High expression of ADAM8 correlates with poor prognosis in hepatocellular carcinoma

Zhang, Yun; Zha, Tian-Zhou; Hu, Ben-Shun; Jiang, Chao; Zhang, Ge; Zhang, Kai; Tan, Yongfei

doi:10.1016/j.surge.2012.07.002

Cited by 5 publications

(2 citation statements)

References 20 publications

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“…ADAM8 (ADAM metallopeptidase domain 8) was overexpressed in concomitant treatment versus control. High expression of ADAM8 was previously found to correlate with progression and poor prognosis in patients with HCC (Jiang et al, 2012;Zhang et al, 2013). These data suggest that despite its ability to target GPCR and AMPK signaling, the combination metformin/sorafenib may also induce adverse signaling pathways that ultimately contribute to drug resistance and treatment failure, raising doubt about its benefit in the treatment of HCC.…”

Section: Discussionmentioning

confidence: 93%

Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells

et al. 2021

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Section: Discussionmentioning

confidence: 93%

Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells

et al. 2021

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“…In hepatocellular carcinoma, high Adam8 expression is found in the majority of cases. Elevated Adam8 levels are associated with increased serum Alpha-fetoprotein (AFP), advanced tumor stage, poor differentiation, increased tumor recurrence and metastasis, and reduced survival [ 28 , 29 ]. Adam8 KO in HepG2 cells exhibited reduced cell migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

RNA Aptamer Targeting of Adam8 in Cancer Growth and Metastasis

Kuo

2023

Cancers

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Cancer progression depends on an accumulation of metastasis-supporting physiological changes, which are regulated by cell-signaling molecules. In this regard, a disintegrin and metalloproteinase 8 (Adam8) is a transmembrane glycoprotein that is selectively expressed and induced by a variety of inflammatory stimuli. In this study, we identified Adam8 as a sox2-dependent protein expressed in MDA-MB-231 breast cancer cells when cocultured with mesenchymal-stem-cell-derived myofibroblast-like cancer-associated fibroblasts (myCAF). We have previously found that myCAF-induced cancer stemness is required for the maintenance of the myCAF phenotype, suggesting that the initiation and maintenance of the myCAF phenotype require distinct cell-signaling crosstalk pathways between cancer cells and myCAF. Adam8 was identified as a candidate secreted protein induced by myCAF-mediated cancer stemness. Adam8 has a known sheddase function against which we developed an RNA aptamer, namely, Adam8-Apt1-26nt. The Adam8-Apt1-26nt-mediated blockade of the extracellular soluble Adam8 metalloproteinase domain abolishes the previously initiated myCAF phenotype, or, termed differently, blocks the maintenance of the myCAF phenotype. Consequently, cancer stemness is significantly decreased. Xenograft models show that Adam8-Apt-1-26nt administration is associated with decreased tumor growth and metastasis, while flow cytometric analyses demonstrate a significantly decreased fraction of myCAF after Adam8-Apt-1-26nt treatment. The role of soluble Adam8 in the maintenance of the myCAF phenotype has not been previously characterized. Our study suggests that the signal pathways for the induction or initiation of the myCAF phenotype may be distinct from those involved with the maintenance of the myCAF phenotype.

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ADAM8 in invasive cancers: links to tumor progression, metastasis, and chemoresistance

et al. 2019

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Ectodomain shedding of extracellular and membrane proteins is of fundamental importance for cell–cell communication in neoplasias. A Disintegrin And Metalloproteinase (ADAM) proteases constitute a family of multifunctional, membrane-bound proteins with traditional sheddase functions. Their protumorigenic potential has been attributed to both, essential (ADAM10 and ADAM17) and ‘dispensable’ ADAM proteases (ADAM8, 9, 12, 15, and 19). Of specific interest in this review is the ADAM proteinase ADAM8 that has been identified as a significant player in aggressive malignancies including breast, pancreatic, and brain cancer. High expression levels of ADAM8 are associated with invasiveness and predict a poor patient outcome, indicating a prognostic and diagnostic potential of ADAM8. Current knowledge of substrates and interaction partners gave rise to the hypothesis that ADAM8 dysregulation affects diverse processes in tumor biology, attributable to different functional cores of the multidomain enzyme. Proteolytic degradation of extracellular matrix (ECM) components, cleavage of cell surface proteins, and subsequent release of soluble ectodomains promote cancer progression via induction of angiogenesis and metastasis. Moreover, there is increasing evidence for significance of a non-proteolytic function of ADAM8. With the disintegrin (DIS) domain ADAM8 binds integrins such as β1 integrin, thereby activating integrin signaling pathways. The cytoplasmic domain is critical for that activation and involves focal adhesion kinase (FAK), extracellular regulated kinase (ERK1/2), and protein kinase B (AKT/PKB) signaling, further contributing to cancer progression and mediating chemoresistance against first-line therapies. This review highlights the remarkable effects of ADAM8 in tumor biology, concluding that pharmacological inhibition of ADAM8 represents a promising therapeutic approach not only for monotherapy, but also for combinatorial therapies.

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High expression of ADAM8 correlates with poor prognosis in hepatocellular carcinoma

Cited by 5 publications

References 20 publications

Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells

Drug-Drug Interaction between Metformin and Sorafenib Alters Antitumor Effect in Hepatocellular Carcinoma Cells

RNA Aptamer Targeting of Adam8 in Cancer Growth and Metastasis

ADAM8 in invasive cancers: links to tumor progression, metastasis, and chemoresistance

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