Coexpression of HGF and c-Met/HGF receptor in human bone and soft tissue tumors

To understand the interaction between hepatocyte growth factor (HGF) and its receptor c-Met on various bone and soft tissue tumors, their expressions were investigated by western blot analysts, immunohistochemistry and enzyme immunoassay. Western blot analysis revealed that c-Met protein was expressed in 21 (38.8%) of 54 tumors, which detailed to seven (25.9%) of 27 bone tumors and 14 (51.8%) of 27 soft tissue tumors. Most malignant fibrous histiocy-tomas (MFH) and all neurofibromas expressed c-Met protein. The highest expression of c-Met protein was seen in a case of biphasic synovial sarcoma, where its immunoreac-tivity was localized only on the epithelial component and not on the sarcomatous component. By enzyme immunoassay for HGF, all but one MFH showed HGF production and the mean level of HGF was the highest among the tumors investigated. Neurofibmmas and osteosarcomas had the next highest mean levels of HGF production, respectively. Coexpression of HGF and c-Met was obsewed in 19 (35.2%) of 54 tumors and was frequently observed in neurofibroma, followed by MFH and synovial sarcoma. Although the mode of interaction between HGF and c-Met varies among the various bone and soft tissue tumors including MFH, their signaling system may play an Important role in the development and progression of bone and soft tissue tumors.     

HGF/c-Met促进大鼠骨髓内皮祖细胞迁移能力

目的探讨肝细胞生长因子(HGF)及其受体c-Met对大鼠骨髓内皮祖细胞(EPCs)迁移能力的影响及其机制。方法提取、培养和鉴定大鼠骨髓EPCs;重组腺病毒载体介导c-Met基因转染EPCs,用real-time PCR、Western blot和CCK8分别检测c-Met的表达和细胞增殖;分别用0、5、10、20和50 ng/m L HGF处理Ad-c-Met-EPCs,并通过Transwell迁移系统检测Ad-c-Met-EPCs的迁移能力;选取适宜浓度的HGF处理EPCs、Ad-GFP-EPCs和Ad-c-MetEPCs,并设置PBS对照组和磷脂酰肌醇3-激酶抑制剂LY294002组(同时加入HGF和10 g/L的LY294002),通过Transwell迁移系统和Western blot分别检测各组细胞的迁移能力、Akt和P-Akt的表达。结果 1)Ad-c-Met-EPCs中c-Met基因与蛋白均为高表达(P0.05)。2)c-Met基因对EPCs的增殖无明显影响。3)HGF在0~50 ng/m L范围内呈浓度依赖性促进Ad-c-Met-EPCs迁移。4)HGF+Ad-c-Met-EPCs组的迁移能力和P-Akt的表达显著高于对照组、HGF+EPCs组、HGF+Ad-GFP-EPCs组和HGF+LY294002+Ad-c-Met-EPCs组(P0.05)。结论 HGF/c-Met能够显著提高EPCs的迁移能力;HGF/c-Met可能通过PI3K/Akt信号通路促进EPCs的迁移。     

腺病毒载体介导的RNAi对SK-BR-3细胞c-Met表达的影响

目的:通过腺病毒载体介导的RNA干扰技术抑制乳腺癌细胞HGF受体c-Met的表达,抑制乳腺癌细胞增殖、诱导细胞凋亡。方法:PCR法获得人U6启动子及带有c-Met反向互补靶序列的片段HU6shmet;利用腺病毒载体将其传递至SK-BR-3细胞;RNA狭缝杂交检测SK-BR-3细胞c-Met mRNA水平,Western印迹检测c-Met蛋白水平。结果:获得了带有人U6启动子及c-Met反向互补靶序列的重组腺病毒载体rAdUshmet1和rAdUshmet2。转导了重组腺病毒的SK-BR-3细胞的c-Met mRNA和蛋白相对表达量均有所下降。结论:腺病毒载体rAdUshmet通过抑制HGF受体c-Met表达,能在一定程度上阻断HGF-c-Met信号转导通路,有可能成为对乳腺癌进行基因治疗的有效载体。     

Hepatocyte growth factor and c-Met expression in pericytes: implications for atherosclerotic plaque development

Intraplaque neovascularization contributes to the progression of atherosclerosis. Our aim is to understand the mobilization of cells and factors involved in this process. We investigated the localization of hepatocyte growth factor (HGF) and its receptor, c-Met, in human atherosclerotic plaques, together with the effects of HGF on pericyte migration in vitro. Atherosclerotic femoral arterial segments were collected and analysed from 13 subjects who were undergoing lower limb amputation. Pericytes were identified in human lesions using a 3G5 antibody. Immunohistochemical analysis localized HGF mainly around microvessels, in association with some, but not all, CD31-positive endothelial cells. c-Met expression was mainly associated with smooth muscle cells and pericytes, around some, but not all, microvessels within the atherosclerotic lesions; no detection was apparent in normal internal mammary arteries. Using RT-PCR, we demonstrated expression of HGF and c-Met in a rat pericyte cell-line, TR-PCT1, and in primary pericytes. HGF treatment of TR-PCT1 cells induced their migration, but not their proliferation, in a dose-dependent manner (10-100 ng/ml, p<0.01), an effect mediated by activation of the serine/threonine kinase Akt, shown by western blot analysis. Treating the cells with the PI3K inhibitors Wortmannin (0.1 microM) or LY294002 (10 microM) abolished these effects. This work demonstrates the expression of c-Met and HGF in human atherosclerotic arteries, in association with SM-actin-positive cells and CD-31-positive cells, respectively. HGF induces pericyte migration via PI3-kinase and Akt activation in vitro. HGF and c-Met may be involved in neovascularization during plaque development, and may recruit pericytes to neovessels. Since pericytes are thought to mechanically stabilize new blood vessels, these factors may function to protect against haemorrhage.     

Coexpression of hepatocyte growth factor and c-Met proto-oncogene product in synovial sarcoma

Hepatocyte growth factor (HGF) is a heterodlmeric polypep-tide growth factor that has pleiotropic roles, Including those of mitogen, motogen and morphogen. The HGF receptor Is characterized as a c-Met proto-oncogene product (c-Met), which is a heterodimeric tyrosine kinase receptor. Hepatocyte growth factor acts as a mediator between the mes-enchymal and epithelial tissues because HGF is produced by mesenchymal cells and c-Met is mainly expressed on various epithelial cells. Furthermore, the HGF/c-Met system plays an important role in embryogenesis and the regeneration of various organs. Synovial sarcoma (SS) are unique sarcoma that show epithelial differentiation, but little is known about their histogenesis. The expression of HGF and c-Met was examined by immunohlstochemlstry In SS specimens from 12 patients (six each of biphasic and monopha-sic fibrous types). lmmunohistochemical coexpression of HGF and c-Met was demonstrated in the epithelial component of five biphasic SS, while only c-Met was expressed in the epithelioid nests of three monophasic fibrous SS. The spindle cell component was negative for HGF and c-Met. In SS, positivity for epithelial markers, such as cytokeratins and epithelial membrane antigen, was diffusely observed in the epithelial component and was focally observed In spindle cells, while vlmentin was positive predominantly in the spindle cell component. The areas expressing HGF and c-Met corresponded to distinct epithelial structures; however, HGF and c-Met expression were not found in any other tumor cells expressing epithelial markers in the spindle cell component of SS. Considering the morphogenlc effect of HGF, which has been known to be one of Its most important roles, the unique immunohlstochemical localization of HGF and c-Met In SS suggests that the HGF/c-Met system may be closely related to the formatlon of epithellal (glandular) structures In biphasic SS.     

PI3K和MAPK信号通路对A549细胞FOXO1蛋白表达及其亚细胞定位的调节

目的探讨非小细胞肺癌中磷脂酰肌醇-3-激酶(PI3K)/AKT和丝裂原活化蛋白激酶MAPK/ERK信号通路对Forkhead转录因子(Fox蛋白家族)FOXO1活性的影响及分子机制。方法体外培养人非小细胞肺癌系A549,分别选用PI3K/AKT信号通路特异性抑制剂LY294002和MAPK/ERK信号通路特异性抑制剂UO126及两种抑制剂联合处理细胞之后,MTT比色法检测其对细胞增殖的影响;Western blot检测蛋白FOXO1、p-FOXO1及信号下游蛋白Bim表达的变化;免疫荧光法检测FOXO1蛋白在A549细胞中亚细胞的定位的变化。结果与对照组相比,LY294002和UO126都能明显地抑制A549细胞的增殖,且具有时间依赖性。Western blot结果显示,FOXO1的蛋白水平未见显著性变化,而FOXO1的磷酸化水平明显下降,Bim的表达相应增加。免疫荧光结果显示,FOXO1在A549细胞中的核转位增多。LY294002和UO126联合处理A549细胞时,较药物单独作用效果明显增加。结论 PI3K/AKT和MAPK/ERK信号通路能调节FOXO1磷酸化水平,且具有协同作用,抑制其转录活性。FOXO1通过激活Bim蛋白,促进细胞凋亡,抑制细胞的增殖。     

Actin-independent exclusion of CD95 by PI3K/AKT signalling: implications for apoptosis

The immune system eliminates infected or transformed cells through the activation of the death receptor CD95. CD95 engagement drives the recruitment of the adaptor protein Fas-associated death domain protein (FADD), which in turn aggregates and activates initiator caspases-8 and -10. The CD95-mediated apoptotic signal relies on the capacity to form the CD95/FADD/caspases complex termed the death-inducing signalling complex (DISC). Cells are classified according to the magnitude of DISC formation as either type I (efficient DISC formation) or type II (inefficient). CD95 localised to lipid rafts in type I cells, whereas the death receptor was excluded from these domains in type II cells. Here, we show that inhibition of both PI3K class IA and serine-threonine kinase Akt in type II cells promoted the redistribution of CD95 into lipid rafts, DISC formation and the initiation of the apoptotic signal. Strikingly, these molecular events took place independently of CD95L and the actin cytoskeleton. Overall, these findings highlight that the oncogenic PI3K/Akt signalling pathway participates in maintaining cells in a type II phenotype by excluding CD95 from lipid rafts.     

Expression of the hepatocyte growth factor/c-Met pathway is increased at the cancer front in breast carcinoma

Expression of hepatocyte growth factor (HGF) and c-Met (HGF receptor) has been reported in many neoplasms. We investigated coexpression of HGF and c-Met to determine the role of the HGF/c-Met pathway in breast carcinoma, especially at the cancer front. Eighty-eight cases of carcinoma of the breast were studied by immunohistochemistry and by in situ hybridization for HGF and c-Met expression. The staining pattern was termed "front accentuation pattern" when it was most conspicuous at the cancer front. HGF and c-Met proteins were expressed in cancer and stromal cells, with autocrine and paracrine patterns. The front accentuation pattern of c-Met was observed in cancer cells, but not in stromal cells. The front accentuation pattern was not observed in HGF. Coexpression of HGF and c-Met at the cancer front was correlated with histologic grade, reduced patient survival and a high Ki-67 labeling index. Our findings suggest that the HGF/c-Met pathway acts primarily as a mitogen, especially at the cancer front, in a paracrine manner and affects some clinical factors, including patient survival.     

Disease-dependent reciprocal phosphorylation of serine and tyrosine residues of c-Met/HGF receptor contributes disease retardation of a transgenic mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by progressive degeneration of motoneurons. We have demonstrated that hepatocyte growth factor (HGF) attenuates loss of both spinal and brainstem motoneurons of ALS model mice expressing mutated human SOD1^G93A (G93A). This study was designed to assess disease-dependent regulatory mechanisms of c-Met/HGF receptor (c-Met) activation in the facial motoneurons of G93A mice. Using double transgenic mice expressing HGF and mutated SOD1^G93A (G93A/HGF), we showed that phosphorylation of c-Met tyrosine residues at positions 1230, 1234 and 1235 (phospho-Tyr), and thereby its activation, was slightly evident in G93A and highly obvious in G93A/HGF mice (but absent in WT and HGF-Tg mice). Phosphorylation of the c-Met serine residue at position 985 (phospho-Ser), a residue involved in the negative regulation of its activation, was evident in WT and HGF-Tg mice. Protein phosphatase 2A (PP2A), which is capable of dephosphorylating c-Met phospho-serine, is upregulated in the facial motoneurons of G93A and G93A/HGF mice compared with WT and HGF-Tg mice. Thus, c-Met activation is reciprocally regulated by phosphorylation between c-Met serine and tyrosine residues through PP2A induction in the presence or absence of mutant SOD1 expression, and HGF functions more efficiently in ALS and ALS-related diseases.     

Role of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways downstream molecules, phosphorylated extracellular signal-regulated kinase, and phosphorylated AKT in colorectal cancer-a tissue microarray-based approach

Tumor budding is defined as dedifferentiated cancer cells at the invasive margin of colorectal cancer (CRC) and correlates with a worse prognosis. The invasive margin and tumor budding are normally not present in a superficial diagnostic biopsy specimen. The aim of this study was to investigate the expression/overexpression of 2 downstream molecules of the mitogen-activated protein kinase and phosphoinositide 3-kinase/AKT pathways, phosphorylated AKT (pAKT) and phosphorylated extracellular signal-regulated kinase (pERK), in areas of CRC away from the invasive margin and determining if these variables were predictive of tumor budding or prognosis. A series of 1420 unselected, nonconsecutive CRC resections were subdivided into 3 groups: (1) DNA mismatch repair (MMR) proficient, (2) MLH1-negative, and (3) presumed HNPCC. Immunohistochemical analysis of pAKT and pERK expression (0% versus > 0%) and overexpression (increasing percentage of positivity) was performed using the tissue microarray technique. The results were correlated with clinicopathologic parameters. Fifty-seven samples of normal colon mucosa were included as a control group. Nuclear pERK expression (P = .008) was associated with presence of tumor budding in the MMR-proficient, but not in the MLH1-negative and presumed-HNPCC groups. In contrast, cytoplasmic pAKT overexpression was associated with early T stage (P = .04), early N stage (P = .02), and absence of tumor budding (P = .03) only in the MLH1-negative group. There was no association between pERK or pAKT and clinicopathologic parameters in the HNPCC group. Dysregulation of the mitogen-activated protein kinase pathway is likely to be implicated in the mechanism of tumor budding only in MMR-proficient CRC, whereas the phosphoinositide 3-kinase/AKT pathway is associated with early stage in MLH1-negative CRC.     

子痫前期患者血清HGF及Inhibin A测定

目的：探讨子痫前期患者血清肝细胞生长因子（HGF）和抑制素A（Inhibin A）水平的变化及临床意义。方法：分别采用酶联免疫法和放射免疫分析35例子痫前期孕妇（子痫前期组）和35例正常妊娠孕妇（对照组）血清HGF和Inhibin A水平。结果：结果显示,子痫前期患者与对照组孕妇新生儿出生体重、胎盘重量差异无统计学意义（P均〉0.05）。子痫前期患者不同病情血清HGF和Inhibin A测定结果表明,无论轻度子痫前期组和重度子痫前期组患者血清HGF含量均非常显著地低于对照组（P均〈0.01）;但轻度子痫前期组和重度子痫前期组之间HGF水平无显著差异（P〉0.05）。Inhibin A水平则轻、重两组均非常显著地高于对照组（P均〈0.01）;且轻、重两组之间比较重度组非常显著地高于轻度组（P〈0.01）。相关分析结果显示,血清HGF和Inhibin A水平两组指标数值之间均无显著相关性（r=0.189,P〉0.05）。子痫前期患者胎盘重量与血清HGF和Inhibin A水平之间也无显著的相关性（r=-0.037、0.235,均P〉0.05）。结论：患者血清HGF和In-hibin A水平的变化参与了子痫前期的发病机制,其测定对于子痫前期的病情评估有帮助。     

Hepatocyte growth factor promotes migration of human hepatocellular carcinoma via phosphatidylinositol 3-kinase

Hepatocyte growth factor (HGF) is known to be a potent mitogen and motogen for epithelial cells. Hepatocellular carcinoma (HCC) often metastasizes, and the c-Met/HGF receptor is highly expressed by HCC cells. The aim of this study was to investigate the signaling pathways associated with the motogenic effect of HGF on HCC cells via c-Met. HCC cell lines (Hep3B, HepG2, PLC, and Huh-7) and HCC cells harvested from patients were used for the Boyden chamber assay of chemotactic activity as well as for immunoprecipitation and immunoblotting studies. HGF stimulated the motility of Hep3B, HepG2, and Huh-7 cells in a dose-dependent manner in association with tyrosine phosphorylation of c-Met and activation of phosphatidylinositol 3-kinase (PI3-K). A tyrosine kinase inhibitor (genistein) and a PI3-K inhibitor (wortmannin) prevented the migration of HCC cells. However, migration was not prevented by calphostin C, an inhibitor of protein kinase C (PKC), which is a downstream target of phospholipase Cγ (PLCγ). HGF also stimulated the migration of HCC cells obtained from three patients, while wortmannin prevented the migration of these cells. These results indicate that HGF stimulates the migration of HCC cells through the tyrosine phosphorylation of c-Met via activation of PI3-K. This revised version was published online in July 2006 with corrections to the Cover Date.     

肝细胞生长因子减轻皮质神经元的缺氧/复氧损伤

目的研究肝细胞生长因子(HGF)对缺氧/复氧诱导大鼠皮质神经元凋亡的保护。方法分离培养SD大鼠皮质神经元,经HGF(15、30和60μg/L)预处理后经缺氧/复氧诱导凋亡,用MTT比色法检测细胞存活率;用Hoechst33258染色法和流式细胞仪检测神经元的凋亡;用比色法检测细胞乳酸脱氢酶(LDH)和caspase-3活性变化。结果与正常对照组相比,缺氧/复氧组神经元的细胞存活率显著下降,细胞凋亡率和caspase-3活性升高(均P<0.05);而HGF预处理12 h可显著逆转缺氧/复氧所致的细胞存活率降低、凋亡率增加、LDH活性上升、caspase-3活性升高的改变(均P<0.05),且这些效应与HGF剂量正相关。此外,HGF的抗凋亡效应可被PI3K/Akt通路抑制剂LY294002阻断。结论HGF减轻缺氧/复氧所诱导的神经元凋亡可能与其激活神经元的PI3K/Akt信号通路、减少caspase-3表达有关。     

Phosphoinositide 3-kinase signalling in lung disease: leucocytes and beyond

The family of lipid kinases termed phosphoinositide-3-kinase (PI3K) is known to contribute at multiple levels to innate and adaptive immune responses, and is hence an attractive target for drug discovery in inflammatory and autoimmune disease, including respiratory diseases. The development of isoform-selective pharmacological inhibitors, targeted gene manipulation and short interfering RNA (siRNA) target validation have facilitated a better understanding of the role that each member of this family of kinases plays in the physiology and pathology of the respiratory system. In this review, we will evaluate the evidence for the roles of specific PI3K isoforms in the lung and airways, and discuss their potential as targets for novel drug therapies.     

PI3K/Akt and ERK1/2 signalling pathways are involved in endometrial cell migration induced by 17beta-estradiol and growth factors

Cell motility and invasion are crucial events for endometrial cells, not only for the establishment of pathological states but also during the physiological tissue remodelling that occurs during the menstrual cycle and embryo implantation. We have characterized these phenomena in endometrial stromal cells evaluating cell migration-specific stimuli and the biochemical pathways involved. Ability of endometrial cells to migrate on collagen type IV substrate was evaluated by means of chemotaxis experiments. Modulation of this phenomenon by different growth factors and steroid hormones and their ability to activate extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3 kinase (PI3K)/Akt signalling in this context were examined. Platelet-derived growth factor (PDGF)-BB, epidermal growth factor and fibroblast growth factor-2 as chemoattractant agents stimulated basal migration of endometrial stromal cells through the rapid activation of both ERK1/2 and PI3K/Akt signalling pathways. Experiments using wortmannin and PD98059, specific inhibitors of the PI3K/Akt and ERK1/2 activity, respectively, showed that the activation of both pathways is required for growth-factor-induced cell motility responses. Similarly, 17beta-estradiol (10(-6)-10(-8) M) could enhance both constitutive and PDGF-induced migration of the cells and their rapid treatment with the hormone significantly increased phosphorylation of ERK1/2 and Akt. Conversely, progesterone did not interfere with the basal migration but inhibits the PDGF-induced motility of this cell type. Rapid activation of intracellular signalling cascades ERK1/2 and PI3K/Akt by growth factors and estrogens is involved in the migration of normal endometrial stromal cells.     

Inhibition of MAP kinase activity moderates changes in expression and function of Cx32 but not claudin-1 during DNA synthesis in primary cultures of rat hepatocytes

The signal transduction pathways and activation of the MAP kinase or PI3 kinase signaling cascade regulate a variety of cellular processes, including proliferation and differentiation in hepatocytes. To elucidate the mechanisms of signal transmission required for the regulation of gap and tight junctions during DNA synthesis in rat hepatocytes, we determined changes of expression and function of gap and tight junctions of cells grown in primary culture, using inhibitors of signaling pathways for MAP kinase (PD98059) and PI3 kinase (LY294002). During the stimulation of DNA synthesis induced by epidermal growth factor (EGF), immunoreactivity and mRNAs of gap junction protein Cx32 and of tight junction protein claudin-1 markedly decreased with reduction of gap junctional intercellular communication (GJIC) and the fence function of tight junctions. In Western blots, whole-cell lysate of claudin-1 protein decreased and phosphorylated Cx32 protein in the insoluble fraction of Triton X-100 increased during the stimulation of DNA synthesis. During reinhibition of DNA synthesis, the changes of Cx32 and claudin-1 returned to control levels, as did both functions. In treatment with the inhibitors before DNA synthesis, PD98059 inhibited the changes of expression and function of Cx32, but not claudin-1, without inhibition of cell growth, whereas LY294002 completely inhibited cell growth. These findings indicate that the PI3 kinase pathway rather than the MAP kinase pathway plays an important role for EGF-induced proliferation of rat hepatocytes, and that changes of Cx32 in hepatocytes during the stimulation of DNA synthesis may be in part controlled through MAP kinase. Furthermore, Cx32, but not claudin-1, protein may be a target of activated MAP kinase in hepatocytes.     

重组腺病毒Ad-HGF-hIL10基因治疗大鼠肝纤维化

目的 探讨人IL-10和HGF双表达的重组腺病毒hIL10-HGF对大鼠肝纤维化的治疗效果,以期为肝纤维化的基因治疗提供实验基础.方法 建立SD大鼠肝纤维化模型后,将1.5×108 PFU的Ad-HGF、Ad-hIL10和Ad-HGF-hIL10经尾静脉注射入大鼠体内,模型组和对照组注射同剂量的0.9％氯化钠注射液.第15天心脏采血,检测血清的肝功能指标,并取肝组织做HE染色,观察各组大鼠肝脏的病理形态.结果 与模型组大鼠相比,治疗组大鼠的肝组织损伤程度减轻,汇管区看不到明显的纤维增生.各治疗组的TBIL、ALT、AST显著低于模型组(P＜0.01),而ALB显著升高(P＜0.01),肝功能得到了明显的改善,而Ad-HGF-hIL10双基因治疗组与Ad-HGF、Ad-hIL-10单基因治疗组相比,ALT、AST显著降低(P＜0.05),白球比(0.83±0.11)与其他两个单基因治疗组Ad-HGF (0.74±0.05)和Ad-hIL-10(0.73±0.05)相比显著上升(P＜0.01).结论 用HGF和hIL-10双基因的腺病毒载体治疗大鼠肝纤维化,肝功能的改善效果明显优于单基因治疗组.     

C-Met tyrosine kinase receptor expression and function in human and canine osteosarcoma cells

To further characterize the role of hepatocyte growth factor-scatter factor (HGF-SF) and its receptor (c-Met) in osteosarcoma (OS), human OS cell lines with low (SAOS-2) and high (SAOS-LM2) metastatic potential, and cell lines derived from spontaneous canine OS were studied. All cell lines were evaluated for c-Met and HGF-SF expression and receptor activation using Northern, RT-PCR, and Western blot analyses, respectively. Functional activity of receptor-ligand interaction was measured using c-Met phosphorylation status, proliferation assays (anchorage-dependent and -independent), Matrigel invasion, modulation of urokinase plasminogen activator (uPA) expression, and cell dispersion (scattering). All cell lines exhibited steady-state mRNA expression of c-Met. The canine OS cell lines also expressed HGF-SF mRNA as determined by RT-PCR analysis. Western analysis showed c-Met protein expression and HGF-stimulated (human) or constitutive (canine) receptor autophosphorylation. Treatment with recombinant human HGF resulted in enhanced proliferation in 3 of 5 OS cell lines and enhanced colony formation in 2 of 5 OS cell lines. Matrigel invasion was significantly enhanced in 3 of the cell lines and uPA levels were significantly increased in the SAOS-2 cells following HGF treatment. Scattering was enhanced in both the SAOS-2 and SAOS-LM2 cells. These data support the involvement of c-Met and HGF-SF in the growth and progression of human and canine OS, and may offer new targets for the development of therapeutic strategies for OS. This revised version was published online in July 2006 with corrections to the Cover Date.     

子痫前期患者胎盘组织PLGF表达及血清HGF和VEGF测定

目的：探讨子痫前期患者血清肝细胞生长因子（HGF）、胎盘生长因子（PLGF）表达水平和血管内皮生长因子（VEGF）水平的变化及意义。方法：分别采用放射免疫分析、酶联免疫分析和免疫组化法测定32例子痫前期孕妇（子痫前期组）和35名正常孕妇（对照组）血清VEGF、HGF和PLGF表达水平。结果：子痫前期患者无论轻度子痫前期组和重度组血清HGF含量均显著低于对照组（P均〈0.01）;但轻度和重度组之间水平无显著性差异（P〉0.05）。胎盘中PLGF表达水平也显示轻度和重度两组均显著低于对照组（P均〈0.01）;且重度组又显著低于轻度组（P〈0.01）。血清VEGF水平轻度组显著低于对照组（P〈0.05）;重度组水平较对照组降低更为显著（P〈0.01）,且重度组显著低于轻度组（P〈0.01）。相关分析显示,HGF含量与PLGF具有显著相关性（r=0.6012,P〈0.01）;而与VEGF水平则无明显相关性（r=0.3010,P〉0.05）。结论：测定结果证实,患者血清三项标志物均参与了子痫前期的病理进程,其测定对于了解病情和预后评估有帮助。     

Recent discoveries in the genetics of melanoma and their therapeutic implications

The incidence of cutaneous malignant melanoma, tumors arising from melanocytes, has increased markedly over the past few years in many countries. Although early melanoma is curable through surgical excision, the prognosis of advanced melanoma is very poor, this tumor being resistant to current therapies. Thus there is a need for new therapies to improve the treatment of advanced melanoma. This review provides an overview of recent discoveries in the genetics of melanoma which could offer new therapeutic opportunities.