Abstract
Gemcitabine (GEM), a commonly used chemotherapeutic agent in hepatocellular carcinoma (HCC) patients, uses oxidative stress induction as a common effector pathway. However, GEM alone or in combination with oxaliplatin hardly renders any survival benefits to HCC patients. We have recently shown that this is part due to the overexpression of the mitochondrial uncoupling protein 2 (UCP2) that in turn mediates resistance to GEM in HCC patients. However, not much is known about regulatory mechanisms underlying UCP2 overexpression in HCC. Differential protein expression in HCC cell lines did not show a concomitant change in UCP2 transcript level, indicating post-transcriptional or post-translational regulatory mechanism. In situ analysis revealed that UCP2 is a putative target of miR-214 miR-214 expression is significantly down-regulated in HCC patient samples as compared with normal adjacent tissues and in cell line, human hepatoblastoma cells (HuH6), with high UCP2 protein expression. We demonstrated using miR-214 mimic and antagomir that the miRNA targeted UCP2 expression by directly targeting the wild-type, but not a miR-214 seed mutant, 3' UTR of UCP2 Overexpression of miR-214 significantly attenuated cell proliferation. Finally, analysis in 20 HCC patients revealed an inverse correlation in expression of UCP2 and miR-214 (Pearson's correlation coefficient, r=-0.9792). Cumulatively, our data indicate that in the context of HCC, miR-214 acts as a putative tumour suppressor by targeting UCP2 and defines a novel mechanism of regulation of UCP2.
Highlights
A widely expressed subcategory of mitochondrial anion-carrier in animals and plants is the uncoupling protein (UCP) family, with the mammalian genome encoding uncoupling protein 1 (UCP1) to uncoupling protein 5 (UCP5) homologues [1,2,3]
uncoupling protein 2 (UCP2) transcript is targeted by miR-214 We have recently observed differential UCP2 protein expression among different hepatocellular carcinoma (HCC) cell lines [14]
Whereas robust steady state UCP2 protein expression was detected in human hepatoblastoma cells (HuH6) cells, it was suppressed in the human lens epithelial cells (HLE) cells (Figure 1A)
Summary
A widely expressed subcategory of mitochondrial anion-carrier in animals and plants is the uncoupling protein (UCP) family, with the mammalian genome encoding uncoupling protein 1 (UCP1) to uncoupling protein 5 (UCP5) homologues [1,2,3]. The most ubiquitous among these five homologues is uncoupling protein 2 (UCP2), with detectable expression in skeletal muscle, brain, pancreas, liver and immune cells [4]. UCP2 is located in chromosome 11q13.4 and encodes for a protein of 309 amino acids and predicted molecular mass of 33.299 kDa. UCP2 is largely expressed in the inner mitochondrial membrane, but expression is noted in the nucleus, peroxisome, cytosol and plasma membrane [4]. UCP2 in conjunction with uncoupling protein 3 (UCP3) function in suppressing electron transport chain mediated generation of reactive oxygen species (ROS) [5,6]. Overproduction of ROS leads to oxidative damage [8]
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