High serum hepatocyte growth factor level in patients with non-Hodgkin's lymphoma

Higher pretreatment serum hepatocyte growth factor (HGF) levels were observed in patients with multiple myeloma and Hodgkin's disease, but not in those with non-Hodgkin's lymphoma (NHL). We examined patients' serum levels at diagnosis using enzyme-linked immunosorbent assay and histological expression of HGF in pathological specimens of lymphoma, in relation to clinical features. The subjects were 77 NHL patients and 40 healthy controls. The serum levels of HGF in NHL patients at diagnosis were significantly higher than those in healthy controls (median 1019 vs. 689 pg/mL, P < 0.001). At diagnosis, patients with more than two sites of extranodal involvement (P = 0.001), higher scores of international prognostic index (P = 0.015), and advanced Ann Arbor stage (P = 0.023) had a higher level of serum HGF. Although the association of pretreatment serum HGF level and survival was not significant, a correlation of serial change of serum HGF levels with treatment response was found in limited cases. Furthermore, HGF expression of lymphoma tissues was shown in 18 of 24 (75%) different NHL subtypes, including most of the diffuse large B cell lymphoma (12 of 15, 80%). In conclusion, our study showed higher pretreatment serum HGF levels in NHL patients, which was related to clinical features; and the serial change of HGF seemed to parallel the treatment response. The pathogenic role of HGF in NHL patients was further highlighted by a modest expression of HGF in most of the diffuse large B cell lymphoma.     

Expression of hepatocyte growth factor and its receptor c-Met in human pituitary adenomas

Hepatocyte growth factor (HGF) and its receptor c-Met have been known as key determinants of growth and angiogenesis in some brain tumors like gliomas, meningiomas, and schwannomas. But little is known about their expression in pituitary adenomas. In this study, the expression of HGF and c-Met in pituitary adenomas of different histology types was investigated by immunohistochemistry, and correlative analysis of their expression with microvessel density (MVD), Ki-67 expression, and other clinicopathologic factors was made. The results showed that the expression of HGF and c-Met exists in 98% (64 of 65) and 92% (60 of 65) pituitary adenomas, respectively, and co-expression of them existed in 91% (59 of 65) adenomas. HGF had significant correlation with MVD (Spearman''s correlation coefficient, r = .31, P = .01) and Ki-67 (r = .32, P = .01). c-Met had significant correlation with MVD (r = .30, P = .02) and Ki-67 (r = .38, P = .00). HGF and c-Met expression had no significant correlation with age or extrasellar extension. There were no significant differences in HGF and c-Met expression between pituitary adenomas of different histology types. The results indicate that HGF and c-Met are widely expressed in pituitary adenomas, and their expression correlates with MVD and Ki-67 expression.     

胃癌组织中nm23-H1、c—Met和survivin蛋白表达及临床意义

目的探讨胃癌组织中nm23-H1、c—Met、survivin蛋白表达及其临床意义。方法对50例胃癌蜡快标本,运用S-P免疫组化技术检测nm23-H1、c-Met、survivin蛋白表达情况。并分析各基因表达与胃癌组织的分化程度、浸润深度、淋巴结转移、TNM分期及转移和复发之间的关系。结果nm23-H1、c—Met、survivin蛋白表达率分别为46％、72％、80％,胃癌TNM分期、淋巴结转移与nm23-H1蛋白低表达有密切关系,c—Met蛋白的高表达与胃癌TNM分期、淋巴结转移有密切关系,survivin蛋白的高表达与胃癌分化程度、TNM分期、淋巴结转移有密切关系,nm23-H1蛋白表达与survivin表达呈负相关,c-Met蛋白的表达与survivin表达呈正相关。结论nm23-H1蛋白低表达和c—Met、survivin高表达对于早期诊断和预后分析有重要指导意义,据其表达开展有选择性地基因治疗应有一个良好的应用前景。     

c-Met signalling is required for efficient postnatal thymic regeneration and repair

We have reported that in vivo administration of the hybrid cytokine rIL-7/HGFβ or rIL-7/HGFα, which contains interleukin-7 (IL-7) and the β- or α-chain of hepatocyte growth factor (HGF), significantly enhances thymopoiesis in mice after bone marrow transplantation. We have shown that the HGF receptor, c-Met, is involved in the effect of the hybrid cytokines. To address the role of c-Met signalling in thymocyte development and recovery, we generated conditional knockout (cKO) mice in which c-Met was specifically deleted in T cells by crossing c-Met^ft/ft mice with CD4-Cre transgenic mice. We show here that although the number of total thymocytes and thymocyte subsets in young c-Met cKO mice is comparable to age-matched control (Ctrl) mice, the cKO mice were more susceptible to sub-lethal irradiation and dexamethasone treatment. This was demonstrated by low recovery in thymic cellularity in c-Met cKO mice after insult. Furthermore, the number of total thymocytes and thymocyte subsets was markedly reduced in 6- to 12-month-old cKO mice compared with age-matched Ctrl mice, and the thymic architecture of 12-month-old cKO mice was similar to that of 20-month-old wild-type mice. In addition, c-Met deficiency reduced cell survival and the expression of Bcl-xL in double-positive thymocytes, and decreased cell proliferation and the expression of cyclin E and cyclin-dependent kinase 5 in single-positive thymocytes. Our data indicate that c-Met signalling plays an important role in thymic regeneration after thymic insult. In addition, T-cell-specific inactivation of c-Met accelerates age-related thymic involution.     

Adenovirus expressing dual c-Met-specific shRNA exhibits potent antitumor effect through autophagic cell death accompanied by senescence-like phenotypes in glioblastoma cells

c-Met, a cognate receptor tyrosine kinase of hepatocyte growth factor, is overexpressed and/or mutated in number of tumors. Therefore, abrogation of c-Met signaling may serve as potential therapeutic targets. In this study, we generated Ads expressing single shRNA specific to c-Met (shMet) (dl/shMet4 and dl/shMet5) or dual shRNAs specific to c-Met (dl/shMet4+5); and examined the therapeutic potential of these newly engineered Ads in targeting c-Met, and delineated their mechanism of action in vitro and in vivo. Ads expressing shMet induced knock-down in c-Met, and phenotypically resulted in autophagy-like features including appearance of membranousvacuoles, formation of acidic vesicular organelles, and cleavage and recruitment of microtubule-associated protein1 light chain 3 to autophagosomes. Ads expressing shMet also suppressed Akt phosphorylation and increased number of senescence-related gene products including SM22, TGase II, and PAI-1. These changes resulted in inhibition of cell proliferation and G₂/M arrest of U343 cells. In vivo, intratumoral injection with dl/shMet4+5 resulted in a significant reduction of tumor growth with corresponding increasing overall survival. Histopathological analysis of these treated tumors revealed that Atg5 was highly up-regulated, indicating the therapeutic induction of autophagy. In sum, these results reveal that autophagic cell death induced by shMet-expressing Ads provide a novel strategy for targeting c-Met-expressing tumors through non-apoptotic mechanism of cell death.     

c-Met inhibitors attenuate tumor growth of small cell hypercalcemic ovarian carcinoma (SCCOHT) populations

A cellular model (SCCOHT-1) of the aggressive small cell hypercalcemic ovarian carcinoma demonstrated constitutive chemokine and growth factor production including HGF. A simultaneous presence of c-Met in 41% SCCOHT-1 cells suggested an autocrine growth mechanism. Expression of c-Met was also observed at low levels in the corresponding BIN-67 cell line (6.5%) and at high levels in ovarian adenocarcinoma cells (NIH:OVCAR-3 (84.4%) and SK-OV-3 (99.3%)). Immunohistochemistry of c-Met expression in SCCOHT tumors revealed a heterogeneous distribution between undetectable levels and 80%. Further characterization of SCCOHT-1 and BIN-67 cells by cell surface markers including CD90 and EpCAM demonstrated similar patterns with differences to the ovarian adenocarcinoma cells. HGF stimulation of SCCOHT-1 cells was associated with c-Met phosphorylation at Tyr¹³⁴⁹ and downstream Thr²⁰²/Tyr²⁰⁴ phosphorylation of p44/42 MAP kinase. This HGF-induced signaling cascade was abolished by the c-Met inhibitor foretinib. Cell cycle analysis after foretinib treatment demonstrated enhanced G2 accumulation and increasing apoptosis within 72 h. Moreover, the IC₅₀ of foretinib revealed 12.4 nM in SCCOHT-1 cells compared to 411 nM and 481 nM in NIH:OVCAR-3 and SK-OV-3 cells, respectively, suggesting potential therapeutic effects. Indeed, SCCOHT-1 and BIN-67 tumor xenografts in NOD^scid mice exhibited an approximately 10-fold and 5-fold reduced tumor size following systemic application of foretinib, respectively. Furthermore, foretinib-treated tumors revealed a significantly reduced vascularization and little if any c-Met-mediated signal transduction. Similar findings of reduced proliferative capacity and declined tumor size were observed after siRNA-mediated c-Met knock-down in SCCOHT-1 cells demonstrating that in vivo inhibition of these pathways contributed to an attenuation of SCCOHT tumor growth.     

抗纤抑癌方调控HGF/c-Met mRNA干预肝癌前病变的实验研究

目的：观察抗纤抑癌方对肝癌前病变大鼠HGF/c-Met mRNA的影响,探讨抗纤抑癌方防治肝癌前病变的作用机制。方法：75只SD雄性大鼠随机分为正常组、模型组、抗纤抑癌组、鳖甲软肝组和秋水仙碱组。以二乙基亚硝胺诱发大鼠肝癌前病变模型,用抗纤抑癌方进行干预,并以复方鳖甲软肝片、秋水仙碱片作为对照,采用免疫组化检测肝组织α-SMA的表达情况,实时荧光定量PCR检测各组大鼠肝脏的HGF和c-Met mRNA的表达量。结果：免疫组化显示,与模型组及秋水仙碱组比较,抗纤抑癌组能明显减少α-SMA表达量,差异有统计学意义（P<0.01,P<0.05）。实时荧光定量PCR结果显示,HGF mRNA的相对表达量抗纤抑癌组与模型组比较有统计学意义(P<0.05),与秋水仙碱组比较亦有统计学意义(P<0.05),抗纤抑癌方能显著提高肝癌前病变大鼠HGF mRNA的表达水平。c-Met mRNA在DEN造模的各组中均低表达,各组间差异无统计学意义（P>0.05）。结论：抗纤抑癌方能够提高肝癌前病变大鼠HGF mRNA的表达水平,这可能是其防治肝癌前病变的作用机制之一。     

乳腺癌恶性程度与HGF/c-Met、端粒酶、微血管密度相关性研究

目的:探讨乳腺癌恶性程度与肝细胞因子及其受体(HGF/c-Met)、端粒酶(hTERT)表达、微血管密度(MVD)的相关性。方法:选择确诊为乳腺癌患者102例为实验组,同期确诊为良性乳腺疾病患者40例为对照组。real～timePCR检测手术切除组织的HGF与c-Met、hTERT基因表达,免疫组织化学SP法检测切除组织MVD。结果:乳腺癌Ⅱ、Ⅲ和Ⅳ期患者的hTERT与MVD均显著高于Ⅰ期和对照组(P<0.01),Ⅱ、Ⅲ、Ⅳ期患者hTERT无显著差异(P>0.05),Ⅰ期MVD显著高于对照组(P<0.01),Ⅲ、Ⅳ期患者HGF、c-Met较Ⅰ、Ⅱ期显著升高(P<0.01),Ⅲ、Ⅳ期患者MVD、hTERT无显著差异(P>0.05)但明显高于Ⅰ、Ⅱ期(P<0.01),Ⅲ、Ⅳ期发生淋巴结转移比例明显高于Ⅰ、Ⅱ期(P<0.01)。结论:HGF及c-Met、hTERT表达与MVD和乳腺癌临床分期和肿瘤的恶性程度具有明显关系,检测这些指标可以辅助判断乳腺癌的恶性程度和预后。     

Signal transduction of Helicobacter pylori during interaction with host cell protein receptors of epithelial and immune cells

Helicobacter pylori infections can induce pathologies ranging from chronic gastritis, peptic ulceration to gastric cancer. Bacterial isolates harbor numerous well-known adhesins, vacuolating cytotoxin VacA, protease HtrA, urease, peptidoglycan, and type IV secretion systems (T4SS). It appears that H. pylori targets more than 40 known host protein receptors on epithelial or immune cells. A series of T4SS components such as CagL, CagI, CagY, and CagA can bind to the integrin α₅β₁ receptor. Other targeted membrane-based receptors include the integrins α_vβ₃, α_vβ₅, and β₂ (CD18), RPTP-α/β, GP130, E-cadherin, fibronectin, laminin, CD46, CD74, ICAM1/LFA1, T-cell receptor, Toll-like receptors, and receptor tyrosine kinases EGFR, ErbB2, ErbB3, and c-Met. In addition, H. pylori is able to activate the intracellular receptors NOD1, NOD2, and NLRP3 with important roles in innate immunity. Here we review the interplay of various bacterial factors with host protein receptors. The contribution of these interactions to signal transduction and pathogenesis is discussed.