Successful Identification of a Novel Therapeutic Compound for Hepatocellular Carcinoma Through Screening of ADAM9 Inhibitors

Ogawa, Keita; Chiba, Tetsuhiro; Nakamura, Masato; Arai, Jun; ZHANG, JIAQI; Ma, Yaojia; Qiang, Na; Ao, Junjie; Yumita, Sae; Ishino, Takamasa; Kan, Motoyasu; Iwanaga, T.; Nakagawa, Miyuki; Fujiwara, Kisako; Sakuma, Takafumi; Kanzaki, Hiroaki; Koroki, Keisuke; Kusakabe, Yuko; Kobayashi, Kazufumi; Kanogawa, Naoya; Kiyono, Soichiro; Kondo, Takayuki; Nakagawa, Ryo; Ogasawara, Satoshi; Muroyama, Ryosuke; Nakamoto, Shingo; Kanda, Tatsuo; Maruyama, Hitoshi; Kato, Jun; Matsumoto, Shoji; ARAI, TAKAYOSHI; MOTOHASHI, SHINICHIRO; Kato, Naoya

doi:10.21873/anticanres.16249

Cited by 3 publications

(1 citation statement)

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“…Another promising approach for the inhibition of MICA shedding is the suppression of ADAM enzymatic activity. In vitro assays for screening potential ADAM inhibitors among US Food and Drug Administration‐approved drugs, including lomofungin, disulfiram, leukotriene receptor antagonists, and retinoids, have shown potential for modulating MICA shedding to induce stronger NK cell‐mediated anticancer functions 41,47–50 . In fact, combination therapy with regorafenib and ADAM enzymatic inhibitors strongly halted MICA shedding compared with either agent alone 8 …”

Section: Future Directions Of Mica‐targeted Therapy For Hccmentioning

confidence: 99%

Natural killer group 2D‐major histocompatibility complex class I polypeptide‐related sequence A activation enhances natural killer cell‐mediated immunity against hepatocellular carcinoma: A review

Arai,

Okumura,

Kato

et al. 2024

Hepatology Research

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The recent clinical introduction of immune checkpoint inhibitors has improved therapeutic outcomes in patients with advanced hepatocellular carcinoma. However, these therapies targeting CD8+ T lymphocytes have a response rate of approximately 30%. In addition to CD8+ T lymphocytes, natural killer (NK) cells represent promising therapeutic targets for hepatocellular carcinoma, because they comprise 30%–50% of all lymphocytes in the liver and contribute to antitumor immunity. A recent meta‐analysis revealed that the percentage of infiltrating NK cells in hepatocellular carcinoma correlates with a better patient outcome. Similarly, our previous genome‐wide association study on chronic viral hepatitis showed that a single‐nucleotide polymorphism of major histocompatibility complex class I polypeptide‐related sequence A (MICA), a ligand to the NK activating receptor, plays a critical role in hepatocarcinogenesis. In this review, we summarize the mechanisms underlying the regulation of MICA and NK group 2D expression in chronic hepatitis. Furthermore, we describe recent reports on MICA single‐nucleotide polymorphism‐driven hepatocarcinogenesis. The suppression of MICA shedding could represent a promising approach for immunosurveillance, as increased expression of membrane‐bound MICA achieved through the use of a MICA shedding inhibitor also enhances NK cell‐mediated cytotoxicity.

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Section: Future Directions Of Mica‐targeted Therapy For Hccmentioning

confidence: 99%

Natural killer group 2D‐major histocompatibility complex class I polypeptide‐related sequence A activation enhances natural killer cell‐mediated immunity against hepatocellular carcinoma: A review

Arai,

Okumura,

Kato

et al. 2024

Hepatology Research

Self Cite

View full text Add to dashboard Cite

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A Disintegrin and metalloproteinase carves T cell abnormalities and pathogenesis in systemic lupus erythematosus

Umeda,

Satyam,

Yoshida

et al. 2024

Clinical Immunology

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Unraveling the role of ADAMs in clinical heterogeneity and the immune microenvironment of hepatocellular carcinoma: insights from single-cell, spatial transcriptomics, and bulk RNA sequencing

Chen,

Yuan,

Guan

et al. 2024

Front. Immunol.

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BackgroundHepatocellular carcinoma (HCC) is a prevalent and heterogeneous tumor with limited treatment options and unfavorable prognosis. The crucial role of a disintegrin and metalloprotease (ADAM) gene family in the tumor microenvironment of HCC remains unclear.MethodsThis study employed a novel multi-omics integration strategy to investigate the potential roles of ADAM family signals in HCC. A series of single-cell and spatial omics algorithms were utilized to uncover the molecular characteristics of ADAM family genes within HCC. The GSVA package was utilized to compute the scores for ADAM family signals, subsequently stratified into three categories: high, medium, and low ADAM signal levels through unsupervised clustering. Furthermore, we developed and rigorously validated an innovative and robust clinical prognosis assessment model by employing 99 mainstream machine learning algorithms in conjunction with co-expression feature spectra of ADAM family genes. To validate our findings, we conducted PCR and IHC experiments to confirm differential expression patterns within the ADAM family genes.ResultsGene signals from the ADAM family were notably abundant in endothelial cells, liver cells, and monocyte macrophages. Single-cell sequencing and spatial transcriptomics analyses have both revealed the molecular heterogeneity of the ADAM gene family, further emphasizing its significant impact on the development and progression of HCC. In HCC tissues, the expression levels of ADAM9, ADAM10, ADAM15, and ADAM17 were markedly elevated. Elevated ADAM family signal scores were linked to adverse clinical outcomes and disruptions in the immune microenvironment and metabolic reprogramming. An ADAM prognosis signal, developed through the utilization of 99 machine learning algorithms, could accurately forecast the survival duration of HCC, achieving an AUC value of approximately 0.9.ConclusionsThis study represented the inaugural report on the deleterious impact and prognostic significance of ADAM family signals within the tumor microenvironment of HCC.

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Successful Identification of a Novel Therapeutic Compound for Hepatocellular Carcinoma Through Screening of ADAM9 Inhibitors

Cited by 3 publications

References 0 publications

Natural killer group 2D‐major histocompatibility complex class I polypeptide‐related sequence A activation enhances natural killer cell‐mediated immunity against hepatocellular carcinoma: A review

Natural killer group 2D‐major histocompatibility complex class I polypeptide‐related sequence A activation enhances natural killer cell‐mediated immunity against hepatocellular carcinoma: A review

A Disintegrin and metalloproteinase carves T cell abnormalities and pathogenesis in systemic lupus erythematosus

Unraveling the role of ADAMs in clinical heterogeneity and the immune microenvironment of hepatocellular carcinoma: insights from single-cell, spatial transcriptomics, and bulk RNA sequencing

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