Role Of HGF Research Articles

Plasma hepatocyte growth factor as a noninvasive biomarker in small cell lung cancer

BackgroundHepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine, which is overexpressed and/or activated in multiple malignancies and is reported to be associated with tumor development and inferior survival. At present, the role of HGF in small cell lung cancer (SCLC) has not been fully explored yet.Materials and methodsThe expression of HGF and its value in predicting survival in SCLC were explored from GEO database and in pan-cancer analysis. Furthermore, we detected the expression of HGF using tumor tissue and paired plasma samples from a validation cohort of 71 SCLC patients at our institute. Correlation between tumor and plasma HGF expression and the prognostic values were analyzed.ResultsGEO database analysis revealed that tumor tissue had lower HGF expression than paired normal tissue in SCLC. At our institute, immunohistochemical staining showed negative expression of HGF in tumor tissue of SCLC at our institute (47/47, 100%). The average baseline plasma HGF was 1.28 (range,0.42–4.35) ng/ml. However, plasma HGF was higher in SCLC patients with patients with N3, M1, liver metastasis (LM) and bone metastasis (BM) disease compared with those N0 − 2 (1.25 vs. 1.75 ng/mL, P = 0.000), M0 (1.26 vs. 1.63 ng/mL, P = 0.003), non-LM (1.32 vs. 2.06 ng/mL, P = 0.009), and non-BM (1.35 vs. 1.77 ng/mL, P = 0.047), respectively. Multivariate analysis revealed plasma HGF was an independent predictor for LM and prognostic factor of OS.ConclusionOur results revealed that plasma HGF rather than tumor HGF exhibited a potential role in predicting metastasis and survival in SCLC. Plasma HGF might be used as a non-invasive detecting and monitoring tool for SCLC.

Overexpressed HGF promotes metastasis of squamous cell carcinoma of the head and neck through the PI3K/Akt and JNK signaling pathways.

Background: The role of HGF in squamous cell carcinoma of the head and neck (SCCHN) is not clear. Methods: Reverse transcription PCR, western blotting, gelatin zymography, immunohistochemistry, actin polymerization, chemotaxis and migration assays were used in the authors' study. Results: HGF expression level was upregulated in SCCHN cells, which was associated with clinical stage; tumor, node, metastasis classification; and lymphatic invasion. SCCHN cells with high Met expression were sensitive to cell invasion, which was blocked by inhibiting PI3K/Akt and JNK. HGF induced MMP9 expression and enhanced its activity. Akt induced the activation of JNK through the PI3K/Akt and JNK signaling pathways. Conclusion: HGF upregulates MMP9 through the activation of the PI3K/Akt and JNK signaling pathways in SCCHN cells.

Abstract B60: Pro-HGF and its activator confer a sustained transformation activity in ovulatory follicular fluid

Abstract The etiology of ovarian high-grade serous ovarian cancers (HGSC) originating from the epithelium of fallopian tube fimbriae is elusive. Based on the incessant ovulation hypothesis, our previous studies found that ROS released during ovulation, collaborated with hemoglobin from retrograde menstruation, caused oxidative damage and DNA breaks to the fimbrial epithelial cells. Repeated exposures of ovulatory follicular fluid could induce tumorigenesis of in Trp53-null mice and transform human fimbrial epithelial cells (FE25) immortalized by E6/E7. In addition to mutagenic ROS, we later identified IGF-axis proteins abundantly present in follicular fluid (FF) are largely responsible for the stemness activation and transformation of FE25 cells. However, FF-IGF signal does not confer other key phenotypes induced by FF, such as mitogenesis and cell migration. In this study, we further clarified the role of HGF, another growth factor abundantly present in FF. Treating FE25 cells with pure HGF and IGF2 could fully recapitulate the anchorage-independent growth (AIG) activity of FF with equal colony number of 55±12 and 60±6, respectively. Inhibitor of HGF cMET receptor, AMG337, greatly reduced the AIG activity to 8±5 colonies. HGF is known to be activated by a cascade of activation by cleavage of its precursor pro-HGF and the precursor (pro-HGFA) of its activating protein HGFA. We found FF contains a high level of these pro-form proteins and a low amount of the cleaved active forms. Interestingly, these pro-form HGF axis proteins are extremely stable in FF. After one-month incubation at 37 degrees Celsius, they could still be activated and exerted AIG of FE25 cells. Once encountering the cell surface, protease cleavage is initiated to activated pro-HGFA to HGFA, which then cleaves pro-HGF to HGF. Via the c-MET/AKT/ERK signaling, the activated HGF confers the mitogenic and transformation activity of FF. In FF, HGF seems to cooperate with IGF2 to sustain a long-term proliferation of fimbrial epithelial cells initiated by ROS-induced mutagenesis and clonally expanded by IGF axis signaling. A reservoir of durable pro-forms of HGFA and HGF are responsible for this sustained transformation activity. Thus, the mutagenic, clonogenic, and sustained mitogenic activities in FF strongly support the incessant ovulation theory with ovulatory carcinogens to be the culprit. Citation Format: Hsuan Shun Huang, Tang-Yuan Chu. Pro-HGF and its activator confer a sustained transformation activity in ovulatory follicular fluid [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B60.

Abstract 4016: c-MET associated with osteogenesis in multiple myeloma patients by induction of MMP9 expression by HGF in BMSCs

Abstract HGF-mediated c-MET signaling plays a critical key in the progression of multiple myeloma. That signaling is associated with cell proliferation, drug resistance and osteoblast. In addition dynamic interplay between MM cell and bone marrow stromal cell regulates that signaling activation. The expression level of HGF in bone marrow plasma of MM patients is higher when compared to case control. However, the role of HGF-mediated c-Met was obscure in the progression of MM. In this study, we elucidate the role of c-Met signaling in osteogenesis in MM using co-culture system. In our previous data, we found that the expression levels of HGF in bone marrow serum of multiple myeloma patients was correlated with the expression levels of OPN and RUNX2. Also, those expression levels were associated with bone lesion. It suggested that HGF might be one of regulators in the progression of osteogenesis. However, mechanisms by HGF-mediated c-MET activation modulate the expression of matrix metalloproteinases still remain unknown. In our study, we found that Our data show that PI3K inhibitor effectively inhibited the MMP9 mRNA expression in both OPN alone treatment and co-treatment with OPN and HGF in BMSCs. Induction of OPN and RUNX2 by HGF in MM cells could be one of the major factors for the progression of MM through interaction of MM cells and BMSCs. We suggested that induction of OPN/MMP9 strongly associated with osteoclast. For further analysis, we performed co-culture system which MM cells were grown with BMSCs obtained from MM patients’ bone marrow specimen in order to verify the role of HGF mediated c-MET activation in the progression of MM patient's osteogenesis. To explore the detail mechanisms of HGF-mediated osteogenesis, various inhibitors was used and the expression levels of a set of genes was examined using real-time PCR. Subsequently, HGF-mediated c-MET activation was regulated the expression of OPN/MMP-9 via co-effects of PIK3 activation and activation of wnt signaling pathway in BMSCs from bone marrow of MM patients. In conclusion, cross-talk between PI3K/AKT pathway and wnt singaling pathway could be one of the major factors for the progression of MM through interaction of MM cells and BMSCs. Citation Format: Hyejoo Park, Jeong In Oh, Kwang-Sung Ahn, Youngil Koh, Sung-Soo Yoon. c-MET associated with osteogenesis in multiple myeloma patients by induction of MMP9 expression by HGF in BMSCs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4016. doi:10.1158/1538-7445.AM2015-4016

Role of HGF in epithelial-stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ

Role of HGF in epithelial-stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ

Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer

Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer

Abstract LB-501: Role of HGF in epithelial-stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ

Abstract Role of HGF in epithelial-stromal cell interactions during progression from benign breast disease to ductal carcinoma in situ. Introduction: Tumor-stroma interactions create a ‘permissive microenvironment’ during cancer progression. Basal and luminal breast cancers (BC) have distinct tumor-stroma interactions, but few studies show how gene expression evolves in premalignant cells. We observed that hepatic fibrosis/HGF signaling is induced in basal-like microenvironments, and previous studies have demonstrated that overexpression of HGF is a predictor of breast cancer recurrence and survival. However it is not known whether HGF signaling is altered in early (premalignant and DCIS) lesions. Methods: To study tumor-stroma interactions during cancer progression, we cocultured breast fibroblasts with a panel of isogenic cell lines, the MCF10 series. The MCF10 series represents different stages of cancer progression (benign, atypical hyperplasia and ductal carcinoma in situ). RNA from cocultures was used to perform gene expression microarrays and proteins secreted into media were analyzed by antibody arrays. Differentially expressed genes were identified using supervised analysis, followed by gene ontology analysis. In addition, a signature of basal-like microenvironment was evaluated to test whether the stroma-epithelial interactions observed in basal-like cancers were also present in premalignant cells. Finally, HGF signaling was inhibited (using an HGF-antibody) to assess effects of this pathway on migration and gene expression. Results: Cocultures with MCF10DCIS express higher levels of RNA involved in immune response processes and connective tissue disorders, as reported previously for basal-like BC. In contrast, premalignant MCF10AT and MCF10A cells showed weak expression of these profiles. In cytokine arrays, striking overexpression of HGF was observed in both MCF10AT1 and MCF10DCIS cocultures relative to cocultures with the benign MCF10A cell line, with corresponding increases in c-MET levels. These changes correlated with increased migration, which was blocked by adding HGF-specific antibodies to the media. Conclusions: Inhibition of HGF alters stromal-epithelial interactions, rendering the premalignant microenvironment more similar to normal microenvironments. HGF signaling is necessary for stroma-induced migratory phenotypes in vitro and is induces widespread gene expression changes. Targeting HGF signaling in early carcinogenesis may have value in preventing progression of basal-like precursor lesions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-501. doi:1538-7445.AM2012-LB-501

Abstract 998: Downregulation of survivin suppresses uPA through transcription factor JunB

Abstract Background: Survivin, identified member of the inhibitor apoptosis protein family, is expressed during development and in various human cancers. However, lts role of clinical relevance in cancers are sill debated. Purpose: We investigated the role of HGF induced activation of a transcription factor JunB, in the expression of survivin and uPA. Methods and Results: Genes induced by HGF were screened by using cDNA microarray technology in stomach cancer cell lines, NUGC3 and MKN28. Expression level of surviving and JunB was further confirmed by read time RT-RCR and western blot analysis. Roles of JunB and survivin in the levels of HGF induced up-regulation of uPA were measured by knock down of survivin with survivin siRNA and chromatic immuno- precipitation assay. The levels of JunB, survivin and uPA were up regulated in cells treated with HGF in a dose dependent manner. HGH-induced up regulations of JunB, surviving, and uPA were inhibited by the pretreatment with an MEK inhibitor, PD 098559. HGH-induced up-regulation of uPA were repressed by survivin knockdown. HGF enhanced the binding activity of JunB to the enhanced the binding activity of JunB to the survivin promoter in control cells, but not in the JunB-sh RNA cells. Transfection with survivin-sh RNA results in decrement of cell proliferation as determined with MTT assays. In an in vitro invasion assay, significantly fewer cells transfected with survivin sh-RNA than control cells were able to invade across a matrigel membrane barrier.Conclusion: Survivin might play an important role in the up-regulation of uPA induced by HGF via JunB and contribute to HGF-mediated tumor invasion and metastasis, which might be promising target for stomach cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 998. doi:10.1158/1538-7445.AM2011-998

Expression of HGF and IGF-1 during regeneration of masseter muscle in mdx mice

This study investigated the expression of the growth factors HGF and IGF-1 during the process of muscle regeneration in mdx mice. HGF and IGF-1 are reportedly expressed during the regeneration of muscle tissue in vitro. However, few studies have focused on the role of HGF and IGF-1 during muscle regeneration in mdx mice, which lack expression of the dystrophin gene. In the present study, we examined the expression of HGF and IGF-1 in masseter muscle during muscle regeneration in mdx and B10 (control) mice using histological analysis, immunohistochemistry and Western blotting, as well as examining gene expression by RT-PCR, at 3, 4 and 9 weeks. Mdx mice showed localized HGF and IGF-1 positivity in the cytoplasm of regenerating muscle cells at 3 and 4 weeks, but hardly any reactivity was evident at 9 weeks. The control group was completely negative for IGF-1 at any of the examined time points. Western blotting showed stronger expression of HGF and IGF-1 in mdx mice than in B10 mice at 3 and 4 weeks, but at 9 weeks the expression was absent in both groups. Similar results were obtained using RT-PCR. These present results suggest that HGF and IGF-1 appear to play an important role during regeneration of the masseter muscle in mdx mice.

Role of HGF and EGF signaling in transdifferentiation of hepatocytes to biliary epithelium in organoid cultures

Role of HGF and EGF signaling in transdifferentiation of hepatocytes to biliary epithelium in organoid cultures

Hepatocyte Growth Factor Promotes Cancer Cell Migration and Angiogenic Factors Expression: A Prognostic Marker of Human Esophageal Squamous Cell Carcinomas

Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, c-Met, play important roles in tumor development and progression. In this study, we measured the serum HGF levels in patients with esophageal squamous cell carcinoma (ESCC) to evaluate its relationships with clinicopathologic features and the role of HGF in ESCC. One hundred and forty-nine patients with ESCC were studied. Pretherapy serum was collected and ELISA was used to detect the concentrations of HGF, vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8). The function of HGF was shown by invasion chamber assay. Pretherapy serum HGF was found to be significantly higher in patients with ESCC than in control subjects. The levels of HGF correlated significantly with advanced tumor metastasis stage and survival. Multivariate analyses showed that serum HGF level in cell migration was an independent prognostic factor. Increased HGF serum levels correlated positively with serum levels of VEGF and IL-8. Our results also showed that HGF was overexpressed in ESCC tissues and cell lines. In vitro study showed that HGF could stimulate ESCC cell to express VEGF and IL-8 and markedly enhance invasion and migration of ESCC cells. Furthermore, HGF-induced IL-8 and VEGF expression was dependent on extracellular signal-regulated kinase signaling pathways. The inhibition of extracellular signal-regulated kinase activation reduced HGF-mediated IL-8 and VEGF expression. Our results suggest that serum HGF may be a useful biomarker of tumor progression and a valuable independent prognostic factor in patients with ESCC. HGF may be involved in the progression of ESCC as an autocrine/paracrine factor via enhancing angiogenesis and tumor cell invasion and migration.

HGF and postnatal testis development

Hepatocyte growth factor regulates many cellular functions acting through c-met, its specific receptor with tyrosine kinase activity. We have previously reported that in prepubertal rats HGF is secreted in the seminiferous tubules by purified peritubular myoid cells whereas Sertoli cells do not express HGF mRNA. In the present paper we report that HGF is expressed by the myoid cells during the entire postnatal testicular development studied and secreted in the culture medium. On the contrary, in Sertoli cells HGF starts to be clearly detectable by northern blot at 25 days of age. HGF is expressed and secreted by Sertoli cells isolated from 35-day-old rats and is able to increase the levels of c-met expression of the Sertoli cells. Although the role of HGF during the development of the postnatal testis need further research to be clarified, the data here presented indicate that HGF is one of the growth factors regulating mammalian testicular function.

HGF: a multifunctional growth factor controlling cell scattering

Hepatocyte Growth Factor, also known as Scatter Factor, is a polypeptide that shows structural homology with enzymes of the blood coagulation cascade. It is a biologically inactive single chain precursor that is then cleaved by specific serine proteases to a fully active αβ heterodimer. All the biological responses induced by HGF/SF are elicited by binding to its receptor, a transmembrane tyrosine kinase encoded by the MET proto-oncogene. The signaling cascade triggered by HGF begins with the autophosphorylation of the receptor and is mediated by concomitant activation of different cytoplasmic effectors that bind to the same multifunctional docking site. During development, HGF function is essential: knock-out mice for both ligand and receptor show an embryonic lethal phenotype. HGF/SF displays a unique feature in inducing “branching morphogenesis”, a complex program of proliferation and motogenesis in a number of different cell types. Moreover, HGF is involved in the invasive behaviour of several tumor cells both in vivo and in vitro. The role of HGF as putative therapeutical agent in pathologies characterized by massive cell loss or deregulated cell proliferation is under investigation.

Role of HGF in growth and differentiation of bone cells during skeletal morphogenesis

Role of HGF in growth and differentiation of bone cells during skeletal morphogenesis