Stimulation of Proliferation of Rat Hepatic Stellate Cells by Galectin-1 and Galectin-3 through Different Intracellular Signaling Pathways

Maeda, Naoto; Kawada, Norifumi; Seki, Shuichi; Arakawa, Tetsuo; Ikeda, Kazuo; Itoh, Hiroshi; Okuyama, Hiroaki; Hirabayashi, Jun; Kasai, Ken‐ichi; Yoshizato, Katsutoshi

doi:10.1074/jbc.m209673200

Cited by 138 publications

(105 citation statements)

References 72 publications

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“…Galectin 1/3 are members of the family of β-galactosidebinding animal lectins (25) and play a role in a variety of cell functions, including proliferation, migration and adhesion characteristics (26,27). In this study, the expression of galectin 1/3 was observed at lower frequencies than the remaining three proteins in the epithelial and stromal cells in AHs, whereas it was strongly expressed in epithelial and stromal cells, respectively, in ACs.…”

Section: Discussionmentioning

confidence: 65%

Novel immunohistochemical marker, integrin αVβ3, for BOP-induced early lesions in hamster pancreatic ductal carcinogenesis

Kitahashi¹,

Yoshimoto²,

Imai³

2011

Oncology Letters

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Abstract. N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic ductal carcinomas and early ductal lesions in Syrian hamsters have been reported to show histopathological resemblance to those in humans. Specific protein expression profiles have been found in human carcinomas, but a detailed molecular approach regarding the dissection of BOP-induced pancreatic carcinogenesis has yet to be determined. The present immunohistochemical study of early and advanced hamster lesions focused on five proteins reported to be overexpressed in human patients, to clarify interspecies phenotype similarity. Integrin α V β 3 was found to be overexpressed in the epithelial cells of 13 of 14 atypical hyperplasias and 6 of 6 adenocarcinomas. This overexpression was more frequent than in the remaining four proteins. However, immunoreactivity for α-enolase in epithelial cells and for kallikrein 7 and galectin-1/3 in both epithelial and stromal cells was also evident at various frequencies. Thus, similarities of tumor-associated protein expression between human and hamster pancreatic ductal lesions were confirmed, and integrin α V β 3 was identified as a potentially useful immunohistochemical marker for early lesions in hamsters. IntroductionPancreatic cancer is among the 10 most frequently occurring type of cancer. In Japan, pancreatic cancer is ranked fifth as a cause of cancer-related mortality. The mortality rate associated with this type of cancer also ranks high in other developed countries (1,2). The detection of pancreatic cancer at early operable stages is difficult, combined with the lack of curative treatment approaches other than complete surgical removal; thus, 5-year relative survival rates are less than 6% (3,4). Therefore, it is crucial to develop new diagnostic and preventive methods to complement any improvements in therapeutic methods for the reduction of mortality and morbidity, and to explore specific proteins overexpressed in early lesions during pancreatic carcinogenesis.Specific protein expression profiles revealed by immunohistochemical and proteomic analyses are currently employed in the application of individualized therapy of advanced human pancreatic carcinomas (5-8). Consequently, a number of candidates of prognostic and/or predictive markers have been established (9,10). Examples expressed in early lesions show potential for the development of novel diagnostic and preventive strategies.Chemically induced and transgenic animal models for pancreatic ductal carcinogenesis have been the target of investigation of the impact of environmental factors and the role of specific gene alterations in multistage carcinogenesis (11)(12)(13)(14)(15). Among the models established thus far, the N-nitrosobis(2-oxopropyl)amine (BOP)-induced hamster model is the first and most widely utilized based on similarities to human diseases in the morphological characteristics of, not only advanced cancers, but also early ductal lesions, as well as pivotal genetic alterations, including K-ras and p16 (13,(16)(17)(18). In particular...

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Section: Discussionmentioning

confidence: 65%

Novel immunohistochemical marker, integrin αVβ3, for BOP-induced early lesions in hamster pancreatic ductal carcinogenesis

Kitahashi¹,

Yoshimoto²,

Imai³

2011

Oncology Letters

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“…20 Other studies have shown that galectin-3 expressed by liver analogues of macrophages (ie, Kupffer cells) induce the synthesis of excess fibril-forming collagens in liver. 21 Earlier studies have demonstrated the relation between galectin-3 expression and the cell cycle. Nuclear galectin-3 expression is associated with cell proliferation, and this effect is mediated through enhanced cyclin D1 promoter activity.…”

Section: Galectin-3 Structure Functions and Relevance For Cardiac Rmentioning

confidence: 99%

Galectin-3 Marks Activated Macrophages in Failure-Prone Hypertrophied Hearts and Contributes to Cardiac Dysfunction

et al. 2004

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Background-Inflammatory mechanisms have been proposed to be important in heart failure (HF), and cytokines have been implicated to add to the progression of HF. However, it is unclear whether such mechanisms are already activated when hypertrophied hearts still appear well-compensated and whether such early mechanisms contribute to the development of HF. Methods and Results-In a comprehensive microarray study, galectin-3 emerged as the most robustly overexpressed gene in failing versus functionally compensated hearts from homozygous transgenic TGRmRen2-27 (Ren-2) rats. Myocardial biopsies obtained at an early stage of hypertrophy before apparent HF showed that expression of galectin-3 was increased specifically in the rats that later rapidly developed HF. Galectin-3 colocalized with activated myocardial macrophages. We found galectin-3-binding sites in rat cardiac fibroblasts and the extracellular matrix. Recombinant galectin-3 induced cardiac fibroblast proliferation, collagen production, and cyclin D1 expression. A 4-week continuous infusion of low-dose galectin-3 into the pericardial sac of healthy Sprague-Dawley rats led to left ventricular dysfunction, with a 3-fold differential increase of collagen I over collagen III. Myocardial galectin-3 expression was increased in aortic stenosis patients with depressed ejection fraction. Conclusions-This study shows that an early increase in galectin-3 expression identifies failure-prone hypertrophied hearts. Galectin-3, a macrophage-derived mediator, induces cardiac fibroblast proliferation, collagen deposition, and ventricular dysfunction. This implies that HF therapy aimed at inflammatory responses may need to be targeted at the early stages of HF and probably needs to antagonize multiple inflammatory mediators, including galectin-3.

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“…Maeda et al showed that galectin-3 induced hepatic stellate cells transdifferentiation into myofibroblasts via the mitogenactivated protein kinase/extracellular signal-regulated kinase (ERK)-ERK 1/2 signaling pathway and, at variance with galectin-1, in a protein kinase C-and A-dependent manner [53], whereas MacKinnon et al showed that galectin-3 ablation reduced alveolar epithelial cell EMT in response to TGF-β1 [50]. In addition, galectin-3 plays a complex role in the modulation of immune/inflammatory function, with distinct pro-inflammatory actions, but also with relevant anti-inflammatory effects which predominate under chronic conditions [7].…”

Section: Galectin-3 As a Disease Mediator: Animal Studiesmentioning

confidence: 99%

Galectin-3 in diabetic patients

Pugliese

Iacobini

Ricci

et al. 2014

Clinical Chemistry and Laboratory Medicine (CCLM)

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Galectin-3 is a versatile molecule which exerts several and sometimes opposite functions in various pathophysiological processes. Recently, galectin-3 has gained attention as a powerful predictor of heart failure and mortality, thus becoming a useful prognostic marker in clinical practice. Moreover, though not specifically investigated in diabetic cohorts, plasma levels of galectin-3 correlated with the prevalence of diabetes and related metabolic conditions, thus suggesting that pharmacological blockade of this lectin might be successful for treating heart failure especially in subjects suffering from these disorders. Indeed, galectin-3 is considered not only as a marker of heart failure, but also as a mediator of the disease, due to its pro-fibrotic action, though evidence comes mainly from studies in galectin-3 deficient mice. However, these studies have provided contrasting results, with either attenuation or acceleration of organ fibrosis and inflammation, depending on the experimental setting and particularly on the levels of advanced glycation endproducts (AGEs)/advanced lipoxidation endproducts (ALEs), of which galectin-3 is a scavenging receptor. In fact, under conditions of increased AGE/ALE levels, galectin-3 ablation was associated with tissue-specific outcomes, reflecting the AGE/ALE-receptor function of this lectin. Conversely, in experimental models of acute inflammation and fibrosis, galectin-3 deficiency resulted in attenuation of tissue injury. There is a need for prospective studies in diabetic patients specifically investigating the relation of galectin-3 levels with complications and for further animal studies in order to establish the effective role of this lectin in organ damage before considering its pharmacological blockade in the clinical setting.

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Stimulation of Proliferation of Rat Hepatic Stellate Cells by Galectin-1 and Galectin-3 through Different Intracellular Signaling Pathways

Cited by 138 publications

References 72 publications

Novel immunohistochemical marker, integrin αVβ3, for BOP-induced early lesions in hamster pancreatic ductal carcinogenesis

Novel immunohistochemical marker, integrin αVβ3, for BOP-induced early lesions in hamster pancreatic ductal carcinogenesis

Galectin-3 Marks Activated Macrophages in Failure-Prone Hypertrophied Hearts and Contributes to Cardiac Dysfunction

Galectin-3 in diabetic patients

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