Asialoglycoprotein Receptor Promotes Cancer Metastasis by Activating the EGFR–ERK Pathway

Ueno, Suguru; Mojić, Marija; Ohashi, Yoshimi; Higashi, Nobuaki; Hayakawa, Yoshihiro; Irimura, Tatsuro

doi:10.1158/0008-5472.can-11-1773

Cited by 24 publications

(17 citation statements)

References 39 publications

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“…16 Recent research documented that ASGR1 activates the epidermal growth factor receptor (EGFR)-ERK pathway and induces matrix metalloproteinase-9 (MMP-9) expression. 31 In the present study, we observed short-term phosphorylation of ERK1/2 within 30 min after TNF-α stimulation, which peaked at 15 min, consistent with previous findings. 8 Although galactose enhanced phosphorylation of ERK1/2 slightly at 30 min, we speculate that this effect is abated.…”

Section: Discussionsupporting

confidence: 93%

Galactose protects hepatocytes against TNF-α-induced apoptosis by promoting activation of the NF-κB signaling pathway in acute liver failure

Liu

Zhu

Liang

et al. 2015

Laboratory Investigation

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Saccharides are reported to protect hepatocytes from acute liver injury through distinct mechanisms. To date, the protective role of galactose against acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) has been attributed to competition with D-GalN. Here, we showed that in addition to its effects on LPS/D-GalN and tumor necrosis factor alpha (TNF-α)/D-GalN models, galactose improves hepatic injury in mice challenged with LPS alone or TNF-α/actinomycin D. Consistent with this result, galactose enhanced the viability of TNF-α-stimulated Chang Liver and Hu7.5 hepatic cell lines. Specifically, galactose prevented TNF-α-induced apoptosis of hepatocytes through promoting phosphorylation of nuclear factor kappa B (NF-κB) p65. Additionally, galactose enhanced expression of the anti-apoptotic genes, c-IAP1 and A20, and inhibited cleavage of caspase-8 and caspase-3. These findings collectively suggest that galactose prevents TNF-α-induced liver injury through activation of the NF-κB signaling pathway. Considering that monosaccharides protect against liver injury via distinct mechanisms, these compounds may represent a promising clinical approach to treat acute liver failure. Acute liver failure (ALF), defined as rapid onset of severe hepatic dysfunction with poor prognosis, is a serious problem in clinical practice. 1 A model of hepatic injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) has been widely used to explore the mechanisms of ALF and screen for potential hepatoprotective drugs. 2 In this model, LPS triggers innate immune responses and induces TNF-α, which subsequently activates the pro-apoptotic caspase reaction directly or indirectly via mitogen-activated protein (MAP) kinases, including p38, JNK1/2 and ERK1/2, as well as an anti-apoptotic signal via the transcription factor nuclear factor kappa B (NF-κB). 3-5 D-GalN, which acts as a sensitizing agent, amplifies the toxicity of LPS and TNF-α to liver. 6 Since liver has a central role in human metabolism, ALF may cause metabolic defects and energy imbalance. 7 As the main source of energy, saccharides have an important role in maintaining hepatocyte survival and physiological processes.A recent study revealed that oral administration of glucose prevents endotoxin-and drug-induced liver failure by promoting secretion of IL-10 to repress liver inflammation in LPS/D-GalN and acetaminophen-treated mice. 8 Another monosaccharide, fructose, prevents TNF-α/ actinomycin D (ActD)-induced apoptosis of hepatocytes through inhibiting JNK signaling in a PKA-dependent manner. 9 Earlier studies have reported that galactose prevents LPS/DGalN-induced liver damage in mice. 10 A recent metabolic profiling study revealed a significant decrease in galactose in the plasma of LPS/D-GalN-treated mice. 7 For decades, the protective role of galactose has been attributed to competition with D-GalN. 11 However, recent evidence has challenged this notion. First, galactose and glucose share the same enzyme machinery for conversion to...

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Section: Discussionsupporting

confidence: 93%

Galactose protects hepatocytes against TNF-α-induced apoptosis by promoting activation of the NF-κB signaling pathway in acute liver failure

Liu

Zhu

Liang

et al. 2015

Laboratory Investigation

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“…The process of cancer cell metastasis was associated with the activation of EGFR signal transduction pathways 45,46…”

Section: Discussionmentioning

confidence: 99%

Correlations between EGFR gene polymorphisms and pleural metastasis of lung adenocarcinoma

Guo

Xing

et al. 2016

OTT

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Proliferation, growth, and differentiation of cells are strictly controlled by the signal system of epidermal growth factor receptor (EGFR). If any link of the EGFR signals system is interfered with or damaged, the proliferation, growth, and differentiation of cells would become uncontrolled. EGFR is overexpressed in a variety of malignant tumors, such as non-small-cell lung cancer, colorectal cancer and breast cancer. Results of the study have proved that EGFR overexpression is closely associated with mutations and variants of the EGFR genes, whose mutations and variants are associated with occurrence, metastasis, and prognosis of different types of tumors, including lung cancer. This study is aimed at investigating whether the polymorphisms of CA simple sequence repeat in intron 1 (CA-SSR1), -216G/T, and R497K in the EGFR are able to induce EGFR activation and whether overexpression is associated with pleural metastasis of lung adenocarcinoma. A total of 432 lung adenocarcinoma patients with pleural metastasis (metastasis group) and 424 patients with lung adenocarcinoma but without pleural metastasis (nonmetastasis group) were enrolled in this study. For all patients, the CA-SSR1 genotypes were determined by capillary electrophoresis, polymerase chain reaction amplification, and direct DNA sequencing, and the R497K and -216G/T genotypes were determined by polymerase chain reaction amplification and direct DNA sequencing. EGFR expression was evaluated by immunohistochemical staining in primary tumor tissues with different -216G/T, R497K, and CA-SSR1 genotypes. Our results showed significant differences between pleural metastasis and nonmetastasis groups in the genotype and allele distribution of -216G/T, R497K, and CA-SSR1 polymorphisms of the EGFR gene. The -216T allele, Arg allele, and shorter CA-SSR1 (<17) had significantly increased risks of pleural metastasis compared with the -216G allele, Lys allele, and longer CA-SSR1 (≥17), respectively. The expression of EGFR was higher in patients with genotypes of -216T/T or -216G/T, Arg/Arg or Arg/Lys, and shorter CA-SSR1 (<17) than that in patients with genotypes of -216G/G, Lys/Lys, and longer CA-SSR1 (≥17), respectively. These results indicate that -216G/T, R497K, and CA-SSR1 polymorphisms are associated with the risk of pleural metastasis of lung adenocarcinoma, which may be related to the overexpression of EGFR protein induced by -216G/T, R497K, and CA-SSR1 polymorphisms.

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“…After stimulation by cytokines, growth factors, or other exogenous activators, MMP9 expression is upregulated mostly at the transcriptional level (53,67,72). MMP9 transcription is also induced by several oncogenic viruses, such as EBV, Kaposi's sarcomaassociated herpesvirus, human papillomavirus 16, and hepatitis B virus (14,43,70,73).…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus Latent Membrane Protein 2A Promotes Invasion of Nasopharyngeal Carcinoma Cells through ERK/Fra-1-Mediated Induction of Matrix Metalloproteinase 9

Lan

Hsiao

Chang

et al. 2012

J Virol

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Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is highly metastatic, and this malignant feature may be promoted by an EBV oncoprotein, latent membrane protein 2A (LMP2A). Acting as a signal regulator, LMP2A can enhance invasiveness and motility of epithelial cells. Downstream from the LMP2A-triggered signaling events, it is largely unknown what key effector proteins are induced and essentially promote cell invasion. In the present study, we found that in NPC cells, LMP2A upregulated matrix metalloproteinase 9 (MMP9), a metastasis-associated protease. LMP2A increased MMP9 expression at both the mRNA and protein levels. It also activated the MMP9 promoter, in which two AP-1 elements were required for the promoter activation. Among AP-1 transcription factors, Fra-1 was induced by LMP2A and is essential for LMP2A-triggered MMP9 expression. Induction of Fra-1 was dependent on the LMP2A-activated ERK1/2 pathway, and induction of the ERK1/2-Fra-1-MMP9 axis required PY motifs in the amino-terminal domain of LMP2A. Notably, LMP2A-promoted invasion of NPC cells was blocked when MMP9 expression, Fra-1 induction, or ERK1/2 activation was inhibited. In addition, we found an association of LMP2A with MMP9 expression in NPC tumor biopsy specimens, where Fra-1 was a major mediation factor. This study reveals an underlying mechanism of LMP2A-induced cell invasion, from signal transduction to upregulation of a critical protease. Considering that MMP9 can also be upregulated by another EBV oncoprotein, LMP1, this protease may be a pivotal effector at which the EBV-induced, invasion-promoting mechanisms converge, serving as an attractive therapeutic target for NPC treatment.

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Asialoglycoprotein Receptor Promotes Cancer Metastasis by Activating the EGFR–ERK Pathway

Cited by 24 publications

References 39 publications

Galactose protects hepatocytes against TNF-α-induced apoptosis by promoting activation of the NF-κB signaling pathway in acute liver failure

Galactose protects hepatocytes against TNF-α-induced apoptosis by promoting activation of the NF-κB signaling pathway in acute liver failure

Correlations between EGFR gene polymorphisms and pleural metastasis of lung adenocarcinoma

Epstein-Barr Virus Latent Membrane Protein 2A Promotes Invasion of Nasopharyngeal Carcinoma Cells through ERK/Fra-1-Mediated Induction of Matrix Metalloproteinase 9

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