Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling

Gantumur, Dolgormaa; Harimoto, Norifumi; Ishii, Norihiro; Yamanaka, Takahiro; Hagiwara, Kaoru; Tsukagoshi, Mariko; Igarashi, Takamichi; Watanabe, Akira; Kubo, Norio; Araki, Kenichiro; Handa, Tadashi; Yokobori, Takehiko; Oyama, Tetsunari; Kuwano, Hiroyuki; Shirabe, Ken

doi:10.1038/s41416-020-0971-y

Cited by 28 publications

(31 citation statements)

References 40 publications

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“…Therefore, our aim was next to investigate the role of Gal-3 in progression of ICC cells and relevant regulatory mechanisms, which may shed some light on potential applications of Gal-3 in treating ICC. Accumulating evidence indicates that high expression of Gal-3 is associated with the development of various malignancies ( Dolgormaa et al, 2020 ; Li et al, 2020 ). In our study, the expression data of Gal-3 in ICC were retrieved from the TCGA database, and its correlation with the clinical stages of ICC was investigated.…”

Section: Discussionmentioning

confidence: 99%

The Therapeutic Potential of Galectin-3 in the Treatment of Intrahepatic Cholangiocarcinoma Patients and Those Compromised With COVID-19

Xiao

et al. 2021

Front. Mol. Biosci.

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The novel coronavirus pneumonia COVID-19 is characterized by all age susceptibility, which imposes a dramatic threat to the human species all over the world. According to current available data, the cytokine storm appears to be the most life-threatening symptom of severe COVID-19 cases accompanied with lung fibrosis. Galectin-3 (Gal-3), a member of soluble β-galactoside-binding lectin families, has been implicated as a key regulator in various inflammation conditions in addition to its well-documented roles in cancer. The pro-inflammatory activity of Gal-3 in the inflammatory response and lung fibrosis of COVID-19 has been proposed by emerging studies, which suggested that inhibition of Gal-3 may represent a novel treatment approach for COVID-19 patients. Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with poor prognosis. ICC accounts for 10–25% of primary liver cancers with limited therapeutic options, which has higher incidence in Asian countries, particularly in China. Cancer patients, including ICC patients, are highly vulnerable to COVID-19 due to their impaired immune system. It is thus undoubtedly a challenge for our oncology department to establish effective treatment strategies under the influence of the COVID-19 crisis. According to our management procedures in the COVID-19 era, emergency treatment will be applied to ICC patients who are under life-threatening conditions, despite the COVID-19 infection. To the best of our knowledge, the modulatory function of Gal-3 in ICC is still barely explored to date. In order to evaluate the therapeutic potential of Gal-3 for ICC patients or those comprised with COVID-19, we herein report our preliminary investigation into roles of Gal-3 in ICC. Our results exhibited that the expression of Gal-3 was significantly up-regulated in ICC tissues, and a significant correlation was observed between its overexpression and malignant progression of ICC cells. We further discussed the activity and possible molecular mechanisms of Gal-3 in ICC, which may pave the ways for further exploring the possibility of Gal-3 as a potential therapeutic target for treating ICC patients or those with COVID-19-related conditions.

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Section: Discussionmentioning

confidence: 99%

The Therapeutic Potential of Galectin-3 in the Treatment of Intrahepatic Cholangiocarcinoma Patients and Those Compromised With COVID-19

Xiao

et al. 2021

Front. Mol. Biosci.

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“…Hepatic stellate cell activation causes an increase in mechanical intrahepatic resistance and contributes to the development of portal hypertension. Furthermore, a study by Dolgormaa et al showed that M2BPGi was detected in cirrhotic liver stromal cells and enhanced the growth of HCC through the galectin-3/mTOR signaling pathway [24]. These mechanistic studies provide the pathophysiologic basis that supports the clinical utility of M2BPGi in cirrhosis.…”

Section: Discussionmentioning

confidence: 87%

Mac-2 Binding Protein Glycosylation Isomer for Screening High-Risk Esophageal Varices in Liver Cirrhotic Patient

Nababan

Kalista

Jasirwan

et al. 2021

Livers

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Background: Esophageal varices occur at middle to advanced stages of cirrhosis and are associated with increased mortality due to their potential for rupture and bleeding. The aim of this study is to examine the accuracy of a surrogate marker, Mac-2 binding protein glycosylation isomer (M2BPGi), for screening high-risk esophageal varices in cirrhotic patients. Methods: Ninety-four cirrhotic patients who underwent endoscopy screening at Cipto Mangunkusumo Hospital, Jakarta, Indonesia were included. Patients with a history of ligation, portal vein thrombosis, or hepatocellular carcinoma were excluded. All enrolled patients underwent ultrasonography, transient elastography, and laboratory tests. The HISCL-5000 Sysmex analyzer was used to measure M2BPGi levels. Results: Of these 94 patients, 27 had high-risk esophageal varices and 67 had non-high-risk esophageal varices. M2BPGi levels were higher in patients with high-risk esophageal varices compared with those with non-high-risk esophageal varices (cutoff index (COI) of 11.4 vs. 3.7, p < 0.001). The sensitivity, specificity, positive predictive value, and negative predictive value of M2BPGi with a cutoff value of 5 COI was 92.6%, 70.1%, 55.6%, and 95.9%, respectively. Conclusions: M2BPGi could be used as a non-invasive surrogate marker for ruling out high-risk esophageal varices in cirrhotic patients. This method is cheap and non-invasive and could be used as a screening tool in resource-limited settings.

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“…In our previous study, we reported that M2BP mRNA is detected in the stroma of the fibrotic liver rather than in hepatocytes, 12 but M2BP, as the main component of M2BPGi, is the secreted glycoprotein 13 . M2BP mRNA is barely expressed in the normal liver but is upregulated in the fibrotic liver 14,15 .…”

Section: Introductionmentioning

confidence: 92%

Hepatic stellate cell as a Mac‐2‐binding protein‐producing cell in patients with liver fibrosis

Gantumur

Harimoto

Muranushi

et al. 2021

Hepatology Research

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Background Mac‐2 binding protein (M2BP) glycosylated isomer (M2BPGi) is a serum marker of liver fibrosis; M2BPGi is a glycosylated form of M2BP. Hepatocytes and hepatic stellate cells (HSCs) have been studied to determine the source of M2BP. This study proposes to identify the origin of M2BP in fibrotic liver. Methods Using liver fibrosis tissue specimens from 15 patients with liver cancer, M2BP mRNA and M2BP were detected by in situ hybridization and immunohistochemistry, respectively. The expression levels of M2BP mRNA were evaluated with scores of 3, 2, and 1. Fluorescent in situ hybridization was carried out to evaluate the distribution of M2BP mRNA and the activated‐HSC marker αSMA mRNA; multicolor fluorescent immunohistochemistry was used for protein localization of M2BP, αSMA, and CD68. The Kruskal–Wallis test analyzed the relationship between M2BP mRNA expression and existing serum fibrosis markers. Results M2BP mRNA was expressed in spindle‐shaped cells along the fibrous septa and in the perisinusoidal area of the fibrotic liver. The HSC markers αSMA mRNA and M2BP mRNA were colocalized in the spindle‐shaped cells; on the protein level, M2BP was expressed in Kupffer cells. M2BP mRNA expression was positively correlated with serum M2BPGi levels. Aspartate transaminase‐to‐platelet ratio index, Fibrosis‐4, hyaluronic acid, and the 15‐minute indocyanine green retention rate were significantly correlated with M2BP mRNA expression. Conclusions M2BP mRNA transcription in fibrotic liver was primarily observed in HSCs but not at the M2BP level, which suggests that HSCs might produce and introduce M2BP to Kupffer cells and serum.

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Mac-2-binding protein glycan isomer enhances the aggressiveness of hepatocellular carcinoma by activating mTOR signaling

Cited by 28 publications

References 40 publications

The Therapeutic Potential of Galectin-3 in the Treatment of Intrahepatic Cholangiocarcinoma Patients and Those Compromised With COVID-19

The Therapeutic Potential of Galectin-3 in the Treatment of Intrahepatic Cholangiocarcinoma Patients and Those Compromised With COVID-19

Mac-2 Binding Protein Glycosylation Isomer for Screening High-Risk Esophageal Varices in Liver Cirrhotic Patient

Hepatic stellate cell as a Mac‐2‐binding protein‐producing cell in patients with liver fibrosis

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