β2-AR与Her2相互作用及在乳腺癌恶性演进中的意义
摘要
很久以来,人们就已经把慢性心理应激刺激与多种疾病的发生联系在一起,特别是恶性肿瘤。生活中的各种事件均可产生心理应激的刺激,包括创伤、不良的家庭及工作环境等。应激反应导致机体各系统的功能变化是生物进化过程中建立的一种防御反应,以防止激源对机体的损害。但是,如果个体无法适应重复性的刺激,则可导致长期而严重的后果。研究结果表明,慢性应激反应与乳腺癌的发生发展密切相关。例如,在离婚或配偶死亡的独身女性群体中,乳腺癌的发生几率为其他女性群体的3倍;长期处于极度压力并缺乏社会支持的女性罹患乳腺癌的风险是正常女性的9倍。
应激可刺激交感神经系统和下丘脑-垂体-肾上腺轴,导致儿茶酚胺的分泌增加。最近的研究表明,长期处于慢性应激反应状态的人群体内儿茶酚胺的水平持续升高。儿茶酚胺的持续刺激不仅可导致免疫系统的功能紊乱,亦可直接影响肿瘤的生物学行为。儿茶酚胺主要通过β-肾上腺素能受体(β-AR)发挥作用,而β-AR在某些肿瘤发生发展过程中的重要作用亦已被报道,但精确的分子机制不清。
在第一部分的研究中,我们应用免疫组化的方法,在50例临床乳腺癌组织标本中检测了Her2与β2-AR的表达。我们发现,Her2与β2-AR在乳腺癌组织中的表达具有良好的相关性。我们又通过体外实验观察到,在乳腺癌细胞MCF-7中过表达Her2可上调β2-AR的水平,提示Her2与β2-AR这两个受体分子之间存在密切的关系。
Her2是重要的癌基因,Her2过表达可激活细胞内多条信号通路。我们的实验结果证实,在MCF-7细胞中过表达Her2可导致细胞外信号调节激酶(ERK)的组成性活化,而ERK信号通路的抑制剂PD98059可明显抑制Her2过表达介导的β2-AR表达水平上调,表明ERK通路活化参与了Her2上调β2-AR表达的过程。我们的进一步实验证明,ERK通路的活化导致乳腺癌细胞中肾上腺素合成相关酶基因转录及自分泌肾上腺素的能力显著增强。通过体外模拟肾上腺素的自分泌或旁分泌,我们发现肾上腺素刺激可诱导乳腺癌细胞β2-AR表达水平上调。同时,我们还发现β2-AR激动剂刺激亦可显著上调乳腺癌细胞中Her2的表达。β2-AR的活化可直接或间接地调控某些转录因子的活性,我们的实验研究证实,异丙肾上腺素(ISO)刺激乳腺癌细胞MCF-7及BT474可诱导STAT3的活化,且活化的STAT3可进入细胞核并结合于Her2启动子区的STAT3元件,从而在转录水平和蛋白水平增强Her2的表达。
上述研究结果提示,β2-AR与Her2在乳腺癌细胞中形成正反馈调节环路:儿茶酚胺刺激乳腺癌细胞可诱导β2-AR信号及STAT3激活,活化的STAT3入核并结合于Her2启动子区功能性STAT3位点,增强Her2启动子的转录活性,导致Her2高表达;而Her2在乳腺癌细胞中过表达可诱导ERK磷酸化、促进肾上腺素合成酶的表达上调及活化,导致肾上腺素自分泌释放,进而上调β2-AR的表达。β2-AR及Her2信号通路的相互促进作用无疑在乳腺癌的恶性演进中具有重要的意义。在乳腺癌细胞中,这一互作机制不仅上调Her2及β2-AR的水平,而且可诱导儿茶酚胺及其他促血管生成、促转移因子的表达。过去认为Her2过表达主要归因于基因扩增,但最近的发现提示,约80%的Her2中度表达(++)的乳腺癌细胞无Her2基因扩增。本研究的深入将可能进一步揭示乳腺癌细胞中Her2过表达的新机制,并有助于阐明β2-AR与Her2协同作用在乳腺癌进展中的意义。
在第二部分的研究中,我们通过免疫组化分析,观察到Her2和β2-AR的表达常出现于肿瘤侵袭的前缘。有趣的是,在β2-AR高表达的肿瘤组织中,Her2受体常发生明显的核定位,提示β2-AR高表达与Her2入核可能存在一定的关系,β2-AR/Her2正反馈通路以及Her2入核可能在肿瘤的侵袭、转移过程中发挥重要作用。
研究发现,Her2 ECD的裂解可导致ICD的组成性活化及增强的信号转导,过表达Her2 ECD缺失突变体可提高酪氨酸激酶活性及细胞的转化效率。但是,在过表达Her2的肿瘤组织中Her2分子被切割的机制却不清楚。以往的多个研究表明,在Her2过表达的肿瘤细胞中,蛋白酶切割可导致Her2 ECD释放,产生含跨膜域和ICD的95 kDa片段(p95)。我们通过Western blot分析发现,在乳腺癌组织中除存在185 kDa和~100 kDa的片段外,尚可检测到~70 kDa的较小片段。裴刚研究小组在有关神经细胞和组织的研究中发现,β2-AR活化可增强γ-secretase的活性,而γ-secretase参与多种膜受体(包括CD44、Notch、E-candherin)胞内域近膜区的切割。我们通过CD44、Notch、E-candherin及Her2的序列对比发现,这些蛋白胞内域近膜区具有相似的组成特征,预测Her2分子由该处裂解恰可产生分子量~70 kDa的片段。我们通过γ-secretase活性分析,证实儿茶酚胺刺激确可导致MCF-7细胞中γ-secretase活性升高,提示Her2切割后的产物可能被γ-secretase进一步裂解。
进一步通过免疫荧光染色及共聚焦显微镜术,我们观察到ISO刺激可诱导Her2受体内化及Her2胞内域入核。以往的研究提示,入核的Her2分子可作为转录因子上调COX-2基因(肿瘤肺转移相关基因)转录。我们的研究结果证实,ISO刺激乳腺癌及卵巢癌细胞后,均可显著增强COX-2 mRNA的表达,提示ISO可能通过诱导Her2 ICD入核,增强Her2靶基因COX-2表达。我们又通过寡核苷酸pull-down分析,证实Her2 ICD可结合于COX-2启动子的Her2结合区。我们通过体内研究,证实了儿茶酚胺持续刺激可诱导Her2高表达的卵巢癌移植瘤在裸鼠体内自发性肺转移。
这些研究结果揭示,β2-AR活化可增强γ-分泌酶活性,诱导Her2切割及Her2胞内域入核,促进Her2靶基因COX-2的表达,进而可能在Her2高表达的卵巢癌肺转移过程中发挥重要的作用。β2-AR活化与Her2受体切割及入核相偶联的发现,揭示了Her2受体入核的全新机制,该机制的阐明不仅可能揭示Her2受体的质膜-核信号传递捷径的重要意义及跨膜受体酪氨酸激酶在核内的重要功能,而且亦将揭示β2-AR反式激活Her2在肿瘤恶性演进中的作用。
综上所述,本研究首次报道:1.β2-AR与Her2可在乳腺癌细胞中形成正反馈调节环路;2.β2-AR信号通路的活化可导致Her2被切割及Her2胞内域入核;3.本研究结果揭示了Her2过表达的新机制以及Her2分子切割、入核的新机制;4.β2-AR/Her2信号的相互作用在肿瘤的侵袭转移过程中发挥重要的作用。
The notion that psychosocial factors can affect the progression of many diseases, especially cancer, has long been suspected. Stress response can be induced by a variety of events, including trauma, family problems and bad working conditions. Stress response, which protects people from harmful stressors, is effective defensive mechanism established in evolvement. However, failure of coping with chronic stress can lead to long term and severe consequences. The data from several studies suggested that chronic stress may associate with the progression of breast cancer. For examples, the incidence of breast cancer is a three fold higher among women who are divorced or loss spouse and even nine fold higher among women experiencing extreme stress and lacking social support than normal population.
Stress initiates a response of the hypothalamic-pituitary-adrenal axis (HPA), resulting in increased catecholamine level. The continuously increased catecholamine levels are observed in individuals who are under chronic stress in the recent studies. Sustained stimulation of catecholamine interferes with not only the immune system but also bio-behaviors of tumor cells. Catecholamine exerts its effects via the activation ofβ-adrenergic receptors (β-AR).β-AR plays an important role in the development and progression of tumors. However, the precise mechanism by whichβ-AR acts in tumor progression is unclear.
In the first part of this study, we collected a total of 50 paraffin embedded breast cancer tissue samples and analyzed the expression of Her2 andβ2-AR by immunohistochemical staining. The results demonstrated thatβ2-AR level correlated with Her2 status in breast cancer samples. Overexpression of Her2 in breast cancer cell line MCF-7 strikingly up-regulatedβ2-AR level, impliying an intimate relationship between Her2 andβ2-AR in breast cancer cells.
Her2 is a very active oncogene and overexpression of Her2 can activates multiple signaling pathways. Our data demonstrated that the constitutive phosphorylation of ERK was induced by ectopic overexpression of Her2 in MCF-7 cells and blocking of ERK signaling by PD98059, which is known to selectively block the activity of ERK, markedly inhibitedβ2-AR up-regulation induced by Her2 overexpression in breast cancer cells, implicating that ERK signaling is involved in Her2-mediatedβ2-AR expression. Further study showed that the activation of ERK up-regulated the expression of the catecholamine synthesis enzymes, and promoted the release of epinephrine from breast cancer cells. By mimicking the autocrine and paracrine of catecholamine, we confirmed that epinephrine stimulation induced the up-regulation ofβ2-AR level in breast cancer cells.
Another interesting finding in this study is thatβ2-AR agonists up-regulated remarkably Her2 expression in breast cancer cells. Activation ofβ2-AR can regulate the activities of some transcriptional factors directly or indirectly. Our data showed that isoproterenol triggered the activation and nuclear translocation of STAT3 in breast cancer cell lines BT474 and MCF-7, subsequently the activated STAT3 bound to STAT3 element in the Her2 promoter and promoted Her2 expression at transcriptional and protein levels.
Above data support a model whereβ2-AR and Her2 comprise a positive feedback loop in human breat cancer cells: Catecholamine stimulates the activation ofβ2-AR mediated signaling, resulting in the activation, nuclear translocation and binding to a functional STAT3 site in the Her2 promoter and thus promoting Her2 transactivaton; Her2-mediated ERK signaling induces the up-regulation ofβ2-AR expression by promoting the expression of catecholamine synthesis enzymes and autocrine of epinephrine in breast cancer cells. In this way, Her2/β2-AR feedback loop plays critical roles in the progression of breast cancer. In addition to enhancing Her2 andβ2-AR expresson, the positive feedback loop also promotes the expression of catecholamine and other cytokines involved in angiogenesis and metastasis in breast cancer cells. The comprised by Her2 andβ2-AR may play an important role in the malignant progression of breast cancer. Her2 overexpression was attributed to Her2 gene amplification. However, the recent studies revealed that Her2 gene amplification was not identified in about 80% of breast cancer patients with Her2 expression at middle level. Further investigation will reveal the novel mechanism of Her2 over-expression, and be also helpful to elucidate the mechanisms of synergism betweenβ2-AR and Her2 in the progression of breast cancer.
In the second part of this study, we found that the continuous stimulation of isoproterenol could induce spontaneous lung metastasis of ovary cancer overexpressing Her2 in nude mice. By immunohistochemical analysis, we observed that the expression ofβ2-AR and Her2 frequently localized at the leading edge of the tumor. Interestingly, the nuclear localization of Her2 was found in the region whereβ2-AR was expressed highly. It strongly suggested a close relationship betweenβ2-AR over-expression and Her2 nuclear localization. Her2/β2-AR feedback loop and Her2 nuclear translocation may play an important role in the development and metastasis of breast cancer.
Noticeably, isoproterenol stimulation resulted in the cleavage of Her2, producing a ~70 kDa fragment derived from Her2 C terminus, suggesting thatβ2-AR-mediated signaling was involved in the process. By analyzing the activities ofγ-secretase that cleaves the juxta-membrane region of a wide variety of transmembrane receptors, the enhancedγ-secretase activities were detected in breast and ovarian cancer cells stimulated by catecholamine. The data from bioinformatics analysis revealed that there is a potentialγ-secretase cleavage site in the juxta-membrane region of Her2 intracellula domain (ICD). Using immunofleuresent staining and confocal microscopy, we demonstrated that isoproterenol treatment induced the internalization of Her2 and nuclear translocation of Her2 ICD. Her2 in the nucleus can act as a transcriptional factor, promoting the transactivation of COX-2 gene, which was related to the lung metastasis of breast carcinoma. Our data proved that isoproterenol treatment up-regulated COX-2 expression in breast and ovarian cancer cells. Importantly, we found that chronic stimulation of isoproterenol induced spontaneous lung metastasis of Her2 over-expressing ovarian caner xenograft in nude mice. These data strongly implicated that the activation ofβ2-AR triggered the expression ofγ-secretase, by which Her2 was cleaved, and that restultant Her2 ICD translocated to the nucleus, promoting COX-2 gene expression and lung metastasis of Her2 over-expressing ovarian cancer cells in nude mice. These findings may illustrate the novel mechanisms of Her2 nuclear translocation. They may also reveal the functional roles of the trans-membrane receptors in the nucleus, cytoplasm-nucleus shortcut of signalings, and Her2 transactivation byβ2-AR in tumor progression.
In conclusion, the main findings in the present study include: 1. a positive feedback loop betweenβ2-AR and Her2 in breast cancer cells; 2. Her2 cleavage and nucleus translocation of Her2 induced byβ2-AR activation; 3. the novel mechanisms of Her2 over-expression and nucleus localization; 4. the interplay ofβ2-AR/Her2 signalings in the progression of cancer.
应激可刺激交感神经系统和下丘脑-垂体-肾上腺轴,导致儿茶酚胺的分泌增加。最近的研究表明,长期处于慢性应激反应状态的人群体内儿茶酚胺的水平持续升高。儿茶酚胺的持续刺激不仅可导致免疫系统的功能紊乱,亦可直接影响肿瘤的生物学行为。儿茶酚胺主要通过β-肾上腺素能受体(β-AR)发挥作用,而β-AR在某些肿瘤发生发展过程中的重要作用亦已被报道,但精确的分子机制不清。
在第一部分的研究中,我们应用免疫组化的方法,在50例临床乳腺癌组织标本中检测了Her2与β2-AR的表达。我们发现,Her2与β2-AR在乳腺癌组织中的表达具有良好的相关性。我们又通过体外实验观察到,在乳腺癌细胞MCF-7中过表达Her2可上调β2-AR的水平,提示Her2与β2-AR这两个受体分子之间存在密切的关系。
Her2是重要的癌基因,Her2过表达可激活细胞内多条信号通路。我们的实验结果证实,在MCF-7细胞中过表达Her2可导致细胞外信号调节激酶(ERK)的组成性活化,而ERK信号通路的抑制剂PD98059可明显抑制Her2过表达介导的β2-AR表达水平上调,表明ERK通路活化参与了Her2上调β2-AR表达的过程。我们的进一步实验证明,ERK通路的活化导致乳腺癌细胞中肾上腺素合成相关酶基因转录及自分泌肾上腺素的能力显著增强。通过体外模拟肾上腺素的自分泌或旁分泌,我们发现肾上腺素刺激可诱导乳腺癌细胞β2-AR表达水平上调。同时,我们还发现β2-AR激动剂刺激亦可显著上调乳腺癌细胞中Her2的表达。β2-AR的活化可直接或间接地调控某些转录因子的活性,我们的实验研究证实,异丙肾上腺素(ISO)刺激乳腺癌细胞MCF-7及BT474可诱导STAT3的活化,且活化的STAT3可进入细胞核并结合于Her2启动子区的STAT3元件,从而在转录水平和蛋白水平增强Her2的表达。
上述研究结果提示,β2-AR与Her2在乳腺癌细胞中形成正反馈调节环路:儿茶酚胺刺激乳腺癌细胞可诱导β2-AR信号及STAT3激活,活化的STAT3入核并结合于Her2启动子区功能性STAT3位点,增强Her2启动子的转录活性,导致Her2高表达;而Her2在乳腺癌细胞中过表达可诱导ERK磷酸化、促进肾上腺素合成酶的表达上调及活化,导致肾上腺素自分泌释放,进而上调β2-AR的表达。β2-AR及Her2信号通路的相互促进作用无疑在乳腺癌的恶性演进中具有重要的意义。在乳腺癌细胞中,这一互作机制不仅上调Her2及β2-AR的水平,而且可诱导儿茶酚胺及其他促血管生成、促转移因子的表达。过去认为Her2过表达主要归因于基因扩增,但最近的发现提示,约80%的Her2中度表达(++)的乳腺癌细胞无Her2基因扩增。本研究的深入将可能进一步揭示乳腺癌细胞中Her2过表达的新机制,并有助于阐明β2-AR与Her2协同作用在乳腺癌进展中的意义。
在第二部分的研究中,我们通过免疫组化分析,观察到Her2和β2-AR的表达常出现于肿瘤侵袭的前缘。有趣的是,在β2-AR高表达的肿瘤组织中,Her2受体常发生明显的核定位,提示β2-AR高表达与Her2入核可能存在一定的关系,β2-AR/Her2正反馈通路以及Her2入核可能在肿瘤的侵袭、转移过程中发挥重要作用。
研究发现,Her2 ECD的裂解可导致ICD的组成性活化及增强的信号转导,过表达Her2 ECD缺失突变体可提高酪氨酸激酶活性及细胞的转化效率。但是,在过表达Her2的肿瘤组织中Her2分子被切割的机制却不清楚。以往的多个研究表明,在Her2过表达的肿瘤细胞中,蛋白酶切割可导致Her2 ECD释放,产生含跨膜域和ICD的95 kDa片段(p95)。我们通过Western blot分析发现,在乳腺癌组织中除存在185 kDa和~100 kDa的片段外,尚可检测到~70 kDa的较小片段。裴刚研究小组在有关神经细胞和组织的研究中发现,β2-AR活化可增强γ-secretase的活性,而γ-secretase参与多种膜受体(包括CD44、Notch、E-candherin)胞内域近膜区的切割。我们通过CD44、Notch、E-candherin及Her2的序列对比发现,这些蛋白胞内域近膜区具有相似的组成特征,预测Her2分子由该处裂解恰可产生分子量~70 kDa的片段。我们通过γ-secretase活性分析,证实儿茶酚胺刺激确可导致MCF-7细胞中γ-secretase活性升高,提示Her2切割后的产物可能被γ-secretase进一步裂解。
进一步通过免疫荧光染色及共聚焦显微镜术,我们观察到ISO刺激可诱导Her2受体内化及Her2胞内域入核。以往的研究提示,入核的Her2分子可作为转录因子上调COX-2基因(肿瘤肺转移相关基因)转录。我们的研究结果证实,ISO刺激乳腺癌及卵巢癌细胞后,均可显著增强COX-2 mRNA的表达,提示ISO可能通过诱导Her2 ICD入核,增强Her2靶基因COX-2表达。我们又通过寡核苷酸pull-down分析,证实Her2 ICD可结合于COX-2启动子的Her2结合区。我们通过体内研究,证实了儿茶酚胺持续刺激可诱导Her2高表达的卵巢癌移植瘤在裸鼠体内自发性肺转移。
这些研究结果揭示,β2-AR活化可增强γ-分泌酶活性,诱导Her2切割及Her2胞内域入核,促进Her2靶基因COX-2的表达,进而可能在Her2高表达的卵巢癌肺转移过程中发挥重要的作用。β2-AR活化与Her2受体切割及入核相偶联的发现,揭示了Her2受体入核的全新机制,该机制的阐明不仅可能揭示Her2受体的质膜-核信号传递捷径的重要意义及跨膜受体酪氨酸激酶在核内的重要功能,而且亦将揭示β2-AR反式激活Her2在肿瘤恶性演进中的作用。
综上所述,本研究首次报道:1.β2-AR与Her2可在乳腺癌细胞中形成正反馈调节环路;2.β2-AR信号通路的活化可导致Her2被切割及Her2胞内域入核;3.本研究结果揭示了Her2过表达的新机制以及Her2分子切割、入核的新机制;4.β2-AR/Her2信号的相互作用在肿瘤的侵袭转移过程中发挥重要的作用。
The notion that psychosocial factors can affect the progression of many diseases, especially cancer, has long been suspected. Stress response can be induced by a variety of events, including trauma, family problems and bad working conditions. Stress response, which protects people from harmful stressors, is effective defensive mechanism established in evolvement. However, failure of coping with chronic stress can lead to long term and severe consequences. The data from several studies suggested that chronic stress may associate with the progression of breast cancer. For examples, the incidence of breast cancer is a three fold higher among women who are divorced or loss spouse and even nine fold higher among women experiencing extreme stress and lacking social support than normal population.
Stress initiates a response of the hypothalamic-pituitary-adrenal axis (HPA), resulting in increased catecholamine level. The continuously increased catecholamine levels are observed in individuals who are under chronic stress in the recent studies. Sustained stimulation of catecholamine interferes with not only the immune system but also bio-behaviors of tumor cells. Catecholamine exerts its effects via the activation ofβ-adrenergic receptors (β-AR).β-AR plays an important role in the development and progression of tumors. However, the precise mechanism by whichβ-AR acts in tumor progression is unclear.
In the first part of this study, we collected a total of 50 paraffin embedded breast cancer tissue samples and analyzed the expression of Her2 andβ2-AR by immunohistochemical staining. The results demonstrated thatβ2-AR level correlated with Her2 status in breast cancer samples. Overexpression of Her2 in breast cancer cell line MCF-7 strikingly up-regulatedβ2-AR level, impliying an intimate relationship between Her2 andβ2-AR in breast cancer cells.
Her2 is a very active oncogene and overexpression of Her2 can activates multiple signaling pathways. Our data demonstrated that the constitutive phosphorylation of ERK was induced by ectopic overexpression of Her2 in MCF-7 cells and blocking of ERK signaling by PD98059, which is known to selectively block the activity of ERK, markedly inhibitedβ2-AR up-regulation induced by Her2 overexpression in breast cancer cells, implicating that ERK signaling is involved in Her2-mediatedβ2-AR expression. Further study showed that the activation of ERK up-regulated the expression of the catecholamine synthesis enzymes, and promoted the release of epinephrine from breast cancer cells. By mimicking the autocrine and paracrine of catecholamine, we confirmed that epinephrine stimulation induced the up-regulation ofβ2-AR level in breast cancer cells.
Another interesting finding in this study is thatβ2-AR agonists up-regulated remarkably Her2 expression in breast cancer cells. Activation ofβ2-AR can regulate the activities of some transcriptional factors directly or indirectly. Our data showed that isoproterenol triggered the activation and nuclear translocation of STAT3 in breast cancer cell lines BT474 and MCF-7, subsequently the activated STAT3 bound to STAT3 element in the Her2 promoter and promoted Her2 expression at transcriptional and protein levels.
Above data support a model whereβ2-AR and Her2 comprise a positive feedback loop in human breat cancer cells: Catecholamine stimulates the activation ofβ2-AR mediated signaling, resulting in the activation, nuclear translocation and binding to a functional STAT3 site in the Her2 promoter and thus promoting Her2 transactivaton; Her2-mediated ERK signaling induces the up-regulation ofβ2-AR expression by promoting the expression of catecholamine synthesis enzymes and autocrine of epinephrine in breast cancer cells. In this way, Her2/β2-AR feedback loop plays critical roles in the progression of breast cancer. In addition to enhancing Her2 andβ2-AR expresson, the positive feedback loop also promotes the expression of catecholamine and other cytokines involved in angiogenesis and metastasis in breast cancer cells. The comprised by Her2 andβ2-AR may play an important role in the malignant progression of breast cancer. Her2 overexpression was attributed to Her2 gene amplification. However, the recent studies revealed that Her2 gene amplification was not identified in about 80% of breast cancer patients with Her2 expression at middle level. Further investigation will reveal the novel mechanism of Her2 over-expression, and be also helpful to elucidate the mechanisms of synergism betweenβ2-AR and Her2 in the progression of breast cancer.
In the second part of this study, we found that the continuous stimulation of isoproterenol could induce spontaneous lung metastasis of ovary cancer overexpressing Her2 in nude mice. By immunohistochemical analysis, we observed that the expression ofβ2-AR and Her2 frequently localized at the leading edge of the tumor. Interestingly, the nuclear localization of Her2 was found in the region whereβ2-AR was expressed highly. It strongly suggested a close relationship betweenβ2-AR over-expression and Her2 nuclear localization. Her2/β2-AR feedback loop and Her2 nuclear translocation may play an important role in the development and metastasis of breast cancer.
Noticeably, isoproterenol stimulation resulted in the cleavage of Her2, producing a ~70 kDa fragment derived from Her2 C terminus, suggesting thatβ2-AR-mediated signaling was involved in the process. By analyzing the activities ofγ-secretase that cleaves the juxta-membrane region of a wide variety of transmembrane receptors, the enhancedγ-secretase activities were detected in breast and ovarian cancer cells stimulated by catecholamine. The data from bioinformatics analysis revealed that there is a potentialγ-secretase cleavage site in the juxta-membrane region of Her2 intracellula domain (ICD). Using immunofleuresent staining and confocal microscopy, we demonstrated that isoproterenol treatment induced the internalization of Her2 and nuclear translocation of Her2 ICD. Her2 in the nucleus can act as a transcriptional factor, promoting the transactivation of COX-2 gene, which was related to the lung metastasis of breast carcinoma. Our data proved that isoproterenol treatment up-regulated COX-2 expression in breast and ovarian cancer cells. Importantly, we found that chronic stimulation of isoproterenol induced spontaneous lung metastasis of Her2 over-expressing ovarian caner xenograft in nude mice. These data strongly implicated that the activation ofβ2-AR triggered the expression ofγ-secretase, by which Her2 was cleaved, and that restultant Her2 ICD translocated to the nucleus, promoting COX-2 gene expression and lung metastasis of Her2 over-expressing ovarian cancer cells in nude mice. These findings may illustrate the novel mechanisms of Her2 nuclear translocation. They may also reveal the functional roles of the trans-membrane receptors in the nucleus, cytoplasm-nucleus shortcut of signalings, and Her2 transactivation byβ2-AR in tumor progression.
In conclusion, the main findings in the present study include: 1. a positive feedback loop betweenβ2-AR and Her2 in breast cancer cells; 2. Her2 cleavage and nucleus translocation of Her2 induced byβ2-AR activation; 3. the novel mechanisms of Her2 over-expression and nucleus localization; 4. the interplay ofβ2-AR/Her2 signalings in the progression of cancer.
引文
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