Abstract
Hypoxia promotes tumour aggressiveness and reduces patient survival. A spectrum of poor outcome among patients with hypoxic tumours suggests that additional factors modulate how tumours respond to hypoxia. PIWI-interacting RNAs (piRNAs) are small non-coding RNAs with a pivotal role in genomic stability and epigenetic regulation of gene expression. We reported that cancer type-specific piRNA signatures vary among patients. However, remarkably homogenous piRNA profiles are detected across patients with renal cell carcinoma, a cancer characterized by constitutive upregulation of hypoxia-related signaling induced by common mutation or loss of von Hippel-Lindau factor (VHL). By investigating >3000 piRNA transcriptomes in hypoxic and non-hypoxic tumors from seven organs, we discovered 40 hypoxia-regulated piRNAs and validated this in cells cultured under hypoxia. Moreover, a subset of these hypoxia-regulated piRNAs are regulated by VHL/HIF signaling in vitro. A hypoxia-regulated piRNA-based score (PiSco) was associated with poor RFS for hypoxic tumours, particularly Stage I lung adenocarcinomas, suggesting that hypoxia-regulated piRNA expression can predict tumour recurrence even in early-stage tumours and thus may be of clinical utility.
Highlights
We found that siRNA-mediated knockdown of von Hippel-Lindau factor (VHL) increased expression of both PIWI-interacting RNAs (piRNAs) (Fig. 4A,B), and that this induction was inhibited when VHL knockdown was combined with siRNA-mediated knockdown of HIF-1α, indicating that HIF-1α stabilization induced by VHL knockdown was responsible for the increase in piRNA expression
Our results indicate that hypoxia can regulate the expression of piRNAs which, in turn, may aid in the prediction of prognosis for patients with hypoxic tumours
Tumours from all tissue types were classified into hypoxic or non-hypoxic groups, except for ovarian and kidney tissues. While this lack of clear classification between hypoxic and non-hypoxic ovarian cancer samples was not anticipated, it was expected in renal cell carcinomas because >75% of sporadic RCCs contain mutated or lost VHL49
Summary
Hypoxic conditions are known to upregulate >90 genes associated with anaerobic glycolysis, pH regulation, angiogenesis, cellular migration, and metastasis[1,2] through the activity of the heterodimeric transcription factors hypoxia-inducible factor-1 (HIF-1) and HIF-23. We found that piRNA expression was remarkably consistent between RCC tumours, a tumour type that commonly harbour loss-of-function mutations in von Hippel-Lindau factor (VHL), causing constitutive, oxygen-independent stabilization of HIF-1α3 and HIF-mediated upregulation of hypoxia-associated gene products. PiRNAs associated with hypoxia may identify patients at higher risk of recurrence, facilitating the development of piRNA signatures for patient prognosis. We discovered that hypoxia is associated with increased expression of a subgroup of piRNAs in patient tumours, and that most of these piRNAs are overexpressed in tumour cell lines exposed to hypoxic conditions or VHL disruption in vitro. We have found that that the expression of these hypoxia-regulated piRNAs (hypoxia-regulated piRNAs) can be used to predict recurrence-free survival (RFS) of patients with hypoxic tumours
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
