Granulin-epithelin precursor as a therapeutic target for hepatocellular carcinoma

Ho, Jenny; Ip, Ying Chi; Cheung, Siu Tim; Lee, Yuk Ting; Chan, Keith; Wong, San Yu; Fan, Sheung Tat

doi:10.1002/hep.22191

Cited by 100 publications

(126 citation statements)

References 31 publications

(47 reference statements)

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“…(25) Treating cancers in mice is far from treating people, but the liver cancer experiments show that PGRN has potential as a cancer drug target and is an extremely promising area for future investigation. Interestingly, the PGRN monoclonal antibodies not only inhibited proliferation of the cancer cells directly, but also had a striking anti-angiogenic action, (25) possibly due to decreased secretion of the angiogenic growth factor VEGF in the treated tumors, (19) although given that PGRN stimulated angiogenesis in wounds, (28) a more direct effect on tumor vascularization can be postulated.…”

Section: Progranulin In Cancermentioning

confidence: 99%

“…(6,7) The role of PGRN in cancer has been repeatedly demonstrated. (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) PGRN has been invoked in early embryogenesis, (27) wound repair, and inflammation. (28)(29)(30) These are diverse roles, extending from control of embryonic development during the first days of life to the survival of long-lived post-mitotic neurons of the adult brain.…”

Section: Introductionmentioning

confidence: 99%

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The granulin gene family: from cancer to dementia

2009

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The growth factor progranulin (PGRN) regulates cell division, survival, and migration. PGRN is an extracellular glycoprotein bearing multiple copies of the cysteine-rich granulin motif. With PGRN family members in plants and slime mold, it represents one of the most ancient of the extracellular regulatory proteins still extant in modern animals. PRGN has multiple biological roles. It contributes to the regulation of early embryogenesis, to adult tissue repair and inflammation. Elevated PGRN levels often occur in cancers, and PGRN immunotherapy inhibits the growth of hepatic cancer xenografts in mice. Recent studies have demonstrated roles for PGRN in neurobiology. An autosomal dominant mutation in GRN, the gene for PGRN, leads to neuronal atrophy in the frontal and temporal lobes, resulting in the disease frontotemporal lobar dementia. In this review we will discuss current knowledge of the multifaceted biology of PGRN.

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Section: Progranulin In Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The granulin gene family: from cancer to dementia

2009

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“…GEP blockade in Hep3B was performed by incubating the cells with or without 50 mg/mL anti-GEP mAb A23 (Versitech Ltd.; ref. 10) or mouse IgG isotype control antibody (Sigma-Aldrich) for 24 hours.…”

Section: Cell Culture and Assaysmentioning

confidence: 99%

“…For coexpression with GEP, cells were stained with the above surface markers, followed by permeabilization with ice-cold 0.1% saponin and then incubated with FITC-conjugated mouse anti-human GEP antibody (Versitech Ltd.; ref. 10) or equal amount of FITCconjugated mouse IgG isotype antibody (Sigma). For NKG2D surface expression on NK cells, cells were stained with APCconjugated mouse anti-NKG2D antibody or an equal amount of corresponding isotype control (BD Biosciences).…”

Section: Immunofluorescence Staining and Flow Cytometric Analysismentioning

confidence: 99%

“…Functional studies demonstrated its role in regulating HCC cell proliferation, invasion, tumorigenicity, and chemoresistance (7)(8)(9). Moreover, GEP blockade with antibody could inhibit the growth of established HCC in a mouse model (10). Recently, we showed that GEP was a hepatic oncofetal protein defining a cancer stem cell (CSC) population in HCC (11).…”

Section: Introductionmentioning

confidence: 99%

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Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

Cheung

Yip

Wong

et al. 2014

Cancer Immunology Research

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Immunoevasion is an emerging hallmark of cancer. Impairment of natural killer (NK) cytotoxicity is a mechanism to evade host immunosurveillance. Granulin-epithelin precursor (GEP) is a hepatic oncofetal protein regulating growth, invasion, and chemoresistance in hepatocellular carcinoma (HCC). We examined the role of GEP in conferring HCC cells the ability to evade NK cytotoxicity. In HCC cell lines, GEP overexpression reduced, whereas GEP suppression enhanced sensitivity to NK cytotoxicity. GEP downregulated surface expression of MHC class I chain-related molecule A (MICA), ligand for NK stimulatory receptor NK group 2 member D (NKG2D), and upregulated human leukocyte antigen-E (HLA-E), ligand for NK inhibitory receptor CD94/NKG2A. Functionally, GEP augmented production of soluble MICA, which suppressed NK activation. Matrix metalloproteinase (MMP)2 and MMP9 activity was involved partly in the GEP-regulated MICA shedding from HCC cells. In primary HCCs (n ¼ 80), elevated GEP (P < 0.001), MICA (P < 0.001), and HLA-E (P ¼ 0.089) expression was observed when compared with those in nontumor (n ¼ 80) and normal livers (n ¼ 10). Serum GEP (P ¼ 0.010) and MICA (P < 0.001) levels were higher in patients with HCC (n ¼ 80) than in healthy individuals (n ¼ 30). High serum GEP and/or MICA levels were associated with poor recurrence-free survival (log-rank test, P ¼ 0.042). Importantly, GEP blockade by mAbs sensitized HCC cells to NK cytotoxicity through MICA. In summary, GEP rendered HCC cells resistant to NK cytotoxicity by modulating MICA expression, which could be reversed by GEP blockade using antibody. Serum GEP and MICA levels are prognostic factors and can be used to stratify patients for targeted therapy.

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Reversal of endothelial progenitor cell dysfunction in patients with type 2 diabetes using a conditioned medium of human embryonic stem cell‐derived endothelial cells

Lai

et al. 2012

Diabetes Metabolism Res

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Granulin-epithelin precursor as a therapeutic target for hepatocellular carcinoma

Cited by 100 publications

References 31 publications

The granulin gene family: from cancer to dementia

The granulin gene family: from cancer to dementia

Granulin–Epithelin Precursor Renders Hepatocellular Carcinoma Cells Resistant to Natural Killer Cytotoxicity

Reversal of endothelial progenitor cell dysfunction in patients with type 2 diabetes using a conditioned medium of human embryonic stem cell‐derived endothelial cells

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