Induction of Peroxiredoxin 1 by Hypoxia Regulates Heme Oxygenase-1 via NF-κB in Oral Cancer

Abstract

Overexpression of peroxiredoxin 1 (Prx1) has been observed in numerous cancers including oral squamous cell carcinoma (OSCC). The precise molecular mechanism of up-regulation of Prx1 in carcinogenesis, however, is still poorly understood. The objective of this study is to investigate the relationship between Prx1 and hypoxia, and potential mechanism(s) of Prx1 in OSCC cell line SCC15 and xenograft model. We treated wild-type and Prx1 knockdown SCC15 cells with transient hypoxia followed by reoxygenation. We detected the condition of hypoxia, production of reactive oxygen species (ROS), and expression and/or activity of Prx1, heme oxygenase 1 (HO-1) and nuclear factor-kappa B (NF-κB). We found that hypoxia induces ROS accumulation, up-regulates Prx1, increases NF-κB translocation and DNA binding activity, and down-regulates HO-1 in vitro. In Prx1 knockdown cells, the expression level of HO-1 was increased, while NFκB translocation and DNA binding activity were decreased after hypoxia or hypoxia/reoxygenation treatment. Moreover, we mimicked the dynamic oxygenation tumor microenvironment in xenograft model and assessed the above indices in tumors with the maximal diameter of 2 mm, 5 mm, 10 mm or 15 mm, respectively. Our data showed that tumor hypoxic condition and expression of Prx1 are significantly associated with tumor growth. The expression of HO-1 and NF-κB, and NF-κB DNA binding activity were significantly elevated in 15 mm tumors, and the level of 8-hydroxydeoxyguanosine was increased in 10 mm and 15 mm tumors, compared to those in size of 2 mm. The results from this study provide experimental evidence that overexpression of Prx1 is associated with hypoxia, and Prx1/NF-κB/HO-1 signaling pathway may be involved in oral carcinogenesis.

Peroxiredoxin 1 promotes invasion and migration by regulating epithelial-to-mesenchymal transition during oral carcinogenesis

“…Nicotine-induced Prx1 overexpression correlates significantly with OSCC carcinogenesis [12, 29], and further investigation of the functional role of Prx1 could provide a novel biomarker for OSCC prevention and therapy.…”

“…Oral mucosa specimens were fixed in 10% neutral-buffered formalin overnight, embedded in paraffin, and serially sectioned at 4 μm as described previously [12]. Deparaffinized sections were briefly heated for 10 min in a pressure cooker containing 10 mM citrate buffer (pH 6.0) for antigen retrieval and then soaked in 3% H 2 O 2 in 0.1 M TBS (pH 7.4) for 15 min to quench endogenous peroxidases.…”

“…Prx1 overexpression was associated with poor prognosis and tumor growth in a xenograft model [10–12]. Prx1 is a major 2-Cys member of the peroxiredoxin family.…”

Expression of hypoxia-induced factor-1 alpha in early-stage and in metastatic oral squamous cell carcinoma

“…5 Hypoxic conditions may occur due to changes in neoplastic cells and angiogenesis. 4,6 HIF-1-induced genes are involved in a wide range of cellular functions associated with tumor development and growth. 7 To adapt to the hypoxic microenvironment, neoplastic cells activate HIF-1 alpha, which dimerizes with the beta subunit (HIF-1 beta) and targets several genes, such as those mediating angiogenesis.…”

Roles of peroxiredoxins in cancer, neurodegenerative diseases and inflammatory diseases

“…PRDX1 is implicated in redox regulation of the cell and plays an important role in eliminating peroxides produced during metabolism that participates in the signaling of growth factors and tumor necrosis factor-alpha (TNF-α) through regulating the intracellular concentrations of H 2 O 2 (Jamaluddin et al, 2010;Liou & Storz, 2010). PRDX1 is overexpressed in several cancer cells including esophageal, pancreatic, lung, thyroid and oral cancer (Gong, Hou, Liu, & Zhang, 2015;Jiang, Wu, Mishra, Chawsheen, & Wei, 2014b;Jiang et al, 2014a;Taniuchi et al, 2015;Yanagawa et al, 1999;Zhang, Liu, Szumlinski, & Lew, 2012b;Zhang et al, 2012aZhang et al, , 2014. Concentrated PRDX1 can be secreted by non-small cell lung cancer cells via unusual pathway (Chang et al, 2005).…”