究CRF受体2在肿瘤血管生成中的作用。尽管人肝细胞癌组织中肿瘤细胞并不表达CRF受体,但是肿瘤中的血管和内皮细胞表达受体,而且主要是CRF受体2。在肝细胞癌荷瘤裸鼠模型中,给予UCN能阻断肝细胞癌的在体生长。而且,给予UCN处理的荷瘤裸鼠发现其肿瘤血管密度显著降低。由于肝细胞癌细胞本身并不表达CRF受体,因此,我们相信通过UCN激活CRF受体2对肿瘤的抑制作用归因于其对血管生成的抑制作用。在体外模型中,利用三维血管生成检测我们发现UCN能剂量依赖性的显著抑制人肝细胞癌的血管生成;而且这一作用能被CRF受体2阻断剂anti-Svg-30所拮抗,但使用CRF受体1阻断剂NBI-27914无此作用。这些说明正是CRF受体2参与了肿瘤血管生成的抑制作用。此外,UCN也能抑制人脐静脉内皮细胞的增殖并促进其凋亡,anti-Svg-30同样也能拮抗这一作用,但NBI-27914无此作用。这些说明UCN通过激活内皮细胞上的CRF受体2来抑制内皮细胞的生长。我们还发现UCN能下调肝细胞荷瘤鼠肿瘤组织和血清中的VEGF表达,同样这一作用能被anti-Svg-30所阻断。所以,我们推断UCN作用于CRF受体2来降低肿瘤组织中内皮细胞VEGF表达来抑制肿瘤血管生成,最终抑制肝细胞癌在体生长。我们相信激活CRF受体2具有的抗血管生成作用有可能提示它是一种潜在的抗肿瘤靶点。由于VEGF对于提高肝细胞癌血管生成活性很重要,UCN能通过CRF受体2来调节VEGF进而抑制肿瘤生长。
根据以上的发现,CRF受体2有可能是一种新型的肿瘤治疗靶点,激活CRF受体2能对肿瘤生长产生一种双重作用:它能对表达CRF受体2的肿瘤细胞有直接抑制作用;而且,它也能抑制肿瘤血管生成来抑制肿瘤的在体生长。这些作用的机制可能归因于对VEGF的下调。因此,有理由相信CRF受体2可能是一种非常有希望的肿瘤治疗新靶点。而作为CRF受体2的天然配体,UCNs可能是一种潜在的肿瘤生物治疗药物。
Corticotropin-releasing factor (CRF) family is composed of CRF, urocortin 1 (UCN 1), UCN 2, and UCN 3, which are identified as about 40-amino acid neuropeptides and bind to their two known receptors, CRF receptor 1 (CRFR1) and CRFR2. These receptors are G-protein coupled, and their activation can mediate responses via protein kinase signaling pathways. Both CRF receptors are distributed in central nervous system (CNS) and periphery, but the two subtypes display quite different pharmacological profiles. It has become apparent that CRF pathway and its components are involved in a wide array of physiological and potentially pathophysiological processes, therefore, the CRF pathway presents is a very promising clinical therapeutic target. Reubi et al. reported that CRFR1 and CRFR2 expressed in many human cancers. CRF/UCN was also found to distribute in many types of cancers, such as pituitary adenoma, prostatic carcinoma, and endometrial carcinoma. Furthermore, series of literatures reported CRF/UCN has anticancer effects via CRFR1. Though there are few reports about the relationship between CRFR2 and tumors, the roles of CRFR2 in tumoral formation and development is being more and more followed with interest.
In this thesis, we investigated the roles and mechanisms of CRFR2 in the formation and development of human tumors. Different type human tumor tissues were used to identify whether they expressed the CRF receptors. Human small lung cancer (SCLC) tissues were found the expression of CRF receptors, CRFR2 only. Therefore, SCLC cells were used to study the direct effect of CRFR2 on tumor cells. Because CRFR2 was recognized as a tonic suppressor of angiogenesis, we also study the role of CRFR2 in tumor angiogenesis with human hepatocelluar carcinoma (HCC), since it is such a hypervascular tumor and there is no effective chemotherapy for this cancer.
In the first chapter of thesis, we investigated the direct effect of CRFR2 on human SCLC cells. CRFR2 was found to be expressed in the human SCLC tissue and SCLC cell lines (NCI-H446 and NCI-H1688). Therefore, the direct effect of CRFR2 on the human SCLC was investigated by using CRFR2 angonists UCN 1 and UCN 2. Based on our observations, UCNs could directly inhibit the proliferation of SCLC cell lines NCI-H446 and NCI-H1688 with a dose-dependent manner, meanwhile, UCNs also could promote the apoptosis of SCLC cells. These anti-proliferative and apoptosis promotive effects could be abolished by pretreatment with CRFR2 antagonist anti-sauvagine-30 (anti-Svg-30). These results indicated that UCNs could inhibit the growth of SCLC cells, and this effect was mediated by activation of CRFR2. Interestingly, treatment with UCNs could inhibit p38 and Akt phosphorylation, while didn’t affect the phosphorylation of ERK1/2 and JNK1/2 in human SCLC cells, implying that the effect of CRFR2 on SCLC cells might be mediated by inhibiting the phosphorylation of p38 and Akt, but not ERK1/2 or JNK1/2. Furthermore, the secretion levels of vascular endothelial growth factor (VEGF) in SCLC cells were measured, activation of CRFR2 by UCNs significantly decreased the VEGF secretion level, but pretreatment with p38 activator anisomysin or Akt activator PIP2 could abolish the UCNs’inhibition on the secretion of VEGF. Taken together, UCNs activated CRFR2 to inhibit the phosphorylation of p38 and Akt, and these effects mediated the down-regulation of VEGF secretion, finally to inhibit the growth of human SCLC cells. Therefore, we concluded that CRFR2 may be a potential anticancer target in SCLC. Moreover, its ligands might become new endocrine biologic response modifiers to neuroendocrine SCLC.
Evidence indicated that activation of CRFR2 resulted in a tonic suppression of angiogenesis and remodeling the juvenile and adult vasculature, and UCN inhibited the proliferation of vascular smooth muscle cells (VSMCs) via CRFR2. Our previous data also showed that UCN could reduce the viability of rat VSMCs. Moreover, as an endothelial cell (EC)-specific mitogen and a major mediator of pathological angiogenesis, VEGF level was also decreased in rat VSMCs by UCN treatment via CRFR2. These reports highly imply that CRFR2 may play an inhibitory role in tumor angiogenesis and thus tumor growth by targeting ECs in tumors. In the second chapter of this thesis, we investigated the potential roles of CRFR2 in the tumor angiogenesis. Because HCC is charactered by its hypervasculature and no effective chemotherapy for this cancer, we used HCC as model to study the roles of CRFR2 in the tumor angiogenesis. Though there was no expression of CRF receptors in human HCC cells in tissues, the vessels and ECs in the HCC were found to express CRF receptors, CRFR2 mainly. In the model of HCC tumor-bearing nude mice, administration with UCN could block the growth of HCC in vivo. Significant reduction in tumor microvessel density (MVD) was also found in UCN-treated tumor-bearing nude mice. Since HCC cells didn’t express CRF receptors, it was believed that tumor suppression was attributed to the inhibition of angiogenesis via activation of CRFR2 by UCN. In the in vitro model, UCN significantly inhibited human HCC angiogenesis in the three-dimensional angiogenesis assay with dose-dependent manner; this effect was reversed by CRFR2 antagonist, anti-Svg-30, but not by CRFR1 antagonist NBI-27914, demonstrating that it’s CRFR2 that involved in the effect of inhibition of tumor angiogenesis. Furthermore, UCN also inhibited the proliferation and promoted the apoptosis of human umbilical vein endothelial cells (HUVEC), anti-Svg-30 also abolished these effects, while CRFR1 antagonist NBI-27914 can not. These data showed that UCN activated CRFR2 on the ECs to inhibit their growth. Moreover, UCN could down-regulate VEGF expression in serum and tumor tissue of HCC-bearing nude mice, which could be abolished by anti-Svg-30. In conclusion, UCN, acting on CRFR2, down-regulated the VEGF expression of ECs in tumor tissue, then, inhibited tumor angiogenesis, finally, inhibited the growth of HCC in vivo. We believed that activation of CRFR2 has antiangiogenic properties, which is a potential anticancer target. Since VEGF is responsible for the increased angiogenic activity of HCC, UCN could regulate this growth factor to inhibit tumor growth by CRFR2.
Based on our observations, activation of CRFR2 produced dual effects on tumor growth: it can directly inhibit the growth of cancer cells which express CRFR2; moreover, it blocks the tumor growth by inhibiting tumor angiogenesis in vivo. The mechanism of these effects is attributed to the down-regulation of VEGF. Therefore, it is reasonable to believe that CEFR2 may be a new promising tumor therapeutic target. UCNs, as CRFR2 natural agonists, may be potential tumor biological therapeutic agents.
本论文主要研究CRF受体2在人类肿瘤中的作用及其机制。不同种类的人肿瘤组织被用来筛查是否表达CRF受体。人小细胞肺癌组织被发现只有CRF受体2的表达。因此,小细胞肺癌细胞被用来研究CRF受体2对于肿瘤细胞的直接作用。由于CRF受体2被认为是一种强烈的血管生成抑制因子,而且由于肝细胞癌是一种高血管密度的肿瘤,且目前没有有效的化疗手段,所以我们利用人肝细胞癌来研究CRF受体2在肿瘤血管生成中的作用。
在论文的第一部分,我们探讨了CRF受体2在人小细胞肺癌细胞中的直接作用。CRF受体2也被发现表达于人小细胞肺癌组织和细胞系(NCI-H446和NCI-H1688)中。因此,我们利用CRF受体2的激动剂UCN 1和UCN 2来研究CRF受体2对于人小细胞肺癌的直接作用。根据我们的研究发现,UCNs能剂量依赖性的抑制小细胞肺癌细胞NCI-H446和NCI-H1688的增殖,同时,UCNs也能促进小细胞肺癌细胞的凋亡。预先给予CRF受体2阻断剂anti-sauvagine-30 (anti-Svg-30)能取消它的抗增殖和促凋亡作用。这些结果说明UCNs能抑制小细胞肺癌的生长,而且这一作用是通过激活CRF受体2来介导的。有趣的是,在人小细胞肺癌细胞中给予UCNs能抑制p38和AKT的磷酸化,然而对ERK1/2和JNK1/2则没有影响。这提示CRF受体2对于小细胞肺癌细胞的作用也许通过抑制p38和AKT磷酸化实现,而不是ERK1/2或JNK1/2来介导。此外,我们也测量了小细胞肺癌细胞分泌血管内皮生长因子(vascular endothelial growth factor, VEGF)的水平,通过给予UCNs激活CRF受体2能显著降低VEGF的表达水平,但是预先给予p38激动剂anisomysin或AKT激动剂PIP2能拮抗UCNs抑制VEGF分泌的作用。总而言之,UCNs激活CRF受体2抑制p38和AKT的磷酸化,使得VEGF分泌下调,最终抑制人小细胞肺癌细胞的生长。因此,我们推断CRF受体2是一种潜在的小细胞肺癌抗肿瘤靶点。此外,它的配体有可能成为一种针对内分泌小细胞肺癌的新型内分泌生物反应调节剂。
有报道指出CRF受体2的激活能强烈抑制血管生成和血管重构,UCN也能通过CRF受体2来抑制血管平滑肌细胞的增殖。我们以前的数据也显示UCN能降低大鼠血管平滑肌细胞的生存率。而且,VEGF作为内皮细胞源性的分裂原和一种主要的病理血管生成的介导子,通过给予UCN激活CRF受体2能降低大鼠血管平滑肌细胞中的VEGF水平。这些报道强烈提示CRF受体2可能在肿瘤血管生成中产生一种抑制作用,进而通过针对肿瘤中的内皮细胞产生抑制肿瘤的作用。在本文的第二部分,我们研究了CRF受体2在肿瘤血管生成中的潜在作用。由于肝细胞癌以高血管生成为特点,而且没有有效的化疗方法,因此我们利用肝细胞癌作为模型研究CRF受体2在肿瘤血管生成中的作用。尽管人肝细胞癌组织中肿瘤细胞并不表达CRF受体,但是肿瘤中的血管和内皮细胞表达受体,而且主要是CRF受体2。在肝细胞癌荷瘤裸鼠模型中,给予UCN能阻断肝细胞癌的在体生长。而且,给予UCN处理的荷瘤裸鼠发现其肿瘤血管密度显著降低。由于肝细胞癌细胞本身并不表达CRF受体,因此,我们相信通过UCN激活CRF受体2对肿瘤的抑制作用归因于其对血管生成的抑制作用。在体外模型中,利用三维血管生成检测我们发现UCN能剂量依赖性的显著抑制人肝细胞癌的血管生成;而且这一作用能被CRF受体2阻断剂anti-Svg-30所拮抗,但使用CRF受体1阻断剂NBI-27914无此作用。这些说明正是CRF受体2参与了肿瘤血管生成的抑制作用。此外,UCN也能抑制人脐静脉内皮细胞的增殖并促进其凋亡,anti-Svg-30同样也能拮抗这一作用,但NBI-27914无此作用。这些说明UCN通过激活内皮细胞上的CRF受体2来抑制内皮细胞的生长。我们还发现UCN能下调肝细胞荷瘤鼠肿瘤组织和血清中的VEGF表达,同样这一作用能被anti-Svg-30所阻断。所以,我们推断UCN作用于CRF受体2来降低肿瘤组织中内皮细胞VEGF表达来抑制肿瘤血管生成,最终抑制肝细胞癌在体生长。我们相信激活CRF受体2具有的抗血管生成作用有可能提示它是一种潜在的抗肿瘤靶点。由于VEGF对于提高肝细胞癌血管生成活性很重要,UCN能通过CRF受体2来调节VEGF进而抑制肿瘤生长。
根据以上的发现,CRF受体2有可能是一种新型的肿瘤治疗靶点,激活CRF受体2能对肿瘤生长产生一种双重作用:它能对表达CRF受体2的肿瘤细胞有直接抑制作用;而且,它也能抑制肿瘤血管生成来抑制肿瘤的在体生长。这些作用的机制可能归因于对VEGF的下调。因此,有理由相信CRF受体2可能是一种非常有希望的肿瘤治疗新靶点。而作为CRF受体2的天然配体,UCNs可能是一种潜在的肿瘤生物治疗药物。
Corticotropin-releasing factor (CRF) family is composed of CRF, urocortin 1 (UCN 1), UCN 2, and UCN 3, which are identified as about 40-amino acid neuropeptides and bind to their two known receptors, CRF receptor 1 (CRFR1) and CRFR2. These receptors are G-protein coupled, and their activation can mediate responses via protein kinase signaling pathways. Both CRF receptors are distributed in central nervous system (CNS) and periphery, but the two subtypes display quite different pharmacological profiles. It has become apparent that CRF pathway and its components are involved in a wide array of physiological and potentially pathophysiological processes, therefore, the CRF pathway presents is a very promising clinical therapeutic target. Reubi et al. reported that CRFR1 and CRFR2 expressed in many human cancers. CRF/UCN was also found to distribute in many types of cancers, such as pituitary adenoma, prostatic carcinoma, and endometrial carcinoma. Furthermore, series of literatures reported CRF/UCN has anticancer effects via CRFR1. Though there are few reports about the relationship between CRFR2 and tumors, the roles of CRFR2 in tumoral formation and development is being more and more followed with interest.
In this thesis, we investigated the roles and mechanisms of CRFR2 in the formation and development of human tumors. Different type human tumor tissues were used to identify whether they expressed the CRF receptors. Human small lung cancer (SCLC) tissues were found the expression of CRF receptors, CRFR2 only. Therefore, SCLC cells were used to study the direct effect of CRFR2 on tumor cells. Because CRFR2 was recognized as a tonic suppressor of angiogenesis, we also study the role of CRFR2 in tumor angiogenesis with human hepatocelluar carcinoma (HCC), since it is such a hypervascular tumor and there is no effective chemotherapy for this cancer.
In the first chapter of thesis, we investigated the direct effect of CRFR2 on human SCLC cells. CRFR2 was found to be expressed in the human SCLC tissue and SCLC cell lines (NCI-H446 and NCI-H1688). Therefore, the direct effect of CRFR2 on the human SCLC was investigated by using CRFR2 angonists UCN 1 and UCN 2. Based on our observations, UCNs could directly inhibit the proliferation of SCLC cell lines NCI-H446 and NCI-H1688 with a dose-dependent manner, meanwhile, UCNs also could promote the apoptosis of SCLC cells. These anti-proliferative and apoptosis promotive effects could be abolished by pretreatment with CRFR2 antagonist anti-sauvagine-30 (anti-Svg-30). These results indicated that UCNs could inhibit the growth of SCLC cells, and this effect was mediated by activation of CRFR2. Interestingly, treatment with UCNs could inhibit p38 and Akt phosphorylation, while didn’t affect the phosphorylation of ERK1/2 and JNK1/2 in human SCLC cells, implying that the effect of CRFR2 on SCLC cells might be mediated by inhibiting the phosphorylation of p38 and Akt, but not ERK1/2 or JNK1/2. Furthermore, the secretion levels of vascular endothelial growth factor (VEGF) in SCLC cells were measured, activation of CRFR2 by UCNs significantly decreased the VEGF secretion level, but pretreatment with p38 activator anisomysin or Akt activator PIP2 could abolish the UCNs’inhibition on the secretion of VEGF. Taken together, UCNs activated CRFR2 to inhibit the phosphorylation of p38 and Akt, and these effects mediated the down-regulation of VEGF secretion, finally to inhibit the growth of human SCLC cells. Therefore, we concluded that CRFR2 may be a potential anticancer target in SCLC. Moreover, its ligands might become new endocrine biologic response modifiers to neuroendocrine SCLC.
Evidence indicated that activation of CRFR2 resulted in a tonic suppression of angiogenesis and remodeling the juvenile and adult vasculature, and UCN inhibited the proliferation of vascular smooth muscle cells (VSMCs) via CRFR2. Our previous data also showed that UCN could reduce the viability of rat VSMCs. Moreover, as an endothelial cell (EC)-specific mitogen and a major mediator of pathological angiogenesis, VEGF level was also decreased in rat VSMCs by UCN treatment via CRFR2. These reports highly imply that CRFR2 may play an inhibitory role in tumor angiogenesis and thus tumor growth by targeting ECs in tumors. In the second chapter of this thesis, we investigated the potential roles of CRFR2 in the tumor angiogenesis. Because HCC is charactered by its hypervasculature and no effective chemotherapy for this cancer, we used HCC as model to study the roles of CRFR2 in the tumor angiogenesis. Though there was no expression of CRF receptors in human HCC cells in tissues, the vessels and ECs in the HCC were found to express CRF receptors, CRFR2 mainly. In the model of HCC tumor-bearing nude mice, administration with UCN could block the growth of HCC in vivo. Significant reduction in tumor microvessel density (MVD) was also found in UCN-treated tumor-bearing nude mice. Since HCC cells didn’t express CRF receptors, it was believed that tumor suppression was attributed to the inhibition of angiogenesis via activation of CRFR2 by UCN. In the in vitro model, UCN significantly inhibited human HCC angiogenesis in the three-dimensional angiogenesis assay with dose-dependent manner; this effect was reversed by CRFR2 antagonist, anti-Svg-30, but not by CRFR1 antagonist NBI-27914, demonstrating that it’s CRFR2 that involved in the effect of inhibition of tumor angiogenesis. Furthermore, UCN also inhibited the proliferation and promoted the apoptosis of human umbilical vein endothelial cells (HUVEC), anti-Svg-30 also abolished these effects, while CRFR1 antagonist NBI-27914 can not. These data showed that UCN activated CRFR2 on the ECs to inhibit their growth. Moreover, UCN could down-regulate VEGF expression in serum and tumor tissue of HCC-bearing nude mice, which could be abolished by anti-Svg-30. In conclusion, UCN, acting on CRFR2, down-regulated the VEGF expression of ECs in tumor tissue, then, inhibited tumor angiogenesis, finally, inhibited the growth of HCC in vivo. We believed that activation of CRFR2 has antiangiogenic properties, which is a potential anticancer target. Since VEGF is responsible for the increased angiogenic activity of HCC, UCN could regulate this growth factor to inhibit tumor growth by CRFR2.
Based on our observations, activation of CRFR2 produced dual effects on tumor growth: it can directly inhibit the growth of cancer cells which express CRFR2; moreover, it blocks the tumor growth by inhibiting tumor angiogenesis in vivo. The mechanism of these effects is attributed to the down-regulation of VEGF. Therefore, it is reasonable to believe that CEFR2 may be a new promising tumor therapeutic target. UCNs, as CRFR2 natural agonists, may be potential tumor biological therapeutic agents.
引文
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[21] Tezval H, Jurk S, Atschekzei F, Serth J, Kuczyk MA, Merseburger AS. The involvement of altered corticotropin releasing factor receptor 2 expression in prostate cancer due to alteration of anti-angiogenic signaling pathways. Prostate 2009; 69(4):443-8.
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[30] Tao J, Chen J, Wu Y, Li S. Urocortin reduces the viability of adult rat vascular smooth muscle cells via inhibiting L-type calcium channels. Peptide 2005; 26(11):2239-45.
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[1] Vaughan J, Donaldson C, Bittencourt J, Perrin MH, Lewis K, Sutton S, Chan R, Turnbull AV, Lovejoy D, River C. Urocortin a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature 1995; 378(6554):287-92.
[2] Grigoriadis DE, Lovenberg TW, Chalmers DT, Liaw C, De Souze EB. Characterization of corticotropin-releasing factor receptor subtypes. Ann N Y Acad Sci 1996; 780:60-80.
[3] Vale W, Speiss J, Rivier C, Rivier J. Characterization of a 41- residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science 1981; 213(4514):1394-7.
[4] Fekete EM, Zorrilla EP. Physiology, pharmacology, and therapeutic relevance of UCNs in mammals: ancient CRF paralogs. Front Neuroendocrinol 2007; 28(1):1-27.
[5] Zorrilla EP, Tache Y, Koob GF. Nibbling at CRF receptor control of feeding and gastrocolonic motility. Trends Pharmacol Sci 2003; 24(8):421-7.
[6] Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C, Prins GS, Perrin M, Vale W, Sawchenko PE. Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 2000; 428(2):191-212.
[7] Muramatsu Y, Sugino N, Suzuki T, Totsune K, Takahashi K, Tashiro A, Hongo M, Oki Y, Sasano H. Urocortin and corticotropinreleasing factor receptor expression in normal cycling human ovaries. J Clin Endocrinol Metab 2001; 86(3):1362-9.
[8] Kimura Y, Takahashi K, Totsune K, Muramatsu Y, Kaneko C, Darnel AD, Suzuki T, Ebina M, Nukiwa T, Sasano H. Expression of urocortin and corticotropin- releasing factor receptor subtypes in the human heart. J Clin Endocrinol Metab2002; 87(1):340-6.
[9] Reubi JC, Waser B, Vale W, Rivier J. Expression of CRF1 and CRF2 receptors in human cancers. J Clin Endocrinol Metab 2003; 88(7):3312-20.
[10] Iino K, Sasano H, Oki Y, Andoh N, Shin RW, Kitamoto T, Totsune K, Takahashi K, Suzuki H, Nagura H, Yoshimi T. Urocortin expression in human pituitary gland and pituitary adenoma. J Clin Endocrinol Metab 1997; 82(11):3842-50.
[11] Arcuri F, Cintorino M, Florio P, Floccari F, Pergola L, Romagnoli R, Petraglia F, Tosi P, Teresa Del Vecchio M. Expression of urocortin mRNA and peptide in the human prostate and in prostatic adenocarcinoma. Prostate 2002; 52(3):167-72.
[12] Florio P, De Falco G, Leucci E, Torricelli M, Torres PB, Toti P, Dell’Anna A, Tiso E, Santopietro R, Leoncini L, Petraglia F. Urocortin expression is downregulated in human endometrial carcinoma. J Endocrinol 2006; 190(1):99-105.
[13] Murakami Y, Mori T, Koshimura K, Kurosaki M, Hori T, Yanaihara N, Kato Y. Stimulation by urocortin of growth hormone (GH) secretion in GH-producing human pituitary adenoma cells. Endocr J 1997; 44(4):627-9.
[14] Schoeffter P, Feuerbach D, Bobirnac I, Gazi L, Longato R. Functional, endogenously expressed corticotropin-releasing factor receptor type 1 (CRF1) and CRF1 receptor mRNA expression in human neuroblastoma SH-SY5Y cells. Fundam Clin Pharmacol 1999; 13(4):484-9.
[15] Graziani G, Tentori L, Portarena I, Barbarino M, Tringali G, Pozzoli G, Navarra P. CRH inhibits cell growth of human endometrial adenocarcinoma cells via CRH-receptor 1-mediated activation of cAMP-PKA pathway. Endocrinology 2002; 143(3):807-13.
[16] Carlson KW, Nawy SS, Wei ET, Sade′e W, Filov VA, Rezsova VV, Slominski A, Quillan JM. Inhibition of mouse melanoma cell proliferation by corticotrophin- releasing hormone and its analogs. Anticancer Res 2001; 21(2A):1173-9.
[17] Slominski A, Roloff B, Zbytek B, Wei ET, Fechner K, Curry J, Wortsman J. Corticotropin-releasing hormone and related peptides can act as bioregulatory factors in human keratinocytes. In Vitro Cell Dev Bio Anim 2000; 36(3):211-6.
[18] Tjuvajev J, Kolesnikov Y, Joshi R, Sherinski J, Koutcher L, Zhou Y, Matei C, Koutcher J, Kreek MJ, Blasberg R. Antineoplastic properties of human corticotropin releasing factor: involvement of the nitric oxide pathway. In Vivo 1998; 12(1):1-10.
[19] Graziani G, Tentori L, Muzi A, Vergati M, Tringali G, Pozzoli G, Navarra P. Evidence that corticotropin-releasing hormone inhibits cell growth of human breast cancer cells via the activation of CRH-R1 receptor subtype. Mol Cell Endocrin 2007; 264(1-2):44-9.
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[25] Yang Y, Park H, Yang Y, Kim TS, Bang SI, Cho D. Enhancement of cell migration by corticotropin releasing hormone through ERK1/2 pathway in murine melanoma cell line, B16F10. Exp Dermatol 2006; 16(1):22-7.
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[7] Muramatsu Y, Sugino N, Suzuki T, Totsune K, Takahashi K, Tashiro A, Hongo M, Oki Y, Sasano H. Urocortin and corticotropinreleasing factor receptor expression in normal cycling human ovaries. J Clin Endocrinol Metab 2001; 86(3):1362-9.
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[10] Iino K, Sasano H, Oki Y, Andoh N, Shin RW, Kitamoto T, Totsune K, Takahashi K, Suzuki H, Nagura H, Yoshimi T. Urocortin expression in human pituitary gland and pituitary adenoma. J Clin Endocrinol Metab 1997; 82(11):3842-50.
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[12] Florio P, De Falco G, Leucci E, Torricelli M, Torres PB, Toti P, Dell’Anna A, Tiso E, Santopietro R, Leoncini L, Petraglia F. Urocortin expression is downregulated in human endometrial carcinoma. J Endocrinol 2006; 190(1):99-105.
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