Subcellular localization of epitope-tagged neurotrophins in neuroendocrine cells

A growing body of evidence suggests that neurotrophins (NTs) play a critical role in synaptic plasticity and other activity dependent processes in the CNS. Release of these growth factors by neurons and neuroendocrine cells was recently shown to occur via the regulated secretory pathway, representing a possible mechanism for preferentially supplying NTs locally to active synapses. However, the identity and characteristics of the intracellular storage compartment for NTs undergoing stimulus-coupled secretion remains controversial. As a step towards addressing these issues we have investigated the subcellular localization of epitope-tagged nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) in neuroendocrine cells. Placement of the myc-epitope tag at the neurotrophin carboxy terminus did not affect essential properties of the NTs such as their ability to induce Trk tyrosine phosphorylation or their sorting into the regulated secretory pathway in PC12 and AtT-20 neuroendocrine cells. Epitope-tagged NTs colocalize with dense core vesicle (DCV)-markers at the light microscopic level in both cell lines investigated. Furthermore, at an EM level immunoreactivity (IR) for myc-tagged NGF was found over dense core granules (DCGs) in PC12 cells. These data provide evidence that NTs can be stored in DCVs in neuronal model cell lines and, potentially, in neurons as well. J. Neurosci. Res. 51:463–472, 1998. © 1998 Wiley-Liss, Inc.     

Trk A, B, and C are commonly expressed in human astrocytes and astrocytic gliomas but not by human oligodendrocytes and oligodendroglioma

Neurotrophins regulate the proliferation and differentiation of neurons in the central nervous system via a family of specialized receptors, including TrkA, TrkB, and TrkC. As little is known about their expression or potential role in human glial tissues and glial tumors, we undertook an immunohistochemical analysis of human glia, glioma tissues and cell cultures of glial tumors to characterize the expression of Trk family members (full-length TrkA, TrkB, the truncated form of TrkB, and TrkC). In normal human brain Trk A, B, and C immunoreactivity was found in neurons and some weak staining was also seen astrocytes. No Trk expression was seen on oligodendrocytes. Strong reactivity was seen in reactive astrocytes in a glial scar. In a total of 34 glioma tissue specimens, which included 16 astrocytic tumors (4 low-grade astrocytomas and 12 glioblastomas multiforme) and 15 oligodendrogliomas (8 low-grade and 7 anaplastic) as well as 3 oligoastrocytomas (WHO grade II), TrkA, B, and C immunoreactivity was observed exclusively in specimens from astrocytic gliomas (16/16), but not in any of the oligodendrocytic gliomas (0/15). In the oligoastrocytomas, staining was restricted to the astrocytic component. In the astrocytoma and oligodendroglioma specimens, Trk A, B, and C immunoreactivity was also seen in the surrounding reactive astrocytes. Trk expression was independent of age, sex or histological grade of the investigated tumors. In six primary cell cultures, one derived from human astrocytes and five established from malignant astrocytomas, only TrkA immunoreactivity could be detected, while TrkB (both full-length and truncated isoforms) and TrkC were absent. The TrkA expression in primary cell cultures decreased with continuous cell passaging, and no Trk could be detected in established cell lines derived from glioblastoma. In conclusion, our data suggest that in human glial tissues Trk A, B, and C may be expressed in a lineage-restricted manner, thereby distinguishing between astrocytes and oligodendrocytes in a marker-like fashion. Trk expression, like GFAP expression appears to be increased in activated (reactive)/ neoplastic astrocytes. Received: 15 January 1998 / Revised, accepted: 27 March 1998     

Elevated levels of neurotrophins in human biceps brachii tissue of amyotrophic lateral sclerosis

Previous studies suggest that neurotrophins support regeneration and survival of injured motoneurons. Based on these findings, brain-derived neurotrophic factor (BDNF) has been clinically investigated for its therapeutic potential in amyotrophic lateral sclerosis (ALS), a rapidly progressing and fatal motoneuronal disease. We questioned whether imbalances of neurotrophic levels are indeed involved in the pathology of ALS. Therefore the expression of nerve growth factor (NGF), BDNF, neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5) was investigated in postmortem muscle tissue of the biceps from 15 patients with neuropathologically confirmed sporadic ALS and 15 age-matched controls. Using mRNA analysis techniques and quantitative protein measurements, we have demonstrated that both mRNA and protein levels of all four neurotrophins are increased in muscle tissue of ALS patients. The production levels displayed a disease duration dependency and different expression patterns emerged for the four neurotrophins. Whereas the early phase of the disease was characterized by a strong upregulation of BDNF, levels of NGF, NT-3, and NT-4/5 gradually increased in the course of the disorder, peaking at later stages. We conclude that decreased neurotrophic support from muscle tissue is most likely not the cause of motoneuron degeneration in ALS. On the contrary, our results suggest that degenerating motoneurons in ALS are exposed to elevated levels of muscle-derived neurotrophins.     

Neurotrophin signal transduction in medulloblastoma

The members of the neurotrophin family play key biological roles in the development of the nervous system. Based on studies initially in cell lines (e.g., the rat pheochromocytoma PC12 cells), neurotrophins have been found to be important mediators of proliferation, differentiation, and survival in the normal brain, but their role in brain tumors remains unclear. Since neurotrophins and neurotrophin receptors are frequently detected in biopsy samples of central nervous system medulloblastomas, efforts have been undertaken in several laboratories to elucidate the potential effects of neurotrophins on the growth and differentiation of these tumors. Results from these studies may have both basic and clinical implications because medulloblastomas resemble embryonic neuroectodermal stem cells and/or their immature neuronal and glial progeny. This review focuses on recent developments in our understanding of the role of neurotrophins in medulloblastomas, especially the ability of nerve growth factor to induce apoptosis in vitro in medulloblastomas. J. Neurosci. Res. 49:522–527, 1997. © 1997 Wiley-Liss, Inc.     

Expression and functional activity of osteoprotegerin in human malignant gliomas

Apo2L/TRAIL-based therapy is a promising experimental approach to the treatment of human malignant gliomas. Osteoprotegerin (OPG) is a soluble decoy receptor for Apo2L/TRAIL that antagonizes Apo2L/TRAIL-induced apoptosis. High levels of OPG expressed by tumor cells might therefore abrogate the activity of exogenously added or adenovirally expessed Apo2L/TRAIL. Here we assessed the expression of OPG in human gliomas in vivo, in primary glioma cell cultures and in established glioma cell lines. Immunohistochemistry revealed weak OPG immunoreactivity in up to 5% of the tumor cells in 8 of 13 glioblastomas. Strong OPG labeling was detected in single scattered tumor cells in one of these specimens. Five glioblastomas did not express OPG. High OPG expression was found in 1 of 6 primary glioma cell cultures and in 1 of 12 established glioma cell lines, T98G. OPG released by T98G cells was biologically active in that it inhibited Apo2L/TRAIL-induced apoptosis in sensitive glioma cells. Altogether, however, these data suggest that OPG expression may not be a major pathway of glioma cell resistance to future Apo2L/TRAIL-based therapeutic approaches.     

Effects of palmitoylethanolamide on release of mast cell peptidases and neurotrophic factors after spinal cord injury

Spinal cord injury (SCI) has a significant impact on quality of life, expectancy, and economic burden, with considerable costs associated with primary care and loss of income. The complex pathophysiology of SCI may explain the difficulty in finding a suitable therapy for limiting neuronal injury and promoting regeneration. Although innovative medical care, advances in pharmacotherapy have been limited. The aim of the present study was to carefully investigate molecular pathways and subtypes of glial cells involved in the protective effect of PEA on inflammatory reaction associated with an experimental model of SCI.The compression model induced by applying an aneurysm clip to the spinal cord in mice is closer to the human situation, since it replicates the persistence of cord compression. Spinal cord trauma was induced in mice by the application of vascular clips to the dura via a four-level T5-T8 laminectomy.Repeated PEA administration (10 mg/kg i.p., 6 and 12 h after SCI) significantly reduced the degree of the severity of spinal cord trauma through the reduction of mast cell infiltration and activation. Moreover, PEA treatment significantly reduced the activation of microglia and astrocytes expressing cannabinoid CB₂ receptor after SCI. Importantly, the protective effect of PEA involved changes in the expression of neurotrophic factors, and in spinal cord dopaminergic function.Our results enhance our understanding about mechanisms related to the anti-inflammatory property of the PEA suggesting that this N-acylethanolamine may represent a crucial therapeutic intervention both diminishing the immune/inflammatory response and promoting the initiation of neurotrophic substance after SCI.     

CB2 cannabinoid receptors promote mouse neural stem cell proliferation

Neurospheres are clonal cellular aggregates of neural stem/precursor cells that grow in culture as free-floating clusters. Activation of CB1 cannabinoid receptors, which are expressed by these cells, promotes proliferation. In the present study we investigated the expression of CB2 cannabinoid receptors and the effect of exogenous cannabinoids on neural stem/precursor cell proliferation. Neurospheres containing nestin-positive and sn-1 diacylglycerol lipase alpha-positive cells expressed both CB1 and CB2 receptors, which were maintained through several passages. Application of the non-selective cannabinoid agonist (HU-210, 0.5 microM) stimulated bromodeoxyuridine incorporation and neurosphere formation. This action involved both CB1 and CB2 receptors as neurosphere formation was stimulated by either selective CB1 [arachidonyl-2'chloroethylamide/(all Z)-N-(2-cycloethyl)-5,8,11,14-eicosatetraenamide (ACEA), 200 nM and 1 microM] or CB2 (JWH-056, 0.5 microM) agonists. In addition, CB1 or CB2 antagonists (1 microM SR-141716A and SR-144528, respectively) blocked basal proliferation, suggesting that endogenous cannabinoids are implicated in neurosphere proliferation. In addition, cannabinoid agonist-stimulated proliferation was reduced by the Akt translocation inhibitor BML-257 (12.5 microM), suggesting a role for phosphoinositide-3 kinase signalling. Together, our results suggest that cannabinoids stimulate proliferation of neural stem/precursor cells acting on both CB1 and CB2 cannabinoid receptors through a phosphoinositide-3 kinase/Akt pathway.     

电压-门控钠离子通道亚型nNav1.5在人脑胶质瘤中的表达

目的 研究电压-门控钠离子通道（VGSCs）亚型nNav1.5在人脑胶质瘤中的表达及其与肿瘤级别的关系.方法 用免疫荧光技术检测nNav1.5蛋白在胶质瘤U251细胞株中的表达定位;按2007年WHO胶质瘤分级,将胶质瘤标本分为低级别组（WHO Ⅰ-Ⅱ级,29例）和高级别组（WHOⅢ-Ⅳ级,37例）,另外13例对照组织标本来自颅脑损伤内减压手术中切除的脑挫裂伤组织.采用RT-PCR法、免疫组化法和Western Blot法分别检测nNav1.5 mRNA和蛋白在胶质瘤组和对照组的表达情况.结果 nNav1.5主要在胶质瘤细胞核内表达,nNav1.5 mRNA和蛋白在胶质瘤组织和对照组织中均有表达,但其在胶质瘤中表达水平均显著升高（P＜0.05）,在高级别胶质瘤组的表达量亦高于低级别胶质瘤组,各组间比较差异有统计学意义（P＜0.05）.结论 nNav1.5在人脑胶质瘤中表达上调并与肿瘤的恶性程度呈正相关,nNav1.5有可能是胶质瘤恶性增殖的一个调控因子,有望成为胶质瘤的一个新标记物和治疗的新靶点.     

Distinct usages of phospholipase C gamma and Shc in intracellular signaling stimulated by neurotrophins

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), members of the neurotrophin family, bind to and activate TrkA, TrkB and TrkC, respectively, members of the Trk receptor tyrosine kinase family, to exert various effects including promotion of differentiation and survival, and regulation of synaptic plasticity in neuronal cells. Many reports have suggested that different neurotrophins show distinct biological functions, although molecular mechanisms by which neurotrophins exert their different functions remain unclear. In the present study, we found distinct usages of phospholipase Cgamma (PLCgamma) and Shc in intracellular signaling stimulated by neurotrophins. BDNF stimulated much stronger interactions of PLCgamma with Trk than NGF and NT-3 in PC12 cells stably expressing TrkB and cultured cerebral cortical neurons, respectively, although BDNF, NGF and NT-3 induced similar levels of tyrosine phosphorylation of Trk. Furthermore, the cultured cortical neurons showed large PLCgamma-dependent increases in intracellular Ca(2+) levels in response to BDNF compared with NT-3. In Shc signaling, NGF, but not BDNF, displayed interactions between Trk and Shc in a phenylarsine oxide (PAO; an inhibitor of tyrosine phosphatase)-dependent manner in TrkB-expressing PC12 cells. These results indicated that neurotrophins stimulate distinct kinds of interactions between Trk and PLCgamma and between Trk and Shc. These differences may lead to the distinct biological functions of neurotrophins.     

Regulation of Neurotrophin mRNA Expression in the Rat Brain by Glucocorticoids

Northern blot analysis was used to examine the effects of glucocorticoids on neurotrophin mRNA expression in the rat cerebral cortex and hippocampus. The results show that 3 days after adrenalectomy the mRNA levels for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) decreased significantly in both these regions. In adrenalectomized animals given dexamethasone replacement the mRNA levels for the three neurotrophins were restored to control levels. The effect of a single dose of dexamethasone (5 mg/kg) administered i p. to intact animals on the expression of neurotrophins was also examined. NGF and NT-3 mRNAs showed a 2.5-fold and a 1.4-fold increase, respectively, during the first 4 h after the injection. The increase was followed by a decrease, with levels -50% of control 24 and 48 h after the injection. In contrast, the level of BDNF mRNA did not change during the first 10 h after the injection, but decreased to 70% of control 48 h after the injection. These data indicate that glucocorticoids regulate neurotrophin mRNA expression both in the cortex and in the hippocampus, and suggest further that the known effects of glucocorticoids on neuronal survival in the brain could be due to changes in the levels of neurotrophins in the brain.     

Expression of neurotrophins BDNF and NT-3, and their receptors in rat brain after administration of antipsychotic and psychotrophic agents

We have investigated the potential role of neurotrophic factors in antipsychotic drug action by examining the effects of antipsychotic and psychotropic treatments on the mRNA expression of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and their receptors, trkB and trkC, respectively, in rat brain. Neither acute nor chronic clozapine treatment significantly affected the expression of these mRNAs in any brain area investigated, except for a decrease in trkB expression in the granule cells of the olfactory bulb. We then examined the effects of the psychotropic agent MK-801. MK-801 (5 mg/kg; 4h) significantly increased BDNF mRNA in the entorhinal cortex, but did not influence NT-3, trkB, or trkC expression in any brain area except for the olfactory bulb. The induction of BDNF mRNA by MK-801 was attenuated by pre-treatment (1 h prior to MK-801 administration) with the antipsychotics, clozapine (25 mg/kg) and haloperidol (2 mg/kg), but not with the antidepressant desipramine (15 mg/kg). Finally, we confirmed that the effects of MK-801 on BDNF mRNA were reflected in the respective changes in BDNF protein levels: MK-801 significantly increased anti-BDNF reactivity in the entorhinal cortex (126 ± 7% of control) while concomitantly decreasing in the hippocampus (71 ± 2% of control). These data do not support the hypothesis that neurotrophins play an important role in antipsychotic drug action, but rather suggest that induction of BDNF in the entorhinal cortex may play a significant role in the psychotropic action of MK-801.     

SOX2基因在胶质瘤中的表达及生物学作用

目的 探讨SOX2基因在人胶质瘤中的表达水平、甲基化状态以及生物学作用。方法 选取人胶质瘤组织标本108例,正常脑组织30例。采用PCR的方法检测SOX2基因的表达水平和甲基化状态。MTT和软琼脂集落形成试验检测SOX2对胶质瘤U87和U251细胞的生物学作用。结果 SOX2在正常脑组织中的相对表达水平明显低于胶质瘤组织（PP<0.01）。过量表达sox2基因可促进胶质瘤u87和u251细胞增殖和集落形成能力。>结论 SOX2基因在胶质瘤组织高表达,其在胶质瘤中的表达水平可能受启动子区域甲基化状态影响,SOX2基因影响胶质瘤的肿瘤学特性。     

Activation of protein kinase C inhibits retrograde transport of neurotrophins in mice

Retrograde axonal transport of neurotrophins from nerve terminal to cell body requires a number of key processes, including internalization of the receptor-neurotrophin complex into vesicles and formation of multivesicular bodies and their transport along the axon. Previous studies have shown that each of these processes can be regulated by kinases. In this study, we looked at the role of protein kinase C (PKC) in retrograde transport by injecting labeled neurotrophins together with relevant pharmacological agents into the eye and measuring the accumulation of radioactivity in the trigeminal and superior cervical ganglia. Inhibitors of PKC, Ro-31-8220 and rottlerin, did not affect the retrograde transport of nerve growth factor (NGF); however, phorbol ester activation of classical and novel PKCs blocked retrograde transport. The effect of phorbol esters was partially reversed by rottlerin and Ro-31-8220. Activation of PKC has been shown to be involved in the disorganization of actin filaments. In this study, we show that Ro-31-8220 reverses growth cone collapse by phorbol 12-myristate 13-acetate and suggest that one of the effects of activating PKC on retrograde transport is to disrupt the actin filaments.     

Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors

The transient receptor potential (TRP) superfamily of cation channels contains four temperature-sensitive channels, named TRPV1-4, that are activated by heat stimuli from warm to that in the noxious range. Recently, two other members of this superfamily, TRPA1 and TRPM8, have been cloned and characterized as possible candidates for cold transducers in primary afferent neurons. Using in situ hybridization histochemistry and immunohistochemistry, we characterized the precise distribution of TRPA1, TRPM8, and TRPV1 mRNAs in the rat dorsal root ganglion (DRG) and trigeminal ganglion (TG) neurons. In the DRG, TRPM8 mRNA was not expressed in the TRPV1-expressing neuronal population, whereas TRPA1 mRNA was only seen in some neurons in this population. Both A-fiber and C-fiber neurons expressed TRPM8, whereas TRPV1 was almost exclusively seen in C-fiber neurons. All TRPM8-expressing neurons also expressed TrkA, whereas the expression of TRPV1 and TRPA1 was independent of TrkA expression. None of these three TRP channels were coexpressed with TrkB or TrkC. The TRPM8-expressing neurons were more abundant in the TG compared with the DRG, especially in the mandibular nerve region innervating the tongue. Our data suggest heterogeneity of TRPM8 and TRPA1 expression by subpopulations of primary afferent neurons, which may result in the difference of cold-sensitive primary afferent neurons in sensitivity to chemicals such as menthol and capsaicin and nerve growth factor.     

Effects of the cannabinoid antagonists AM281 and AM630 on deprivation-induced intake in Lewis rats

Male Lewis rats (two groups of 10) received intracerebroventricular injections of either AM 630 (vehicle, 2.5, 5, 10 and 20 microg) or AM 281 (vehicle, 5, 10, 20 and 40 microg) following overnight food deprivation. The CB2 antagonist AM 630 failed to block deprivation-induced intake at 0.5, 1, 2, 4 and 6 h. The CB1 antagonist AM 281 significantly blocked intake following 20 microg (1 h) and 40 microg (1, 2, 4 and 6 h). Results are discussed with respect to cannabinoid receptor systems' involvement in ingestion and the differential pharmacological profiles of AM 630 and AM 281.     

脑胶质瘤中PTEN、MMP2与MMP9表达的研究

目的探讨PTEN、MMP2与MMP9在脑胶质瘤增殖、侵袭过程中的相互作用机制。方法应用SP 免疫组化法检测了50例不同级别脑胶质瘤中的3种蛋白表达情况。结果不同级别的脑胶质瘤中3种抗体的表达程度不同,Ⅱ级与Ⅲ、Ⅳ级肿瘤之间的表达差异具有统计学意义(P<0．01);PTEM与MMP2、MMP9在脑胶质瘤中的表达呈负相关(rMMP2=-0．27,rMMP9=-O．35,P<0．01)。结论 PTEN表达缺失可引起基质金属蛋白酶的过表达,从而使脑胶质瘤的侵袭性增强。     

人脑胶质瘤逃逸免疫监视机制的研究

目的 探讨Thl／Th2类细胞因子基因在人脑胶质瘤中的表达情况，以及它们在脑胶质瘤发生及发展中的作用。方法 以IL-2、IFNγ代表Thl类细胞因子，IL-4、IL-6及IL-10代表Th2类细胞因子，采用逆转录聚合酶链反应方法(RT-PCR)检测Thl／Th2类细胞因子基因在脑胶质瘤细胞、肿瘤浸润淋巴细胞及细胞株中的表达情况。结果 人脑胶质瘤细胞、肿瘤浸润淋巴细胞及脑胶质瘤细胞株均呈现明显的Th2类细胞因子基因优势表达，而正常人脑组织中则无这种表达趋势。结论 Th2类细胞因子在人脑胶质瘤中的优势表达可能是导致脑胶质瘤患者细胞免疫功能低下的原因之一，有可能在脑胶质瘤的发生及发展中起一定作用。     

Neonatal lipopolysaccharide treatment has long‐term effects on monoaminergic and cannabinoid receptors in the rat

Brain inflammation in early life has been proposed to play important roles in the development of anxiety and psychosis‐related behaviors in adulthood, behaviors that rely on the integrity of dopamine and/or serotonin systems. Moreover recent behavioral and anatomical evidence suggests involvement of CB1 receptors in the control of emotion and mood. In this study, we determined the effects of neonatal LPS treatment on dopamine, serotonin, and cannabinoid receptor binding in adulthood. Rats were treated with the bacterial endotoxin lipopolysaccharide (LPS) on postnatal day (PND) 3 and 5. Dopamine D1, D2, serotonin 5HT1A, 5HT2A, and serotonin transporter and cannabinoid CB1 receptor binding across several brain regions were measured autoradiographically in adulthood (PND 85). Neonatal LPS treatment caused a significant increase in dopamine D2 in the nucleus accumbens and olfactory tubercle, a decrease in 5HT1A receptor binding in the hippocampus CA1 and ventromedial hypothalamus. A decrease in CB1 receptor binding after neonatal LPS was observed in the amygdala. Neonatal LPS had no significant impact on dopamine D1, serotonin 5HT2A or serotonin transporter binding in any of the brain regions examined. Our results suggest long lasting, region specific effects and differential impact on dopamine, serotonin and cannabinoid receptor systems following neonatal inflammation, that may form the basis for compromised anxiety and psychosis related behaviors. Synapse, 2013. © 2013 Wiley Periodicals, Inc.     

Characterization of NTera2/D1 cells as a model system for the investigation of cannabinoid function in human neurons and astrocytes

The limited availability and potential to culture primary human brain cells means that there is still a need for cell lines that reliably model human neurons and glial cells. The human-derived NTera2/D1 (NT2) cell line is a promising tool from which both neuronal (NT2N) and astrocytic (NT2A) cells can be derived in vitro. Here we have investigated the potential to use this cell model to investigate the endocannabinoid system in the CNS. Through immunocytochemical characterization with a range of neuronal and glial markers, we found that these cell lines differentiate into cells with immature neuronal and astrocytic phenotypes, respectively. By real-time PCR, immunocytochemistry, and functional inhibition of cAMP accumulation, the cannabinoid 1 receptors were identified only on NT2N cells, consistent with high levels of expression of this receptor in neuronal cells of the CNS. No evidence of cannabinoid 2 receptor expression was found on any of the NT2 cell types. Both the precursors and the differentiated NT2N and NT2A cells demonstrated mRNA expression for the key enzymes involved in endocannabinoid synthesis and degradation. This work establishes a cannabinergic phenotype in NT2N and NT2A cells, providing an alternative human derived renewable cell model for investigation of cannabinoid receptor function and endocannabinoid synthesis and metabolism in the CNS.     

人脑胶质瘤中CCND1基因的转录与表达

目的检测和分析人脑胶质瘤中CCND1基因的转录与表达,及其对肿瘤发生、发展的生物学意义.方法采用免疫组化、原位杂交法检测52例人脑胶质瘤及8例正常人脑组织中Cyclin D1 mRNA蛋白以及增殖细胞核抗原(PCNA)的表达水平.结果脑胶质瘤中CD1蛋白及mRNA呈过度表达,其标记指数和阳性率随肿瘤的恶性程度增高而增加.两者的标记指数之间、以及与PCNA标记指数之间均为显著正性相关.结论人脑胶质瘤中CCND1过度转录和表达,随胶质瘤临床病理分级增加而增高,同时与肿瘤细胞增殖状态密切相关,提示CCND1基因的异常转录和表达在胶质瘤的发生与发展中起着重要的促进作用.