Granulin-Epithelin Precursor and ATP-Dependent Binding Cassette (ABC)B5 Regulate Liver Cancer Cell Chemoresistance

Cheung, Siu Tim; Cheung, Phyllis F.; Cheng, Christine Kei Chin; Wong, Nicholas C.L.; Fan, Sheung Tat

doi:10.1053/j.gastro.2010.07.049

Cited by 126 publications

(142 citation statements)

References 49 publications

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“…Genes involved in tumorigenesis have been also found to contribute to chemoresistance of hepatocellular carcinoma (13,15,22,23). Identification of hepatocellular carcinoma-associated targets is thus critical not only for understanding the molecular mechanisms of both intrinsic and acquired chemoresistance but also for developing hepatocellular carcinoma-associated targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

“…CD133 þ hepatocellular carcinoma cancer stem cells can also contribute to chemoresistance through activation of the Akt/ PKB pathway (14). Overexpression of granulin epithelin precursor and ABCB5 in liver cancer stem cells can lead to significant increment of chemoresistance (15). Besides, a study from acquired doxorubicin-resistant hepatocellular carcinoma cell lines has identified a panel of differentially overexpressed genes and subsequently characterized that upregulation of TOP2A gene is one of the contributors of acquired doxorubicin-resistance in hepatocellular carcinoma (16).…”

Section: Introductionmentioning

confidence: 99%

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Identification of Transmembrane Protein 98 as a Novel Chemoresistance-Conferring Gene in Hepatocellular Carcinoma

Guo

et al. 2014

Molecular Cancer Therapeutics

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Chemoresistance is one of the major obstacles in systemic chemotherapy and targeted therapy for patients with advanced hepatocellular carcinoma. To identify novel chemoresistance-associated targets in hepatocellular carcinoma, chemoresistant hepatocellular carcinoma cell lines were established. By comparing the global gene expression profiles between chemoresistant and chemosensitive cell lines, eight novel chemoresistance-associated genes were identified to be significantly associated with the commonly augmented chemoresistance of hepatocellular carcinoma cells. One upregulated candidate named transmembrane protein 98 (TMEM98) was found to be overexpressed in 80 of 118 (67.80%) of patients with hepatocellular carcinoma. TMEM98 mRNA in tumor tissues was significantly higher than nontumor tissues of patients with hepatocellular carcinoma (P < 0.0001). Upregulation of TMEM98 was significantly correlated with advanced tumor stage (P ¼ 0.048), high incidence of early tumor recurrence (P ¼ 0.005), poor overall survival (P ¼ 0.029), and poor disease-free survival (P ¼ 0.011) of patients with hepatocellular carcinoma after hepatectomy. Importantly, upregulation of TMEM98 mRNA in patients with hepatocellular carcinoma who received transarterial chemoembolization (TACE) treatment was significantly higher than in patients without TACE treatment (P ¼ 0.046). Moreover, patients with poor response to TACE treatment had higher degree of TMEM98 upregulation than the responsive patients. In vitro and in vivo studies showed that suppression of TMEM98 in chemoresistant hepatocellular carcinoma cells restored their chemosensitivity, while forced overexpression of TMEM98 enhanced their chemoresistance. The mechanism of TMEM98 in conferring chemoresistance of hepatocellular carcinoma might be possibly through activation of the AKT pathway and deactivation of p53. In conclusion, we identified a panel of novel common chemoresistance-associated genes and demonstrated that TMEM98 is a chemoresistanceconferring gene in hepatocellular carcinoma. Mol Cancer Ther; 13(5); 1285-97. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Transmembrane Protein 98 as a Novel Chemoresistance-Conferring Gene in Hepatocellular Carcinoma

Guo

et al. 2014

Molecular Cancer Therapeutics

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“…Our group has characterized GEP overexpression in more than 70% of human HCCs, and its expression was associated with aggressive HCC features (7). 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).…”

Section: Introductionmentioning

confidence: 99%

“…Quantification was performed with the ABI Prism 7700 sequence detection system (Applied Biosystems). The MICA and HLA-E data presented were new data, whereas part of the GEP data have been extracted from a previous cohort (8), and the current study has increased sample size to parallel datasets on MICA and HLA-E. The relative amount of GEP, MICA, and HLA-E, which had been normalized with control 18s for RNA amount variation and calibrator for plate-to-plate variation, was presented as the relative fold change.…”

Section: Real-time Qrt-pcrmentioning

confidence: 99%

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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“…ABCB5 with its several distinct forms is expressed in various tissues, including testis, mammary tissue, melanocytes and retinal pigmented epithelium, and has also been shown to have enhanced expression in several cancer subtypes, including breast cancer, malignant melanoma, colorectal cancer and hepatocellular carcinoma, when compared with their normal tissue counterpart. 1,[3][4][5][6][7][8] The b form of ABCB5 (ABCB5.a) specifically is a half-transporter that has been shown to be expressed in melanocytes and melanoma. 1 It has been shown to be a determinant of membrane potential and regulator of cell fusion in physiological skin progenitor cells.…”

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confidence: 99%

Profiling of ABC transporters ABCB5, ABCF2 and nestin-positive stem cells in nevi, in situ and invasive melanoma

et al. 2012

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Distinct ABCB5 forms and ABCF2, members of the ATP-binding cassette (ABC) superfamily of transporters, are normally expressed in various tissues and cells, and enhanced expression of both has been demonstrated in select cancers. In melanoma cell lines, gene expression profiling of ABC transporters has revealed enhanced expression of melanocyte-specific ABCB5 and ABCF2 proteins. Given this, our primary aim was to ascertain immunohistochemical expression of the ABC transporters ABCB5 and ABCF2 and, the stem cell marker, nestin in a spectrum of benign and malignant nevomelanocytic proliferations, including nevi (n ¼ 30), in situ (n ¼ 31) and invasive (n ¼ 24) primary cutaneous melanomas to assess their role in the stepwise development of malignancy. In addition, their expression was compared with established melanoma prognosticators to ascertain their utility as independent prognosticators. A semiquantitative scoring system was utilized by deriving a cumulative score (based on percentage positivity cells and intensity of expression) and statistical analyses was carried out using analysis of variance with linear contrasts. Mean cumulative score in nevi, in situ and invasive melanoma were as follows: 3.8, 4.4 and 5.3 for ABCB5, respectively (Po0.005 for all), and 4.6, 4.6 and 5.3 for nestin, respectively (P ¼ not significant for all). No appreciable expression of ABCF2 was noted in any of the groups. While ulcerated lesions of melanoma demonstrated lower levels of expression of ABCB5 and nestin than non-ulcerated lesions, and nestin expression was lower in lesions with mitoses 41, after controlling for the presence of ulceration and mitotic activity, the expression of both proteins did not significantly correlate with known melanoma prognosticators. The gradual increase in the expression of ABCB5 from benign nevus to in situ to invasive melanoma suggests that it plays a role in melanomagenesis. On the basis of our findings, a prospective study with follow-up data is required to ascertain the utility of ABCB5 as a therapeutic target.

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Granulin-Epithelin Precursor and ATP-Dependent Binding Cassette (ABC)B5 Regulate Liver Cancer Cell Chemoresistance

Cited by 126 publications

References 49 publications

Identification of Transmembrane Protein 98 as a Novel Chemoresistance-Conferring Gene in Hepatocellular Carcinoma

Identification of Transmembrane Protein 98 as a Novel Chemoresistance-Conferring Gene in Hepatocellular Carcinoma

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

Profiling of ABC transporters ABCB5, ABCF2 and nestin-positive stem cells in nevi, in situ and invasive melanoma

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