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

backgroundCircular 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.

methodsA 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.

resultsWe 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.

conclusionsIt 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.