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Metastasis is the leading cause of death in patients with hepatocellular carcinoma (HCC) and microRNAs have been implicated to influence this process. Emerging evidence indicates that miR-198 is down-regulated in HCC compared to normal liver parenchyma, but the functional roles of miR-198 in HCC cells remains unexplored. Herein, we show that miR-198 directly targets c-MET via its 3'UTR. Forced expression of miR-198 decreased c-MET expression at both mRNA and protein levels and consequently diminished HGF induced phosphorylation of p44/42 MAPK in HCC cells. Forced expression of miR-198 inhibited HGF promotion of HCC cell migration and invasion in a c-MET dependent manner. In conclusion, we have identified miR-198 as a novel suppressor of HCC cell invasion by negative regulation of the HGF/c-MET pathway. 相似文献
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Ovarian cancer is the leading cause of death from gynecological cancers in North America and Europe. Despite its clinical significance, the factors that regulate the development and progression of ovarian cancer are among the least understood of all major human malignancies. A growth factor with pleiotropic effects, which has attracted increasing attention in recent years, is the hepatocyte growth factor (HGF) and its receptor MET. While deregulated HGF/MET signaling is observed in many tumors, the consequences of MET activation are complex and context dependent. Recent observations have demonstrated a cross-talk of other signaling pathways with MET signaling. This review summarizes the key findings and recent advances in our understanding of HGF and MET in the transformation and progression of ovarian cancer. We will begin with a brief discussion on the role of HGF and MET in the physiology of normal ovarian surface epithelium (OSE) and ovarian cancer development. In particular, the coexpression of HGF and MET in OSE of women with hereditary ovarian cancer syndromes emphasizes their importance in neoplastic transformation of OSE. The involvement of HGF in other aspects of tumor progression, such as invasion and metastasis, and novel downstream target genes activated by HGF is summarized next. The therapeutic potential of HGF to treat ovarian cancer and to improve response to conventional chemotherapy is also described. Finally, the most recent progress in drug development and future areas of research in terms of their potential clinical implications are discussed. 相似文献
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HGF/SF-Met signaling in tumor progression 总被引:11,自引:0,他引:11
Tumor progression is a multi-step process that requires a sequential selection of specific malignant phenotypes. Met activation may induce different phenotypes depending on tumor stage: inducing proliferation and angiogenesis in primary tumors, stimulating motility to form micrometastases, and regaining the proliferation phenotype to form overt metastases. To study how HGF/SF-induced proliferative phenotypes switch to the invasive phenotype is important for understanding the mechanism of tumor progression and will provide an attractive target for cancer intervention and therapy. 相似文献
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D. A. Gnatenko E. P. Kopantsev E. D. Sverdlov 《Biochemistry (Moscow) Supplemental Series B: Biomedical Chemistry》2017,11(2):101-110
Fibroblast growth factors (FGFs) are signaling molecules with a wide range of actions that are involved in various processes in the body. Specifically for pancreas, FGFs are important for both organogenesis and carcinogenesis. They belong to the factors involved in the interaction between cancer and stromal cells representing a key component in the development of pancreatic cancer. Pathological changes in the FGF/FGFR signaling pathway is a complex process, which depends on type/isoforms of FGF receptors (FGFR) regulating the remodeling effect and subsequent activation of pancreatic cancer cells by FGF. FGFs and their receptors FGFR are considered as potential specific markers and putative targets for treatment of pancreatic cancer. 相似文献
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Biphasic regulation of the NADPH oxidase by HGF/c-Met signaling pathway in primary mouse hepatocytes
Denise Clavijo-Cornejo Cristina Enriquez-Cortina Alberto López-Reyes Mayra Domínguez-Pérez Natalia Nuño Marcela Domínguez-Meraz Leticia Bucio Verónica Souza Valentina M. Factor Snorri S. Thorgeirsson María Concepción Gutiérrez-Ruiz Luis E. Gómez-Quiroz 《Biochimie》2013
Redox signaling is emerging as an essential mechanism in the regulation of biological activities of the cell. The HGF/c-Met signaling pathway has been implicated as a key regulator of the cellular redox homeostasis and oxidative stress. We previously demonstrated that genetic deletion of c-Met in hepatocytes disrupts redox homeostasis by a mechanism involving NADPH oxidase. Here, we were focused to address the mechanism of NADPH oxidase regulation by HGF/c-Met signaling in primary mouse hepatocytes and its relevance. HGF induced a biphasic mechanism of NADPH oxidase regulation. The first phase employed the rapid increase in production of ROS as signaling effectors to activate the Nrf2-mediated protective response resulting in up-regulation of the antioxidant proteins, such as NAD(P)H quinone oxidoreductase and γ-glutamylcysteine synthetase. The second phase operated under a prolonged HGF exposure, caused a suppression of the NADPH oxidase components, including NOX2, NOX4, p22 and p67, and was able to abrogate the TGFβ-induced ROS production and improve cell viability. In conclusion, HGF/c-Met induces a Nrf2-mediated protective response by a double mechanism driven by NADPH oxidase. 相似文献
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Min Yang Min Wang Xianping Li Yixin Xie Xiaomeng Xia Jingjing Tian Kan Zhang Aiguo Tang 《Journal of cellular biochemistry》2019,120(3):2703-2712
Cervical cancer (CC) is the second most common malignancy in females. Owing to poor diagnosis, resistance to the systemic therapies, and high recurrence rate, patients with CC have a relatively poor prognosis. The role of a signaling pathway in CC has always been the focus among worldwide researchers. As reported before, aberrant expression of proteins associated with signaling pathways, such as phosphatidylinositol 3-kinase(PI3K), EGF-R, β-catenin, and Erk and Bcl-2 was discovered in CC. Therefore, aberrant molecular signaling pathways are significant parts of cervical carcinogenesis. Recently discovered long noncoding RNAs (lncRNAs) as a new regulator player of molecular biology in CC have always been reported. In this review, we highlighted the role of lncRNA in signaling pathway implicated in CC and outlined the molecular mechanism of lncRNA in it. All of these present an opportunity for developing diagnosis and therapies against CC. 相似文献
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Haruo Kanno Hiroshi Ozawa Akira Sekiguchi Seiji Yamaya Satoshi Tateda Kenichiro Yahata Eiji Itoi 《Cell cycle (Georgetown, Tex.)》2012,11(17):3175-3179
The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in multiple cellular functions, such as cell metabolism, proliferation and survival. Many previous studies have shown that mTOR regulates both neuroprotective and neuroregenerative functions in trauma and various diseases in the central nervous system (CNS). Recently, we reported that inhibition of mTOR using rapamycin reduces neural tissue damage and locomotor impairment after spinal cord injury (SCI) in mice. Our results demonstrated that the administration of rapamycin at four hours after injury significantly increases the activity of autophagy and reduces neuronal loss and cell death in the injured spinal cord. Furthermore, rapamycin-treated mice show significantly better locomotor function in the hindlimbs following SCI than vehicle-treated mice. These findings indicate that the inhibition of mTOR signaling using rapamycin during the acute phase of SCI produces neuroprotective effects and reduces secondary damage at lesion sites. However, the role of mTOR signaling in injured spinal cords has not yet been fully elucidated. Various functions are regulated by mTOR signaling in the CNS, and multiple pathophysiological processes occur following SCI. Here, we discuss several unresolved issues and review the evidence from related articles regarding the role and mechanisms of the mTOR signaling pathway in neuroprotection and neuroregeneration after SCI. 相似文献
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《Cell cycle (Georgetown, Tex.)》2013,12(17):3175-3179
The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in multiple cellular functions, such as cell metabolism, proliferation and survival. Many previous studies have shown that mTOR regulates both neuroprotective and neuroregenerative functions in trauma and various diseases in the central nervous system (CNS). Recently, we reported that inhibition of mTOR using rapamycin reduces neural tissue damage and locomotor impairment after spinal cord injury (SCI) in mice. Our results demonstrated that the administration of rapamycin at four hours after injury significantly increases the activity of autophagy and reduces neuronal loss and cell death in the injured spinal cord. Furthermore, rapamycin-treated mice show significantly better locomotor function in the hindlimbs following SCI than vehicle-treated mice. These findings indicate that the inhibition of mTOR signaling using rapamycin during the acute phase of SCI produces neuroprotective effects and reduces secondary damage at lesion sites. However, the role of mTOR signaling in injured spinal cords has not yet been fully elucidated. Various functions are regulated by mTOR signaling in the CNS, and multiple pathophysiological processes occur following SCI. Here, we discuss several unresolved issues and review the evidence from related articles regarding the role and mechanisms of the mTOR signaling pathway in neuroprotection and neuroregeneration after SCI. 相似文献
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Apoptosis is a fundamental process that contributes to tissue homeostasis, immune responses, and development. The receptor CD95, also called Fas, is a member of the tumor necrosis factor receptor (TNF-R) superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance, and various lineages of malignant cells exhibit loss-of-function mutations in this pathway; therefore, CD95 was initially classified as a tumor suppressor gene. However, more recent data indicate that in different pathophysiological contexts, this receptor can transmit non-apoptotic signals, promote inflammation, and contribute to carcinogenesis. A comparison with the initial molecular events of the TNF-R signaling pathway leading to non-apoptotic, apoptotic, and necrotic pathways reveals that CD95 is probably using different molecular mechanisms to transmit its non-apoptotic signals (NF-κB, MAPK, and PI3K). As discussed in this review, the molecular process by which the receptor switches from an apoptotic function to an inflammatory role is unknown. More importantly, the biological functions of these signals remain elusive. 相似文献
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目的:探讨Toll样受体4(TLR4)/P38/JNK信号通路在海马神经元凋亡中的作用及其机制,为神经退行性疾病(ND)的发病机制与防治研究提供新的实验依据。方法:采用体外培养7 d的新生大鼠海马神经元,免疫荧光双标法鉴定海马神经元纯度。用TLR4配体脂多糖(LPS)或TLR4抗体预处理海马神经元,以激活或阻断TLR4的作用。实验1设正常对照组、LPS组及TLR4抗体+ LPS组;免疫荧光法检测P-P38,P-JNK的表达。实验2分为6组:正常对照组,LPS组,TLR4抗体+ LPS组,SB202190(抑制P38) + LPS组,SP600125(抑制JNK) + LPS组,PD98059(抑制ERK) + LPS组;分别用TLR4抗体、P38、JNK及ERK的抑制剂预处理海马神经元后再给以LPS刺激24 h,Western blot法检测Bcl-2,Bax,Active-caspase-3的表达变化;流式细胞术检测海马神经元凋亡率。结果:LPS组海马神经元P-P38、P-JNK的表达明显高于正常对照组(P < 0. 01),TLR4抗体+ LPS组P-P38,P-JNK表达显著低于LPS组(P <0.01)。与正常对照组相比,LPS组海马神经元Bcl-2/Bax表达减少、Active-caspase-3表达增加,海马神经元凋亡率增加(P < 0.01)。而TLR4抗体+ LPS组、SB202190 + LPS组、SP600125 + LPS组Bcl-2/Bax显著高于LPS组、Active cas-pase-3显著低于LPS组(P < 0.01),海马神经元凋亡率显著低于LPS组(P < 0. 05,P < 0. 01)。PD98059 + LPS组与LPS组海马神经元凋亡率无明显差异。结论:①海马神经元中有TLR4介导的P38/JNK信号通路。②海马神经元TLR4激活后,P-P38、P-JNK表达增加,使Bcl-2/Bax的比例降低和Active-caspase-3表达增加,从而促进海马神经元的凋亡。海马神经元凋亡过程中有TLR4介导的P38/JNK信号通路的参与。 相似文献
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Laurent Dortet Esteban Veiga Matteo Bonazzi Pascale Cossart 《Microbes and infection / Institut Pasteur》2010,12(12-13):919-927
Listeria monocytogenes is a facultative intracellular Gram-positive bacterium responsible for listeriosis. It is able to invade, survive and replicate in phagocytic and non-phagocytic cells. The L. monocytogenes surface protein InlB interacts with c-Met, the hepatocyte growth factor (HGF) receptor, inducing bacterial internalization in numerous non-phagocytic cells. As InlB and HGF are known to trigger similar signaling pathways upon c-Met activation, we investigated the role of CD44, and more specifically its isoform CD44v6, in bacterial internalization in non-phagocytic cells. Indeed, CD44, the hyaluronic acid transmembrane receptor, and more specifically its isoform CD44v6 have been reported as necessary for the activation of c-Met upon the interaction with either the endogenous ligand HGF or the L. monocytogenes surface protein InlB. Our results demonstrate that, in the cell lines that we used, CD44 receptors play no role in the activation of c-Met, neither during L. monocytogenes entry, nor upon HGF activation. Furthermore, none of the CD44 isoforms was recruited at the L. monocytogenes entry site, and depletion by siRNA of total CD44 or of CD44v6 isoform did not reduce bacterial infections. Conversely, the overexpression of CD44 or CD44v6 had no significant effect on L. monocytogenes internalization. Together our results reveal that the activation of c-Met can be largely CD44-independent. 相似文献
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Immunohistochemical expression of HGF, c-MET and transcription factor STAT3 in colorectal tumors 总被引:4,自引:0,他引:4
Trovato M Vitarelli E Grosso M Alesci S Benvenga S Trimarchi F Barresi G 《European journal of histochemistry : EJH》2004,48(3):291-297
By immunohistochemistry, we have investigated the expression of hepatocyte growth factor (HGF), HGF-R or c-met and the transcritor factor STAT3 in a series of 80 colorectal tumours (40 adenomas and 40 adenocarcinomas). The expression of HGF, c-met and STAT3 was revealed in 40/40 (100%) of adenomas and in 26/40 (65%) of adenocarcinomas; the remaining 14/40 (35%) carcinomas expressed c-met but failed to express HGF and STAT3. Positive immunoreaction score was defined through the number of stained cells: low (1-10%), moderate (11-50%) and high (>51%). In adenomas, the HGF immunoreaction was high in 33 (82.5%) and moderate in 7 (17.5%); the c-met staining was high in 3 (7.5%) and moderate in 37 (92.5%); and the STAT3 reactivity was high in 25 (62.5%) and moderate in 15(37.5%). In carcinomas, the HGF immunoreaction was moderate in 21 (80.7%) and low in 5 (19.2%); the c-met staining was high in 14 (35%), moderate in 25 (62.5) and low in 1 (2.5%); and the STAT3 reactivity was moderate in 17 (65.3%) and low in 9 (34.6%). In both type of lesions, HGF and c-met showed a membranous and cytoplasmic location. In adenomas, STAT3 was detected in cytoplasm and nucleus and in carcinomas it was limited to cytoplasm. While the HGF/c-met/STAT3 expression in adenomas was significantly different from carcinomas (c2 = 17, p < 0.0001), no correlation was found among HGF, c-met, or STAT3 immunostaining with histotype or degree of dysplasia in adenomas and the same for histotype, grading or staging in carcinomas. These features, suggesting a role of the HGF/c-met/STAT3 signal in colon tumorigenesis, indicate that a reduced expression of HGF and c-met is associated to progression of adenoma into carcinoma. 相似文献
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《Journal of receptor and signal transduction research》2013,33(6):440-444
AbstractThe uromodulin (UMOD) is a glycoprotein expressed exclusively by renal tubular cells lining the thick ascending limb of the loop of Henle. UMOD acts as a regulatory protein in health and in various conditions. For kidney diseases, its role remains elusive. On one hand, UMOD plays a role in binding and excretion of various potentially injurious products from the tubular fluid. On the other hand, chronic kidney disease is associated with higher serum levels of UMOD. Signaling pathways might be very important in the pathogenesis of kidney diseases. We performed this review to provide a relatively complete signaling pathway flowchart for UMOD to the investigators who were interested in the role of UMOD in the pathogenesis of kidney diseases. Here, we reviewed the signal transduction pathway of UMOD and its role in the pathogenesis of kidney diseases. 相似文献