摘要
研究背景：
Janus蛋白酪氨酸激酶(Janus protein tyrosine kinase, JAK)/信号转导和转录激活因子(Signal transducer and activator of transcription, STAT)信号通路代表的是从细胞外到细胞核的信号通路。通过对IFN反应的研究发现了JAKs和STATs家族以及二者的相关联性。在肿瘤细胞系和人的肿瘤组织中,JAKs(包括JAK1、JAK2、JAK3和TYK2)选择性地激活STATs蛋白(包括STAT1-4、STAT5a、STAT5b和STAT6)调节肿瘤细胞的生长分化从而参与肿瘤的形成。在STATs蛋白中,活化的STAT3在多发性骨髓瘤、淋巴瘤、白血液以及实体肿瘤中均检测到。在头颈部鳞状上皮细胞癌中发现IL-6诱导STAT3表达的信号通路。酸性黄可抑制IL-6诱导STAT3的磷酸化和细胞核转移。在结肠癌细胞中当抑制STAT3和VEGF的表达时可抑制血管的生成和肿瘤的转移。因此,STAT3可作为肿瘤治疗的目的基因。
相关研究发现JAKs和STATs蛋白家族对脑瘤的发生发展具有重要作用。JAK/STAT的功能通过SCID小鼠动物模型得以验证。JAK1或STAT3缺陷的小鼠由于神经系统和淋巴系统发育不平衡而在胚胎期就死亡。JAK1/STAT3在细胞转化和致瘤方面具有重要作用,在胶质瘤中的表达高低与肿瘤的分化程度密切相关。
STAT3是一重要的信号转导蛋白,在传导信号和肿瘤形成方面发挥重要作用。在恶性胶质母细胞瘤细胞系中,通过STAT3的作用,IL-6可诱导VEGF的表达。活化的STAT3在恶性胶质瘤的肿瘤组织中表达增高且与病人的存活时间相关。研究发现STAT3在肿瘤细胞的转化和增值过程中是必需的。STAT3通过调节靶基因如cyclin D1、VEGF等参与细胞生长和血管生成。
肿瘤的发生发展是一个多因素作用、多基因参与、多阶段才最终形成的极其复杂的生物学现象。肿瘤细胞最明显的特征是细胞增殖失去控制,而在肿瘤细胞内与生长分化有关的信号转导通路发生障碍则是生长失控的重要因素。由血管诱导因子诱导的肿瘤血管生成在肿瘤的发生、发展过程中是必需的。肿瘤血管的形成受多种血管生成因子的调控,包括呈纤维细胞生长因子(FGF)、血管内皮细胞生长因子(VEGF)家族及其受体、表皮生长因子(EGF)、血小板衍生生长因子(PDGF)、转化生长因子-β(TGF-β)等。作为重要的血管生成因子,VEGF(又称VEGFa)最初是从肿瘤细胞中发现,它参与肿瘤细胞的增殖、肿瘤血管的形成以及肿瘤的转移。VEGF几乎在所有人的实体肿瘤以及肿瘤细胞株中过度表达,包括肉瘤、淋巴瘤、脑膜瘤、胶质瘤、胃癌、结肠癌、卵巢癌、肝癌、腺癌等。VEGF对实体肿瘤血管的生成、肿瘤的生长和转移具有重要的作用。动物模型研究发现,通过抑制VEGF的表达可减少肿瘤血管的形成且抑制肿瘤的生长。血管生成是脑的重要的生物学特征,详细了解神经系统肿瘤血管的形成对提高脑瘤的治疗效果有重要意义。在各种脑瘤中,VEGF被认为是重要的血管生成因子。
新生血管生成是肿瘤最基本的特征,是肿瘤发生发展的必要条件。脑膜瘤、胶质瘤是初发性脑瘤,WHO按脑瘤的诊断标准将脑膜瘤分为Ⅰ到Ⅲ级、胶质瘤分为Ⅰ到Ⅳ级。外科手术如全部切除肿瘤组织,治愈是有可能的,但非全切或恶性程度高即分级高的肿瘤术后很容易复发,必须进行多次的放射治疗或立体定向治疗。肿瘤是依赖血管生成提供营养和氧分而生长。抑制新生毛细血管的生成可能是治疗肿瘤的有效的方法。尽管有多种分子机制参与血管的形成,但VEGF途径是很重要的,在肿瘤治疗方面可能是有效的治疗靶位。
目的：
VEGF最初是从肿瘤细胞中发现,它参与肿瘤细胞的增殖、肿瘤血管的形成以及肿瘤的转移。作为实体肿瘤,血管生成是脑膜瘤和胶质瘤生长的重要条件。STAT3潜在的致癌作用在肿瘤的发生、发展过程中起到重要作用。本研究探讨JAK1/STAT3调节VEGF的表达是否参与脑膜瘤和胶质瘤的致病过程。材料与方法:检测对像是40例脑膜瘤(26例男性,平均年龄49.0±13.0)和63例胶质瘤(25例男性,平均年龄47.9±14.9)以及6例正常脑组织。所有病例均未进行包括化疗和放疗等的术前治疗。肿瘤的分型参照2000年世界卫生组织规定的人脑瘤的分类标准。
采用RT-PCR、Western blot analysis和免疫组织化学方法检测脑膜瘤和胶质瘤及正常组织中JAK1、STAT3和VEGF的表达。
结果：
1、在正常脑膜组织中未见JAK1、p-JAK1、STAT3、p-STAT3和VEGF的表达：而在脑膜瘤组织中高表达;RT-PCR检测JAK1和STAT3的表达与VEGF的表达密切相关(P<0.05)；Western blot检测发现,JAK1与STAT3、STAT3与VEGF、p-JAK1与P-STAT3、p-JAK1与VEGF以及P-STAT3与VEGF的表达均密切相关,表达量均与组织的分化程度有关(P<0.05)；免疫组化检测的阳性率与Western blot检测的阳性率一致,P-STAT3在细胞核中表达,P-STAT3阳性的样本均表达VEGF,且与肿瘤的分化程度密切相关(P<0.05)。
2、在正常脑组织中未见JAK1、STAT3和VEGF的表达；而在胶质瘤组织中高表达,JAK1和STAT3的表达均与VEGF的表达密切相关(P<0.05)；在Ⅰ级和Ⅱ级肿瘤组织中表达升高,在Ⅲ级肿瘤组织中表达量最高(P<0.05);STAT3磷酸化(P-STAT3)是进行信号传导的重要步骤,在胶质瘤组织中未检测JAK1、STAT3的磷酸化状态,但JAK1的表达与STAT3的表达密切相关且与肿瘤的分化程度密切相关(P<0.05)。因此,JAK1与STAT3在肿瘤组织中的高表达可以认为是致癌因素。
结论：
在脑膜瘤和胶质瘤中,VEGF的表达由JAK1/STAT3信号通路调节且与肿瘤的分化程度密切相关。STAT3在调节血管生成的事件中是一重要因素,因此在脑膜瘤、胶质瘤的发生、发展中可能发挥重要作用。
Background
The Janus protein tyrosine kinase/Signal transducer and activator of transcription signal pathway is one of the main effectors in transducing signals from the cell surface to the nucleus. The correlation between JAKs and STATs families was found during studies on interferon (IFN) gamma-dependent gene expression. The selectively activation of the proteins signal transducers and activators of transcription (STATs) (STAT1-4, STAT5a, STAT5b, and STAT6) by Janus kinases (JAKs) (JAK1, JAK2, JAK3 and TYK2) is involved in the oncogenesis by regulating cell survival, growth and differentiation in many cancerous cell lines and human tumors. Of the seven STAT proteins, constitutive activated STAT3 has been implicated in multiple myeloma, lymphomas, leukemias, and several solid tumors. IL-6 inducible STAT3 pathway was found in head and neck squamous cell carcinoma cells. Evidences show that curcumin inhibition of IL-6 induced STAT3 phosphorylation and consequent STAT3 nuclear translocation. Colon cancer cells showed inhibited angiogenesis and metastasis with blocked STAT3 and VEGF expression. So STAT3 may be a target gene for cancer therapy.
Evidences show that The JAK and STAT families of proteins are important effectors in brain tumors. The function of JAK/STAT signal pathway is best explained in SCID mice models. JAK1-/- and STAT3-/- mice die during embryogenesis because of impaired neurological and lymphoid development. The JAK1/STAT3 signal pathway is important in cell transformation and carcinogenesis, and their expression is associated with glioma differentiation.
STAT3 is a key signal transduction protein that mediates signaling by cytokines and contributes to oncogenesis. Interleukin-6 induces VEGF expression in glioblastoma cell lines via STAT3. Activated STAT3 may be increased in malignant glioma patients and is associated with poor patient survival. Evidence indicates that STAT3 is necessary for tumor cell proliferation and transformation. STAT3 regulates target genes such as cyclin Dl and VEGF that are involved in cell survival and angiogenesis.
For most solid tumors, tumor angiogenesis is required for tumor growth and development stimulated by angiogenic inducers, and regulated by many angiogenic inducers, including fibroblast growth factor (FGF), VEGF, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor-β(TGF-β). As a key angiogenic factor, vascular endothelial growth factor (VEGF, also called VEGFa) originally isolated from tumor cells, is involved in tumor cell proliferation, angiogenesis and metastasis. The expression of the oncogene VEGF is an important factor in tumor angiogenesis for solid tumor growth and leads to tumor proliferation and metastasis. VEGF expresses in most of solid tumors and tumor cell lines including fleshy tumor, lymphadenoma, meningioma, glioma, gastric cancer, colon carcinoma, ovarian cancer, liver cancer. Animal experiments indicate that inhibition of VEGF expression reduces tumor angiogenesis and inhibits tumor growth. Angiogenesis is a crucial characteristic of brain biology, and detailed knowledge about angiogenesis of tumors of the central nervous system is important to improve therapy of brain tumors. VEGF is considered a major regulator of angiogenesis in various brain tumors.
Angiogenesis is a fundamental process of blood vessel growth that is a hallmark of cancer. Angiogenesis, the recruitment of new blood vessels, is an essential component of tumor progression. Meningioma and glioma are common primary brain tumors, and classifiedⅠ-Ⅲgrade andⅠ-Ⅳgrade according to the 2000 World Health Organization classification of human brain tumors. Surgical resection is curative when complete removal of benign cancers is possible, incompletely resected tumors and high-grade lesions are frequently treated with fractionated radiotherapy or stereotactic radiosurgery. Malignant brain tumors are highly vascularized and their growth is angiogenesis-dependent. As such, inhibition of the sprouting of new capillaries from pre-existing blood vessels is one of the most promising therapeutic approaches. Although several molecular mechanisms contribute to angiogenesis in tumors, VEGF pathway appears particularly important and has been a prominent therapeutic target in cancer treatment.
Objective
VEGF, originally isolated from tumor cells, induces tumor angiogenesis and promotes tumor cell proliferation, angiogenesis and metastasis. As a solid tumor, meningioma and glioma depend on neovascularization by angiogenesis for expansion. The oncogenic potential of STAT3 is critical in tumor occurrence and development of human cancers. Here, we studied whether VEGF expression regulated by a Janus kinase 1 (JAK1)/STAT3 signal pathway might be involved in the pathogenesis of human meningioma and glioma.
Materials and Methods
We obtained 40 meningioma specimens (26 from males; donor mean age 49.0±13.0 years),63 glioma specimens (from 25 males, donor mean age 47.9±14.9 years) and 6 normal brain tissues. All patients had not undergone preoperative treatments such as chemotherapy or radiotherapy. All tumors were histologically classified as malignant according to the 2000 World Health Organization classification of human brain tumors.
Using RT-PCR, western blot analysis and immunohistochemistry, we measured JAK1, STAT3 and VEGF expression in brain tissue from patients with meningioma and glioma.
Results
1. Normal brain tissue did not expressed JAK1, p-JAK1, STAT3, p-STAT3 and VEGF, but highly expressed in tumor tissues; Relative expression of JAK1, STAT3 were strongly correlated with VEGF expression in meningioma by RT-PCR (P< 0.05); Correlation analysis of JAK1 versus STAT3, STAT3 versus VEGF, p-JAK1 versus p-STAT3, p-JAK1 versus VEGF and p-STAT3 versus VEGF in showed strong correlation at protein level in meningioma by western blot analysis, expression level was associated with tumor differentiation (P< 0.05); Results of frequency of positivity seen on immunohistochemistry were in agreement with those seen on western blot analysis; p-STAT3 expressed in cell nuclear, all meningioma tumors positive for p-STAT3 also showed VEGF expression VEGF expression, and correlated with meningioma differentiation (P< 0.05).
2. Normal brain tissue did not show elevated expression of JAK1, STAT3 and VEGF at mRNA and protein level. The relative expression of JAK1 was strongly correlated with that of STAT3, and the expression of JAK1 and STAT3 was highly correlated with that of VEGF in glioma tissues (P< 0.05); The frequency and intensity of the expression was increased in grade I and grade II glioma tissues at mRNA and protein level, with the highest levels in grade III tissues (P< 0.05); Tyrosine phosphorylation is considered a switching signal to activate STATs, in glioma tissues, we did not study the tyrosine phosphorylation status of JAK1 and STAT3, but the expression of JAK.1 was stably associated with that of STAT3 in tumor tissues, and significantly correlated with differentiated status of human glioma (P< 0.05). So upregulation of JAK1 and STAT3 may be a pathological event.
Conclusions
VEGF is regulated by a JAK1/STAT3 signal pathway and is associated with meningioma and glioma histological differentiation. STAT3 represents a point of convergence for angiogenic events in the signal pathway and may play a central role during occurrence, development of human meningioma and glioma.
引文
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23. Bowman T, Garcia R, Turkson J, et al. STATs in oncogenesis. Oncogene 2000 19: 2474-2488.
24. Akira S. Functional roles of STAT family proteins:lessons from knockout mice. Stem Cells 1999 17:138-146.
25. Sinibaldi D, Wharton W, Turkson J, et al. Induction of p21 WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts:role of activated STAT3 signaling. Oncogene 2000 19:5419-27.
26. Niu G, Wright KL, Huang M, et al. Constitutive STAT3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002 21:2000-2008.
27. Lee CK, Bluyssen HA, Levy DE. Regulation of interferon-alpha responsiveness by the duration of Janus kinase activity. J Biol Chem 1997 72:21872-21877.
28. Zhang Y, Turkson J, Carter-Su C, et al. Activation of STAT3 in v-Src-transformed fibroblasts requires cooperation of JAK1 kinase activity. J Biol Chem 2000 275: 24935-24944.
29. Knoops L, Hornakova T, Royer Y, et al. JAK kinases overexpression promotes in vitro cell transformation. J Cardiovasc Pharmacol 2007 50:126-141.
30. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. STAT3 as an oncogene. Cell 199998:295-303.
31. Mahboubi K, Li F, Plescia J, et al. Interleukin-11 up-regulates survivin expression in endothelial cells through a signal transducer and activator of transcription-3 pathway. Lab Invest 2001 81:327-334.
32. Turkson J. STAT proteins as novel targets for cancer drug discovery. Expert Opin.Ther Targets 2004 8:409-422.
33. Ohta Y, Endo Y, Tanaka M, et al. Significance of vascular endothelial growth factor messenger RNA expression in primary lung cancer. Clin Cancer Res 1996 2: 1411-1416.
34. Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation. Nature 2000 407:242-248.
35. Kwak BK, Shim HJ, Park ES, et al. Hepatocellular carcinoma:correlation between vascular endothelial growth factor level and degree of enhancement by multiphase contrast-enhanced computed tomography. Invest Radiol 200136:487-492.
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37. Lu N, Gao Y, Ling Y, et al. Wogonin suppresses tumor growth in vivo and VEGF-induced angiogenesis through inhibiting tyrosine phosphorylation of VEGFR2. Life Sci 2008 82:956-963.
38. Nishikawa R, Cheng SY, Nagashima R, et al. Expression of vascular endothelial growth factor in human brain tumors. Acta Neuropathol 1998 96:453-462.
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27. Akira S. Functional roles of STAT family proteins:lessons from knockout mice. Stem Cells 1999 17:138-146.
28. Lee CK, Bluyssen HA, Levy DE. Regulation of interferon-alpha responsiveness by the duration of Janus kinase activity. J Biol Chem 1997 72:21872-21877.
29. Zhang Y, Turkson J, Carter-Su C, et al. Activation of STAT3 in v-Src-transformed fibroblasts requires cooperation of JAK1 kinase activity. J Biol Chem 2000 275:24935-24944.
30. Knoops L, Hornakova T, Royer Y, et al. JAK kinases overexpression promotes in vitro cell transformation. J Cardiovasc Pharmacol 2007 50:126-141.
31. Bromberg JF, Wrzeszczynska MH, Devgan G, et al. STAT3 as an oncogene. Cell 199998:295-303.
32. Mahboubi K, Li F, Plescia J, et al. Interleukin-11 up-regulates survivin expression in endothelial cells through a signal transducer and activator of transcription-3 pathway. Lab Invest 200181:327-334.
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