Lack of galectin‐1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

Potikha, Tamara; Pappo, Orit; Mizrahi, Lina; Olam, Devorah; Maller, Sebastián M.; Rabinovich, Gabriel A.; Galun, Eithan; Goldenberg, Daniel

doi:10.1096/fj.201900017r

Cited by 18 publications

(19 citation statements)

References 52 publications

(69 reference statements)

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“…Supporting these findings, GH induced hepatic GAL1 expression when this hormone was continuously administered for a short period. Interestingly, the results obtained with murine HCC models suggested that GAL1 may act as a protective anti-inflammatory agent at early stages of chronic liver pathology and as a pro-tumorigenic agent at late stages of the disease contributing to HCC growth and metastasis (37, 38). Because of the broad immunosuppressive and pro-angiogenic activities of GAL1 within tumor microenvironments (20, 29, 39), its upregulation could, at least in part, mediate GH-driven hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Growth hormone upregulates the pro-tumorigenic galectin 1 in mouse liver

Bacigalupo

Piazza

Cicconi

et al. 2019

Endocrine Connections

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Transgenic mice overexpressing growth hormone (GH) spontaneously develop liver tumors, including hepatocellular carcinoma (HCC), within a year. The preneoplastic liver pathology in these mice recapitulates that observed in humans at high risk of developing hepatic cancer. Although increased expression of galectin 1 (GAL1) in liver tissue is associated with HCC aggressiveness, a link between this glycan-binding protein and hormone-related tumor development has not yet been explored. In this study, we investigated GAL1 expression during liver tumor progression in mice continuously exposed to high levels of GH. GAL1 expression was determined by Western blotting, RT-qPCR and immunohistochemistry in the liver of transgenic mice overexpressing GH. Animals of representative ages at different stages of liver pathology were studied. GAL1 expression was upregulated in the liver of GH-transgenic mice. This effect was observed at early ages, when animals displayed no signs of liver disease or minimal histopathological alterations and was also detected in young adults with preneoplastic liver pathology. Remarkably, GAL1 upregulation was sustained during aging and its expression was particularly enhanced in liver tumors. GH also induced hepatic GAL1 expression in mice that were treated with this hormone for a short period. Moreover, GH triggered a rapid increment in GAL1 protein expression in human HCC cells, denoting a direct effect of the hormone on hepatocytes. Therefore, our results indicate that GH upregulates GAL1 expression in mouse liver, which may have critical implications in tumorigenesis. These findings suggest that this lectin could be implicated in hormone-driven liver carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Growth hormone upregulates the pro-tumorigenic galectin 1 in mouse liver

Bacigalupo

Piazza

Cicconi

et al. 2019

Endocrine Connections

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“…There are some findings suggesting that galectin-1 inhibits the development of acute and chronic inflammation in some disease models associated with inflammation. [10][11][12][13]26,27 Injection of phospholipase A2 (PLA-2) with or without galectin-1 in rats inhibited PLA-2-induced paw edema by reducing leukocyte infiltration and mast cell degranulation. Also, it showed a protective effect against acute inflammation.…”

Section: Discussionmentioning

confidence: 99%

Galectin-1 exhibits a protective effect against hepatotoxicity induced by dextran sulfate sodium in mice

et al. 2019

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Galectin-1 is an important mediator that regulates the T-cell-mediated immune response. It has many other biological functions such as cell growth, immunomodulation, and wound healing. The aim of this study was to reveal the role of galectin-1 on liver morphology, cell proliferation, apoptosis, inflammatory and anti-inflammatory mediators, oxidative stress, and antioxidant system in colitis-mediated hepatotoxicity induced by dextran sulfate sodium (DSS). In the present study, adult mice were divided into four groups: The control group intraperitoneally injected with phosphate buffer saline (I), the group which was orally administered with DSS (II), the control group which was injected with galectin-1 (III), and the group which was given DSS and galectin-1 (IV). DSS administration caused degenerative changes and diffuse necrotic damage, an increase in caspase-3 and cyclooxygenase-2 expression, the levels of lipid peroxidation and tumor necrosis factor-alpha, lactate dehydrogenase, and myeloperoxidase activities, and a decrease in cell proliferation, interleukin-10 levels, and antioxidant system parameters in liver tissues. Treatment of DSS group with galectin-1 reversed these effects and prevented liver damage. This study showed that galectin-1 has proliferative, antiapoptotic, anti-inflammatory, and antioxidant effects against DSS-induced liver injury in mice. It is expected considering all results of this study that galectin-1 may be useful as a protective agent against liver toxicity.

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“…Moreover, aged knockout mice displayed earlier hepatocarcinogenesis and increased tumor growth. The mechanisms underlying these effects revealed modulation of pro-oncogenic cytokines, including osteopontin, Ntrk2 (TrkB) and S100A4 as critical targets of Gal1 activity ( Potikha et al, 2019 ). Conversely, in ovary cancer models Gal1 contributes to tumor-promoting inflammation linking TLR5-dependent IL-6 production and distant tumor progression ( Rutkowski et al, 2015 ).…”

Section: Tumor-promoting Inflammationmentioning

confidence: 99%

Sweetening the hallmarks of cancer: Galectins as multifunctional mediators of tumor progression

Girotti

Salatino

Dalotto-Moreno

et al. 2019

Journal of Experimental Medicine

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Hanahan and Weinberg have proposed 10 organizing principles that enable growth and metastatic dissemination of cancer cells. These distinctive and complementary capabilities, defined as the “hallmarks of cancer,” include the ability of tumor cells and their microenvironment to sustain proliferative signaling, evade growth suppressors, resist cell death, promote replicative immortality, induce angiogenesis, support invasion and metastasis, reprogram energy metabolism, induce genomic instability and inflammation, and trigger evasion of immune responses. These common features are hierarchically regulated through different mechanisms, including those involving glycosylation-dependent programs that influence the biological and clinical impact of each hallmark. Galectins, an evolutionarily conserved family of glycan-binding proteins, have broad influence in tumor progression by rewiring intracellular and extracellular circuits either in cancer or stromal cells, including immune cells, endothelial cells, and fibroblasts. In this review, we dissect the role of galectins in shaping cellular circuitries governing each hallmark of tumors, illustrating relevant examples and highlighting novel opportunities for treating human cancer.

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Lack of galectin‐1 exacerbates chronic hepatitis, liver fibrosis, and carcinogenesis in murine hepatocellular carcinoma model

Cited by 18 publications

References 52 publications

Growth hormone upregulates the pro-tumorigenic galectin 1 in mouse liver

Growth hormone upregulates the pro-tumorigenic galectin 1 in mouse liver

Galectin-1 exhibits a protective effect against hepatotoxicity induced by dextran sulfate sodium in mice

Sweetening the hallmarks of cancer: Galectins as multifunctional mediators of tumor progression

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