Tumor‐Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma
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...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Karel P. Alcedo [verfasserIn] Andres Guerrero [verfasserIn] Venkatesha Basrur [verfasserIn] Dong Fu [verfasserIn] Monea L. Richardson [verfasserIn] Joshua S. McLane [verfasserIn] Chih‐Chiang Tsou [verfasserIn] Alexey I. Nesvizhskii [verfasserIn] Theodore H. Welling [verfasserIn] Carlito B. Lebrilla [verfasserIn] Carol A. Otey [verfasserIn] Hong Jin Kim [verfasserIn] M. Bishr Omary [verfasserIn] Natasha T. Snider [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2019 |
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| Übergeordnetes Werk: |
In: Hepatology Communications - Wolters Kluwer Health/LWW, 2017, 3(2019), 10, Seite 1400-1414 |
|---|---|
| Übergeordnetes Werk: |
volume:3 ; year:2019 ; number:10 ; pages:1400-1414 |
| Links: |
|---|
| DOI / URN: |
10.1002/hep4.1410 |
|---|
| Katalog-ID: |
DOAJ051626748 |
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| 520 | |a 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. | ||
| 653 | 0 | |a Diseases of the digestive system. Gastroenterology | |
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| 700 | 0 | |a Venkatesha Basrur |e verfasserin |4 aut | |
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10.1002/hep4.1410 doi (DE-627)DOAJ051626748 (DE-599)DOAJ550bf2b9b1d9441695df8b5476ab00f0 DE-627 ger DE-627 rakwb eng RC799-869 Karel P. Alcedo verfasserin aut Tumor‐Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Diseases of the digestive system. Gastroenterology Andres Guerrero verfasserin aut Venkatesha Basrur verfasserin aut Dong Fu verfasserin aut Monea L. Richardson verfasserin aut Joshua S. McLane verfasserin aut Chih‐Chiang Tsou verfasserin aut Alexey I. Nesvizhskii verfasserin aut Theodore H. Welling verfasserin aut Carlito B. Lebrilla verfasserin aut Carol A. Otey verfasserin aut Hong Jin Kim verfasserin aut M. Bishr Omary verfasserin aut Natasha T. Snider verfasserin aut In Hepatology Communications Wolters Kluwer Health/LWW, 2017 3(2019), 10, Seite 1400-1414 (DE-627)877444587 (DE-600)2881134-3 2471254X nnns volume:3 year:2019 number:10 pages:1400-1414 https://doi.org/10.1002/hep4.1410 kostenfrei https://doaj.org/article/550bf2b9b1d9441695df8b5476ab00f0 kostenfrei https://doi.org/10.1002/hep4.1410 kostenfrei https://doaj.org/toc/2471-254X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2088 GBV_ILN_2118 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 3 2019 10 1400-1414 |
| spelling |
10.1002/hep4.1410 doi (DE-627)DOAJ051626748 (DE-599)DOAJ550bf2b9b1d9441695df8b5476ab00f0 DE-627 ger DE-627 rakwb eng RC799-869 Karel P. Alcedo verfasserin aut Tumor‐Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Diseases of the digestive system. Gastroenterology Andres Guerrero verfasserin aut Venkatesha Basrur verfasserin aut Dong Fu verfasserin aut Monea L. Richardson verfasserin aut Joshua S. McLane verfasserin aut Chih‐Chiang Tsou verfasserin aut Alexey I. Nesvizhskii verfasserin aut Theodore H. Welling verfasserin aut Carlito B. Lebrilla verfasserin aut Carol A. Otey verfasserin aut Hong Jin Kim verfasserin aut M. Bishr Omary verfasserin aut Natasha T. Snider verfasserin aut In Hepatology Communications Wolters Kluwer Health/LWW, 2017 3(2019), 10, Seite 1400-1414 (DE-627)877444587 (DE-600)2881134-3 2471254X nnns volume:3 year:2019 number:10 pages:1400-1414 https://doi.org/10.1002/hep4.1410 kostenfrei https://doaj.org/article/550bf2b9b1d9441695df8b5476ab00f0 kostenfrei https://doi.org/10.1002/hep4.1410 kostenfrei https://doaj.org/toc/2471-254X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2088 GBV_ILN_2118 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 3 2019 10 1400-1414 |
| allfields_unstemmed |
10.1002/hep4.1410 doi (DE-627)DOAJ051626748 (DE-599)DOAJ550bf2b9b1d9441695df8b5476ab00f0 DE-627 ger DE-627 rakwb eng RC799-869 Karel P. Alcedo verfasserin aut Tumor‐Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Diseases of the digestive system. Gastroenterology Andres Guerrero verfasserin aut Venkatesha Basrur verfasserin aut Dong Fu verfasserin aut Monea L. Richardson verfasserin aut Joshua S. McLane verfasserin aut Chih‐Chiang Tsou verfasserin aut Alexey I. Nesvizhskii verfasserin aut Theodore H. Welling verfasserin aut Carlito B. Lebrilla verfasserin aut Carol A. Otey verfasserin aut Hong Jin Kim verfasserin aut M. Bishr Omary verfasserin aut Natasha T. Snider verfasserin aut In Hepatology Communications Wolters Kluwer Health/LWW, 2017 3(2019), 10, Seite 1400-1414 (DE-627)877444587 (DE-600)2881134-3 2471254X nnns volume:3 year:2019 number:10 pages:1400-1414 https://doi.org/10.1002/hep4.1410 kostenfrei https://doaj.org/article/550bf2b9b1d9441695df8b5476ab00f0 kostenfrei https://doi.org/10.1002/hep4.1410 kostenfrei https://doaj.org/toc/2471-254X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2021 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2088 GBV_ILN_2118 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 3 2019 10 1400-1414 |
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Karel P. Alcedo @@aut@@ Andres Guerrero @@aut@@ Venkatesha Basrur @@aut@@ Dong Fu @@aut@@ Monea L. Richardson @@aut@@ Joshua S. McLane @@aut@@ Chih‐Chiang Tsou @@aut@@ Alexey I. Nesvizhskii @@aut@@ Theodore H. Welling @@aut@@ Carlito B. Lebrilla @@aut@@ Carol A. Otey @@aut@@ Hong Jin Kim @@aut@@ M. Bishr Omary @@aut@@ Natasha T. Snider @@aut@@ |
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Karel P. Alcedo Andres Guerrero Venkatesha Basrur Dong Fu Monea L. Richardson Joshua S. McLane Chih‐Chiang Tsou Alexey I. Nesvizhskii Theodore H. Welling Carlito B. Lebrilla Carol A. Otey Hong Jin Kim M. Bishr Omary Natasha T. Snider |
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tumor‐selective altered glycosylation and functional attenuation of cd73 in human hepatocellular carcinoma |
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Tumor‐Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma |
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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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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. |
| abstract_unstemmed |
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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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. 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