Abstract
Reactive oxygen species (ROS) can drive the de-differentiation of tumor cells leading to the process of epithelial-to-mesenchymal transition (EMT) to enhance invasion and metastasis. The invasive and metastatic phenotype of malignant cells is often linked to loss of E-cadherin expression, a hallmark of EMT. Recent studies have demonstrated that hypoxic exposure causes HIF-1-dependent repression of E-cadherin. However, the mechanism by which ROS and/or HIF suppresses E-cadherin expression remains less clear. In the present study, we found that ROS accumulation in ovarian carcinoma cells upregulated HIF-1α expression and subsequent transcriptional induction of lysyl oxidase (LOX) which repressed E-cadherin. Loss of E-cadherin facilitated ovarian cancer (OC) cell migration in vitro and promoted tumor growth in vivo. E-cadherin immunoreactivity correlated with International Federation of Gynecology and Obstetrics (FIGO) stage, tumor differentiation and metastasis. Negative E-cadherin expression along with FIGO stage, tumor differentiation and metastasis significantly predicted for a lower 5-year survival rate. These findings suggest that ROS play an important role in the initiation of metastatic growth of OC cells and support a molecular pathway from ROS to aggressive transformation which involves upregulation of HIF-1α and its downstream target LOX to suppress E-cadherin expression leading to an increase in cell motility and invasiveness.
Highlights
Ovarian cancer (OC) is the fifth leading cause of cancer‐related death among women in the USA and has the highest mortality rate of all gynecologic cancers with an estimated 14,030 deaths in 2013 [1]
Given that hypoxic reduction in E-cadherin has been considered as an essential feature of the transitional process shifting from an epithelial cell to a motile and invasive phenotype, we examined whether Reactive oxygen species (ROS) stimulated the migration of OC cells and whether lysyl oxidase (LOX) plays a role in this effect
We showed that the expression levels of E-cadherin mRNA and protein were substantially reduced when HIF-1α was induced by increased intracellular ROS levels, and that this effect was reversible when HIF-1α was knocked down by an small interfering RNA (siRNA) targeted to HIF-1α
Summary
Ovarian cancer (OC) is the fifth leading cause of cancer‐related death among women in the USA and has the highest mortality rate of all gynecologic cancers with an estimated 14,030 deaths in 2013 [1]. A major contributor to the high mortality rate is the fact that 75% of women with OC present with metastasis at diagnosis [2]. Tumor cell populations that adapt to a hypoxic condition tend to undergo transformation into a more aggressive phenotype leading to metastasis and therapy resistance [10,12,13]. Under hypoxic conditions where O2 is limited for prolyl hydroxylase (PHD) activity, ubiquitination of HIF-1α is inhibited [14]. HIF-1α accumulates and binds to the hypoxia-response elements of various target genes activating transcription of these genes that are involved in angiogenesis, energy metabolism, vasomotor regulation, adaptive survival or apoptosis [15,16].
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