Gene expression of NOX family members and their clinical significance in hepatocellular carcinoma

Abstract

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-derived reactive oxygen species (ROS) promote chronic liver inflammation and remodeling that can drive hepatocellular carcinoma development. The role of NOX expression in hepatocellular carcinoma (HCC) has been partially investigated; however, the clinical relevance of collective or individual NOX family member expression for HCC survival remains unclear. Here, we obtained NOX mRNA expression data for 377 HCC samples and 21 normal liver controls from the TCGA data portal and performed Kaplan-Meier survival, gene ontology functional enrichment, and gene set enrichment analyses. Although most NOX genes exhibited little change, some were significantly induced in HCC compared to that in normal controls. In addition, HCC survival analyses indicated better overall survival in patients with high NOX4 and DUOX1 expression, whereas patients with high NOX1/2/5 expression showed poor prognoses. Gene-neighbour and gene set enrichment analyses revealed that NOX1/2/5 were strongly correlated with genes associated with cancer cell survival and metastasis, whereas increased NOX4 and DUOX1 expression was associated with genes that inhibit tumour progression. On the basis of these data, NOX family gene expression analysis could be a predictor of survival and identify putative therapeutic targets in HCC.

Human hepatocellular carcinoma: Protection by melatonin

“…HuH-7 cells incubated with melatonin (2.5 mM, 48 hr) exhibit weak pro-apoptotic effect, and that this effect is evolved in the cells only after incubation with combination of melatonin and sorafenib (Lin et al, 2017). In contrast, HepG2 and Bel-7402 cells incubated with lower melatonin dosage (10 −5 mol/L) for the same exposure time show noticeable induction of apoptosis (Fan et al, 2010). Similarly, HepG2 cells incubated with melatonin (1 mM) for 2, 4, 6, 8, and 10 days also show considerable induction of apoptosis (increase of PARP cleavage, caspases 3, 8, and 9 activities, Bax protein level, and cyt c release from mitochondria) (Martín-Renedo et al, 2008).…”

“…Caspase enzymes and B cell lymphoma-2 (Bcl-2) family are two essential family of proteins contributing to apoptosis (Fan et al, 2010).…”

“…Caspase-3 catalyzes specific cleavage of various essential cellular proteins (Fan et al, 2010), and its activation occurs as a common event initiated by several stimuli (Martín-Renedo et al, 2008). Caspase-3 is primarily involved in the 116 kDa protease poly ADP-ribose polymerase (PARP)-1 protein cleavage (degradation) into a 85 kDa fragment, whose appearance represents that the studying cells undergo apoptosis (Martín-Renedo et al, 2008).…”

“…Ceramide release and p53 activation are involved in increase of ROS levels in the early apoptotic stages (Sainz et al, 2003). ROS activate JNK/c-jun pathway (Lin et al, 2017) contributed to the inhibition of tumor progression (Eun et al, 2017).…”

“…NOX is considered as the key source for ROS in the liver (De Minicis et al, ). High NOX1 , NOX2 , and NOX5 expressions in HCC patients are related to poor prognosis, while increased expressions for NOX4 and DUOX1 are contributed to the inhibition of tumor progression (Eun et al, ). NOX‐derived ROS contribute to the HGF‐induced HepG2 migration (Lin et al, ) as well as HCC invasion (Ren, Zhang et al, ), which has been described in detail below.…”