Ecto‐5′‐nucleotidase (CD73) is a potential target of hepatocellular carcinoma

Shali, Shalaimaiti; Yu, Jiangang; Zhang, Xin; Wang, Xue; Jin, Youping; Su, Minsheng; Liao, Xiaohong; Yu, Jerry; Zhi, Xiuling; Zhou, Ping

doi:10.1002/jcp.27694

Cited by 19 publications

(20 citation statements)

References 34 publications

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“…CD73 was significantly increased in patients with HCC and cirrhosis, and increased CD73 expression was associated with reduced overall survival of HCC (Sasikala et al, 2011; Sciarra et al, 2019; Snider et al, 2014). Mechanistically, adenosine produced by CD73 binds to adenosine A2A receptor and induces Rap1‐mediated membrane localization of P110β to activate PI3K/AKT signaling, and upregulates the expression of epidermal growth factor receptor in HCC, thereby promoting HCC growth and metastasis (Ma et al, 2019; Shali et al, 2019). Moreover, CD73 sustains cancer stem cells traits by upregulating SOX9 expression and enhancing its protein stability, further promoting HCC development and progression (Ma et al, 2020).…”

Section: Adenosinergic Pathway In Hccmentioning

confidence: 99%

The role of the CD39–CD73–adenosine pathway in liver disease

Wang

Gao

Zhou

et al. 2020

Journal Cellular Physiology

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Extracellular adenosine triphosphate (ATP) is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. The ectonucleotidases CD39/ectonucleoside triphosphate diphosphohydrolase-1 and CD73/ecto-5′-nucleotidase are cell-surface enzymes that breakdown extracellular ATP into adenosine. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39-CD73-adenosine pathway changes dynamically with the pathophysiological context in which it is embedded. Accumulating evidence suggests that CD39 and CD73 play important roles in liver disease as critical components of the extracellular adenosinergic pathway. Recent studies have shown that the modification of the CD39-CD73-adenosine pathway alters the liver's response to injury. Moreover, adenosine exerts different effects on the pathophysiology of the liver through different receptors. In this review, we aim to describe the role of the CD39-CD73-adenosine pathway and adenosine receptors in liver disease, highlighting potential therapeutic targets in this pathway, which will facilitate the development of therapeutic strategies for the treatment of liver disease.

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Section: Adenosinergic Pathway In Hccmentioning

confidence: 99%

The role of the CD39–CD73–adenosine pathway in liver disease

Wang

Gao

Zhou

et al. 2020

Journal Cellular Physiology

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“…In HepG2 cells, we have already observed a correlation between a decrease in the expression levels of CD73 upon Abcc6 silencing [ 17 ] or probenecid treatment [ 18 ]. CD73 is the main source of extracellular adenosine in all tissues and is a key regulator in some tumor processes such as invasion, migration, and metastasis [ 12 , 13 ]. In this study, we found that the inhibition of CD73 activity by AOPCP ( Figure 5 E) mimicked the effect of probenecid in the filipodia retraction; however, the addition of adenosine together with probenecid preserved the filipodia architecture, suggesting that ABCC6 could modulate the extracellular adenosine availability with a combined action on the rate of ATP efflux and, at same time, on the expression levels of the CD73 enzyme.…”

Section: Discussionmentioning

confidence: 99%

“…The ecto-5 -nucleotidase CD73 is able to catalyze the conversion of extracellular AMP to adenosine and phosphate; it is the main source of extracellular adenosine in all tissues in which ATP is poorly present in extracellular fluids [10,11]. CD73 is considered a key regulator in some cancer processes such as drug resistance, tumor metastasis, and tumor angiogenesis [12,13], therefore is an excellent candidate for cancer therapy [14][15][16]. In previous studies, we have reported that knockdown of Abcc6 in hepatocarcinoma cancer cells (HepG2), or the inhibition of its activity lead to the downregulation of NT5E gene, which codifies for the CD73 protein [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of ABCC6 Transporter Modifies Cytoskeleton and Reduces Motility of HepG2 Cells via Purinergic Pathway

Ostuni

Carmosino

Miglionico

et al. 2020

Cells

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ABCC6, belonging to sub-family C of ATP-binding cassette transporter, is an ATP-dependent transporter mainly present in the basolateral plasma membrane of hepatic and kidney cells. Although the substrates transported are still uncertain, ABCC6 has been shown to promote ATP release. The extracellular ATP and its derivatives di- and mono-nucleotides and adenosine by acting on specific receptors activate the so-called purinergic pathway, which in turn controls relevant cellular functions such as cell immunity, inflammation, and cancer. Here, we analyzed the effect of Abcc6 knockdown and probenecid-induced ABCC6 inhibition on cell cycle, cytoskeleton, and motility of HepG2 cells. Gene and protein expression were evaluated by quantitative Reverse Transcription PCR (RT-qPCR) and western blot, respectively. Cellular cycle analysis was evaluated by flow cytometry. Actin cytoskeleton dynamics was evaluated by laser confocal microscopy using fluorophore-conjugated phalloidin. Cell motility was analyzed by in vitro wound-healing migration assay. Cell migration is reduced both in Abcc6 knockdown HepG2 cells and in probenecid treated HepG2 cells by interfering with the extracellular reserve of ATP. Therefore, ABCC6 could contribute to cytoskeleton rearrangements and cell motility through purinergic signaling. Altogether, our findings shed light on a new role of the ABCC6 transporter in HepG2 cells and suggest that its inhibitor/s could be considered potential anti-metastatic drugs.

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“…Studies examining how CD73 loss impacts HCC development in rodent models have not been performed, with the exception of a limited analysis reporting that subcutaneous inoculation of MHCC97‐derived tumors showed decreased growth in CD73 −/− compared to WT mice . Use of global and tissue‐specific CD73 knockout models in combination with standard HCC induction models, such as chemical carcinogenesis, fatty liver disease, and alcohol‐induced liver disease, will help address this question in a rigorous manner in future studies.…”

Section: Discussionmentioning

confidence: 99%

Tumor‐Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma

Alcedo

Guerrero

Basrur³

et al. 2019

Hepatol Commun

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CD73, a cell‐surface N‐linked glycoprotein that produces extracellular adenosine, is a novel target for cancer immunotherapy. Although anti‐CD73 antibodies have entered clinical development, CD73 has both protumor and antitumor functions, depending on the target cell and tumor type. The aim of this study was to characterize CD73 regulation in human hepatocellular carcinoma (HCC). We examined CD73 expression, localization, and activity using molecular, biochemical, and cellular analyses on primary HCC surgical specimens, coupled with mechanistic studies in HCC cells. We analyzed CD73 glycan signatures and global alterations in transcripts encoding other N‐linked glycoproteins by using mass spectrometry glycomics and RNA sequencing (RNAseq), respectively. CD73 was expressed on tumor hepatocytes where it exhibited abnormal N‐linked glycosylation, independent of HCC etiology, tumor stage, or fibrosis presence. Aberrant glycosylation of tumor‐associated CD73 resulted in a 3‐fold decrease in 5′‐nucleotidase activity (P < 0.0001). Biochemically, tumor‐associated CD73 was deficient in hybrid and complex glycans specifically on residues N311 and N333 located in the C‐terminal catalytic domain. Blocking N311/N333 glycosylation by site‐directed mutagenesis produced CD73 with significantly decreased 5′‐nucleotidase activity in vitro, similar to the primary tumors. Glycosylation‐deficient CD73 partially colocalized with the Golgi structural protein GM130, which was strongly induced in HCC tumors. RNAseq analysis further revealed that N‐linked glycoprotein‐encoding genes represented the largest category of differentially expressed genes between HCC tumor and adjacent tissue. Conclusion: We provide the first detailed characterization of CD73 glycosylation in normal and tumor tissue, revealing a novel mechanism that leads to the functional suppression of CD73 in human HCC tumor cells. The present findings have translational implications for therapeutic candidate antibodies targeting cell‐surface CD73 in solid tumors and small‐molecule adenosine receptor agonists that are in clinical development for HCC.

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Ecto‐5′‐nucleotidase (CD73) is a potential target of hepatocellular carcinoma

Cited by 19 publications

References 34 publications

The role of the CD39–CD73–adenosine pathway in liver disease

The role of the CD39–CD73–adenosine pathway in liver disease

Inhibition of ABCC6 Transporter Modifies Cytoskeleton and Reduces Motility of HepG2 Cells via Purinergic Pathway

Tumor‐Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma

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