Hypoxia-induced exosomal circ_0006840 promotes pancreatic cancer progress by regulating the WIF1 decay.

[BACKGROUND] Circular RNAs (circRNAs) have been recognized as key contributors to tumorigenesis in various cancer types. However, the biological functions and mechanisms of hypoxia-induced exosomal circRNAs in pancreatic cancer (PC) are largely unknown.

[METHODS] A comparison of hypoxic versus normoxic PC cells was conducted using RNA sequencing to identify differentially expressed circRNAs. Quantitative reverse transcription PCR (RT-qPCR) and in situ hybridization (ISH) was used to assess the expression levels of circ_0006840 in PC patients. In vitro and in vivo experiments were conducted to validate the biological functions of circ_0006840 in PC. Gene expression regulation was observed by RNA pull-down, ChIP, RIP, dual-luciferase assays. Gain- and loss-of-function studies were performed to observe the impacts of circRNA and its partners on the invasion, and metastasis of PC cells.

[RESULTS] We identified differentially expressed circRNAs in exosomes derived from normoxic and hypoxic PC cells through RNA sequencing. We show that high level of circ_0006840 was found in PC tissues and serum exosomes, which was associated with poor patient survival. Both in vitro and in vivo, circ_0006840 enhanced PC cell proliferation and migration. At the transcriptional level, HIF1A mediated circ_0006840 activation. WNT inhibitory factor 1 (WIF1), a key component of the WNT signaling pathway, was identified as the primary target of circ_0006840, suppressed at the post-transcriptional level. These findings suggest that circ_0006840, activated by HIF1A, regulated WIF1 transcripts promoting their decay. Exosomal circ_0006840 thus emerges as a potential therapeutic target for PC.

[CONCLUSIONS] It has been shown that circ_0006840 was transcriptionally activated by HIF1A and specifically regulated WIF1 transcripts, which is considered a potential target for PC therapy.