AEG-1 is associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating PI3K/AKT/HIF-1alpha/MDR-1 pathway
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Date
2016-11-30
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Abstract
Hypoxia is a common characteristic of hepatocellular carcinoma (HCC) associated with reduced
response to chemotherapy, thus increasing the probability of tumor recurrence. Astrocyte elevated
gene-1 (AEG-1) has been involved in a wide array of cancer progression including proliferation,
chemoresistance, angiogenesis and metas- tasis, but its effect on HCC chemoresistance induced by
hypoxia is unclear. In this study, expression of AEG-1 and multiple drug resistance (MDR-1) were
examined in HCC using immunohistochemical staining and RT- PCR. Furthermore, their expression
levels were detected in HCC HepG2 cells in normoxia or hypoxia via RT- PCR and Western blot assays.
Specific shRNAs were used to silence AEG-1 expression in HepG2 cells. Results showed AEG-1 and
MDR-1 expression were higher in HCC tissues than in adjacent normal tissues. Incubation of HepG2
cells in hypoxia increased expression of AEG-1 and MDR-1, compared to incubation in normoxia.
Exposure to hypoxia blunted sensitivity of HepG2 cells to Adriamycin, 5-fluorouracil and
cis-platinum, as evi- denced by modest alterations in cell viability and apoptosis rate, however
the sensitivity was elevated with AEG- 1 knockdown. PI3K/AKT/HIF-1/MDR-1 pathway was attenuated
following AEG-1 knockdown in hypoxia. Based on these data, it was suggested that AEG-1 is
associated with hypoxia-induced hepatocellular carcinoma chemoresistance via regulating
PI3K/AKT/HIF-1/MDR-1 pathway. This study uncovered a novel potential tar-
get for development of an effective therapy against hypoxia-induced HCC chemoresistance.
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Keywords
AEG-1, hypoxia, hepatocellular carcinoma, chemoresistance, PI3K/AKT/HIF-1-1α/MDR-1 pathway