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Macrophage stimulating protein (MSP) is a multifunctional serum protein produced in the liver, belonging to the plasminogen-related kringle protein family. It exerts diverse biological functions by activating a transmembrane receptor protein-tyrosine kinase known as RON in humans and SKT in mice. MSP plays a pivotal role in innate immunity and is involved in various activities such as cell survival, migration, and phagocytosis. Elucidating the regulatory mechanisms governing MSP gene expression is of great importance. In this study, we comprehensively elucidate the molecular mechanism underlying hepatic MSP gene expression in response to alcoholism. Exposure to ethanol specifically upregulated the expression of ERRγ and MSP in the liver, while not in other organs. Liver-specific knockout of the cannabinoid receptor type 1 (CB1R), an upstream regulator of ERRγ, inhibited the alcohol-induced upregulation of MSP expression. Overexpression of ERRγ alone was sufficient to enhance MSP expression in hepatic cell lines and in mice. Conversely, knockdown of ERRγ in cell lines or liver-specific knockout of ERRγ in mice reversed ethanol-induced MSP gene expression. Promoter studies revealed the direct binding of ERRγ to the MSP gene promoter at the ERR response element (ERRE), resulting in the positive regulation of MSP gene expression in response to alcohol. This finding was further supported by ERRE-mutated MSP-luciferase reporter assays. Notably, treatment with GSK5182, an ERRγ-specific inverse agonist, significantly suppressed alcohol-induced hepatic MSP expression. Collectively, we exposed a novel mechanistic understanding of how alcohol-induced ERRγ controls the transcriptional regulation of MSP gene expression in the liver., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Blood brain barrier (BBB) disruption is an important contributor to brain edema and neurological deficits following intracerebral hemorrhage (ICH). Macrophage stimulating protein (MSP) is a hepatocyte growth factor-like protein that mediates its functions via activating receptor tyrosine kinase recepteur d'origine nantais (RON). Grb2-associated binder 1 (GAB1) is a docking protein that mediates downstream receptor signal transduction pathways. This study aimed to evaluate the role of MSP and RON activated signaling pathway in preserving BBB integrity after collagenase-induced ICH. ICH mice received recombinant human MSP (rhMSP) or rhMSP combined with siRNA knockdown of RON or GAB1. rhMSP was administered by intranasal route 1 h after ICH. Brain edema, neurobehavior, BBB tight junction protein expression, and BBB permeability were evaluated. The expression of endogenous MSP and p-RON was decreased after ICH. Exogenous rhMSP administration reduced brain edema, neurological deficits, BBB permeability, and increased the expression of tight junction proteins in ICH mice. rhMSP administration increased the expression of p-RON, p-GAB1, p-Src, nuclear β-catenin, and tight junction proteins after ICH. These effects were reversed with RON and GAB1 siRNA. We conclude that MSP activation of RON preserved BBB integrity via GAB-1/Src/β-catenin pathway, thereby reducing brain edema and neurological deficits after ICH in mice., (© 2018 International Society for Neurochemistry.)

Pancreatic cancer (PC) ranks twelfth in frequency of diagnosis but is the fourth leading cause of cancer related deaths with a 5 year survival rate of less than 7 percent. This poor prognosis occurs because the early stages of PC are often asymptomatic. Over-expression of several growth factors, most notably vascular endothelial growth factor (VEGF), has been implicated in PC resulting in dysfunctional signal transduction pathways and the facilitation of tumor growth, invasion and metastasis. Hepatocyte growth factor (HGF) acts via the Met receptor and has also received research attention with ongoing efforts to develop treatments to block the Met receptor and its signal transduction pathways. Macrophage-stimulating protein (MSP), and its receptor Ron, is also recognized as important in the etiology of PC but is less well studied. Although the angiotensin II (AngII)/AT1 receptor system is best known for mediating blood pressure and body water/electrolyte balance, it also facilitates tumor vascularization and growth by stimulating the expression of VEGF. A metabolite of AngII, angiotensin IV (AngIV) has sequence homology with the "hinge regions" of HGF and MSP, key structures in the growth factor dimerization processes necessary for Met and Ron receptor activation. We have developed AngIV-based analogs designed to block dimerization of HGF and MSP and thus receptor activation. Norleual has shown promise as tested utilizing PC cell cultures. Results indicate that cell migration, invasion, and pro-survival functions were suppressed by this analog and tumor growth was significantly inhibited in an orthotopic PC mouse model., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To study the effect of macrophage stimulating protein (MSP) on the cell cycle of non-small cell lung cancer PC14 cells without expression of recepteur d'originenanta (RON) and MSP,and analyse its effect on PC14's epithelial mesenchymal transition (EMT) capacity., Methods: Vitro culture PC14 (blank control),PC14-Mst1-pEGFP-N1 (stablely expressed MSP) and PC14-pEGFP-N1. Cell cycles were detected by flow cytometry and the gaps between cells during growth were measured by transmission electron microscope (TEM); RT-PCR and Western blot were used to figure out the shifts of EMT related gene expression in PC14-Mst1-pEGFP-N1 cells., Results: Compared with the PC14 group and PC14-pEGFP-N1 group,PC14-Mst1-pEGFP-N1 population of G1/G0 phase were significantly increased while S and G2/M phase were significantly reduced;The gaps between PC14-Mst1-pEGFP-N1 cells decreased; RT-PCR and Western blot showed that mRNA and protein levels of E-cadherin of PC14-Mst1-pEGFP-N1 were significantly higher than that of PC14,but mRNA and protein levels of Vimentin were significantly lower., Conclusion: MSP may affect the cell cycle of PC14 and inhibit its EMT procedure by regulating the expression of related proteins including E-cadherin and Vimentin when RON was not expressed., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Objectives: To determine the effects of macrophage stimulating protein (Msp) on the proliferation, migration and invasion of human non-small cell lung cancer cells PC14., Methods: The eukaryotic expression vector for st1 was constructed and transfected into Msp(-)and RON(-)human non-small cell lung cancer cells PC14. The expression of st1 mRNA in PC14 cells was observed by RT-PCR. The expression levels of Msp protein in PC14, PC14- st1 -pEGFP-N1 and PC14-pEGFP-N1 groups as well as the expression of RON in PC14 and SKBR-3 cells were detected by Western blot. RAW264.7 (mouse monocyte macrophage) and SKBR-3 cells were cultured in the supernatant of cells(PC14, PC14- st1 -pEGFP-N1and PC14-pEGFP-N1 groups)and tested with Transwell microporous membrane, through which the biologic activity of Msp was evaluated by calculating the cell number migrated. The proliferation of PC14 was measured by MTT assay. The capabilities of PC14 to migrate and invade were measured by Transwell chamber and Matrigel invasion tests, respectively., Results: The expressions of mRNA and protein of Mst1 in PC14 were stable after transfection with Mst1. Msp (PC14- st1 -pEGFP-N1 group) promoted the migration of RON (+) cells (SKBR-3 and RAW264.7). Compared with PC14 and PC14-pEGFP-N1 groups, the proliferation, migration and invasion of PC14 cells in PC14- st1 -pEGFP-N1 group were inhibited significantly., Conclusions: Msp can promote the migration of RON (+) cancer cells in paracrine secretion manner and inhibit the proliferation, migration and invasion of human non-small cell lung cancer cells PC14 in an unknown way.

Objective: To investigate the roles of macrophage stimulating protein (MSP) and its tyrosine kinase receptor RON in smoke-induced airway inflammation of rats., Methods: Inhalation of combustion smoke was administered in rats to induce airway inflammation. Alveolar macrophages (AM) of healthy and smoking rats were isolated at different time points, cultured and then treated with different concentrations of MSP for 24 h., Results: When compared with healthy rats, MSP increased in the serum and bronchoalveolar lavage fluid (BALF) of smoking rats in a time dependent manner. In smoking rats, the RON expression in the lung and AM was higher than in healthy rats, and these increases were time dependent. MSP stimulated the production of malondialdehyde (MDA) and reduced superoxide dismutase (SOD) activity in rat AM cells in a dose dependent manner. MSP also stimulated the release of inflammatory factors TNF-α, IL-8, IL-1β and IL-10 in rat AM in a dose-dependent manner. Moreover, at the same MSP concentration, the contents of MDA, TNF-α, IL-8 and IL-1β in the AM of smoking rates were higher than in healthy rats, while the IL-10 content and SOD activity were lower than in healthy rats., Conclusion: MSP and its receptor RON are involved in the smoke-induced airway inflammation in rats via promoting AM to release inflammatory cytokines and inducing the increase of oxygen free radical.

Background In former studies we showed in a rat model of renal transplantation that Mesenchymal Stromal Cells (MSC) prevent acute rejection in an independent way of their endowing in the graft. In this study we investigated whether MSC operate by resetting cytokine network and Scatter Factor systems, i.e. Hepatocyte Growth Factor (HGF), Macrophage Stimulating Protein (MSP) and their receptors Met and RON, respectively. Methods MSC were injected into the renal artery soon after reperfusion. Controls were grafted untreated and normal rats. Rats were sacrificed 7 days after grafting. Serum and renal tissue levels of IFN-γ, IL-1, IL-2, IL-4, IL-6, IL-10, MSP/RON, HGF/Met systems, Treg lymphocytes were investigated. Results In grafted untreated rats IFN-γ increased in serum and renal tissue and IL-6 rose in serum. MSC prevented both the phenomena, increased IL-10 serum levels and Treg number in the graft. Furthermore MSC increased serum and tissue HGF levels, Met tubular expression and prevented the suppression of tubular MSP/RON expression. Conclusions Our results demonstrate that MSC modify cytokine network to a tolerogenic setting, they suppress Th1 cells, inactivate monocytes/macrophage, recruit Tregs. In addition, MSC sustain the expression of the Scatter Factor systems expression, i.e. systems that are committed to defend survival and stimulate regeneration of tubular cells. [ABSTRACT FROM AUTHOR]

RON is a member of the receptor tyrosine kinase gene family that includes the MET oncogene, whose germline mutations have been causally related to human tumorigenesis. In vitro, RON and MET receptors cross-talk, synergize in intracellular signaling, and cooperate in inducing morphogenic responses. Here we show that the RON and MET oncogenes were expressed in 55% and 56% of human ovarian carcinomas, respectively, and were significantly coexpressed in 42% (P < 0.001). In ovarian carcinoma samples and cell lines we did not find mutations in RON and MET gene kinase domain, nor coexpression of RON and MET receptor ligands (MSP and HGF, respectively). We show that motility and invasiveness of ovarian cancer cells coexpressing MET and RON receptors were elicited by HGF and, to a lesser extent, by MSP. More interestingly, invasion of both reconstituted basement membrane and collagen gel was greatly enhanced by the simultaneous addition of the two ligands. These data suggest that coexpression of the MET and RON receptors confer a selective advantage to ovarian cancer cells and might promote ovarian cancer progression. [Copyright &y& Elsevier]