Prognostic significance of metadherin overexpression in hepatitis B virus-related hepatocellular carcinoma

Gong, Zhenbin; Liu, Weihui; You, Nan; Wang, Tao; Wang, Xing; Lü, Peng; Zhao, Ge; Yang, Ping; Wang, Desheng; Dou, Kefeng

doi:10.3892/or.2012.1749

Cited by 15 publications

(16 citation statements)

References 33 publications

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“…Additionally, AEG-1/MTDH has been shown to be closely associated with the abilities of the orientation chemotaxis and adhesion of HCC cells (17). In hepatitis B virus (HBV)-related HCC patients, AEG-1/MTDH expression has been found to significantly correlate with the American Joint Committee on Cancer (7th edition) (72) stage, T and N classification, vascular invasion and histological differentiation (54). In addition, patients with high AEG-1/MTDH levels have been found to exhibit poor survival rates compared with those with low AEG-1/MTDH levels (54).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

“…In hepatitis B virus (HBV)-related HCC patients, AEG-1/MTDH expression has been found to significantly correlate with the American Joint Committee on Cancer (7th edition) (72) stage, T and N classification, vascular invasion and histological differentiation (54). In addition, patients with high AEG-1/MTDH levels have been found to exhibit poor survival rates compared with those with low AEG-1/MTDH levels (54). In HBV-related HCC patients, AEG-1/MTDH is a potential prognostic marker for overall survival (OS) and tumor progression, and is a chemotherapeutic target (54).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

“…In addition, patients with high AEG-1/MTDH levels have been found to exhibit poor survival rates compared with those with low AEG-1/MTDH levels (54). In HBV-related HCC patients, AEG-1/MTDH is a potential prognostic marker for overall survival (OS) and tumor progression, and is a chemotherapeutic target (54). In HCC tumors, the high expression of AEG-1/MTDH has also been found to correlate with microvascular invasion, pathological satellites, poor differentiation and tumor-node-metastasis (TNM) stages II to III.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

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Progress of cancer research on astrocyte elevated gene-1/Metadherin (Review)

Huang

2014

Oncology Letters

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Tumor development is initiated by an accumulation of numerous genetic and epigenetic alterations that promote tumor initiation, invasion and metastasis. Astrocyte elevated gene-1 [AEG-1; also known as Metadherin (MTDH) and Lysine-rich CEACAM1 co-isolated (LYRIC)] has emerged in recent years as a potentially crucial mediator of tumor malignancy, and a key converging point of a complex network of oncogenic signaling pathways. AEG-1/MTDH has a multifunctional role in tumor development that has been found to be involved in the following signaling cascades: i) The Ha-Ras and PI3K/Akt pathways; ii) the nuclear factor-κB signaling pathway; iii) the ERK/mitogen-activated protein kinase and Wnt/β-catenin pathways; and iv) the Aurora-A kinase signaling pathway. Studies have established that AEG-1/MTDH is crucial in tumor progression, including transformation, the evasion of apoptosis, invasion, angiogenesis and metastasis. In addition, recent clinical studies have convincingly associated AEG-1/MTDH with tumor progression and poor prognosis in a number of cancer types, including hepatocellular, esophageal squamous cell, gallbladder and renal cell carcinomas, breast, non-small cell lung, prostate, gastric and colorectal cancers, and glioma, melanoma, neuroblastoma and osteosarcoma. AEG-1/MTDH may be used as a biomarker to identify subgroups of patients who require more intensive treatments and who are likely to benefit from AEG-1/MTDH-targeted therapies. The therapeutic targeting of AEG-1/MTDH may simultaneously block metastasis, suppress tumor growth and enhance the efficacy of chemotherapeutic treatments.

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Section: Clinical-translational Advancesmentioning

confidence: 99%

Section: Clinical-translational Advancesmentioning

confidence: 99%

Section: Clinical-translational Advancesmentioning

confidence: 99%

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Progress of cancer research on astrocyte elevated gene-1/Metadherin (Review)

Huang

2014

Oncology Letters

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“…HCC with more microvascular invasion or pathologic satellites, poorer differentiation, and TNM stages II to III are prone to exhibit higher AEG-1 expression (29). HCC patients with high AEG-1 expression documented higher recurrence and poor overall survival (29, 30). Overexpression of AEG-1 in a poorly aggressive HCC cell line HepG3, which expresses low level of AEG-1, significantly increases in vitro proliferation, invasion and anchorage-independent growth and in vivo tumorigenesis, angiogenesis and metastasis in nude mice (22).…”

Section: Introductionmentioning

confidence: 99%

Genetic Deletion of AEG-1 Prevents Hepatocarcinogenesis

et al. 2014

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Activation of the oncogene AEG-1 (MTDH, LYRIC) has been implicated recently in the development of hepatocellular carcinoma (HCC). In mice, HCC can be initiated by exposure to the carcinogen DEN, which has been shown to rely upon activation of NF-κB in liver macrophages. Since AEG-1 is an essential component of NF-κB activation, we interrogated the susceptibility of mice lacking the AEG-1 gene to DEN-induced hepatocarcinogenesis. AEG-1-deficient mice displayed resistance to DEN-induced HCC and lung metastasis. No difference was observed in the response to growth factor signaling or activation of Akt, ERK and β-catenin, compared to wild-type control animals. However, AEG-1-deficient hepatocytes and macrophages exhibited a relative defect in NF-κB activation. Mechanistic investigations showed that IL-6 production and STAT-3 activation, two key mediators of HCC development, were also deficient along with other biological and epigenetics findings in the tumor microenvironment confirming that AEG-1 supports an NF-κB-mediated inflammatory state that drives HCC development. Overall, our findings offer in vivo proofs that AEG-1 is essential for NF-κB activation and hepatocarcinogenesis, and they reveal new roles for AEG-1 in shaping the tumor microenvironment for HCC development.

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“…HCC with more microvascular invasion or pathologic satellites, poorer differentiation, and TNM stages II to III are prone to exhibit higher AEG-1 expression [10]. HCC patients with high AEG-1 expression documented higher recurrence and poor overall survival [11]. Overexpression of AEG-1 in poorly aggressive HCC cell line HepG3, which expresses low level of AEG-1, significantly increases in vitro proliferation, invasion and anchorage-independent growth and in vivo tumorigenesis, angiogenesis and metastasis in nude mice [6, 12, 13].…”

Section: Introductionmentioning

confidence: 99%

Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC)

et al. 2015

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Hepatocellular carcinoma (HCC) is a fatal cancer with no effective therapy. Astrocyte elevated gene-1 (AEG-1) plays a pivotal role in hepatocarcinogenesis and inhibits retinoic acid-induced gene expression and cell death. Combination of a lentivirus expressing AEG-1 shRNA and all-trans retinoic acid (ATRA) profoundly and synergistically inhibited subcutaneous human HCC xenografts in nude mice. We now have developed liver-targeted nanoplexes by conjugating poly(amidoamine) (PAMAM) dendrimers with polyethylene glycol (PEG) and lactobionic acid (Gal) (PAMAM-PEG-Gal) which were complexed with AEG-1 siRNA (PAMAM-AEG-1si). The polymer conjugate was characterized by 1H-NMR, MALDI and mass spectrometry, and optimal nanoplex formulations were characterized for surface charge, size and morphology. Orthotopic xenografts of human HCC cell QGY-7703 expressing luciferase (QGY-luc) were established in the livers of athymic nude mice and tumor development was monitored by bioluminescence imaging (BLI). Tumor-bearing mice were treated with PAMAM-siCon, PAMAM-siCon+ATRA, PAMAM-AEG-1si and PAMAM-AEG-1si+ATRA. In the control group the tumor developed aggressively. ATRA showed little effect due to high AEG-1 levels in QGY-luc cells. PAMAM-AEG-1si showed significant reduction in tumor growth and the combination of PAMAM-AEG-1si+ATRA showed profound and synergistic inhibition so that the tumors were almost undetectable by BLI. A marked decrease in AEG-1 level was observed in tumor samples treated with PAMAM-AEG-1si. The group treated with PAMAM-AEG-1si+ATRA nanoplexes showed increased necrosis, inhibition of proliferation and increased apoptosis when compared to other groups. Liver is an ideal organ for RNAi therapy and ATRA is an approved anti-cancer agent. Our exciting observations suggest that the combinatorial approach might be an effective way to combat HCC.

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Prognostic significance of metadherin overexpression in hepatitis B virus-related hepatocellular carcinoma

Cited by 15 publications

References 33 publications

Progress of cancer research on astrocyte elevated gene-1/Metadherin (Review)

Progress of cancer research on astrocyte elevated gene-1/Metadherin (Review)

Genetic Deletion of AEG-1 Prevents Hepatocarcinogenesis

Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC)

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