Correlation of circular RNA abundance with proliferation – exemplified with colorectal and ovarian cancer, idiopathic lung fibrosis and normal human tissues

Abstract

Circular RNAs are a recently (re-)discovered abundant RNA species with presumed function as miRNA sponges, thus part of the competing endogenous RNA network. We analysed the expression of circular and linear RNAs and proliferation in matched normal colon mucosa and tumour tissues. We predicted >1,800 circular RNAs and proved the existence of five randomly chosen examples using RT-qPCR. Interestingly, the ratio of circular to linear RNA isoforms was always lower in tumour compared to normal colon samples and even lower in colorectal cancer cell lines. Furthermore, this ratio correlated negatively with the proliferation index. The correlation of global circular RNA abundance (the circRNA index) and proliferation was validated in a non-cancerous proliferative disease, idiopathic pulmonary fibrosis, ovarian cancer cells compared to cultured normal ovarian epithelial cells, and 13 normal human tissues. We are the first to report a global reduction of circular RNA abundance in colorectal cancer cell lines and cancer compared to normal tissues and discovered a negative correlation of global circular RNA abundance and proliferation. This negative correlation seems to be a general principle in human tissues as validated with three different settings. Finally, we present a simple model how circular RNAs could accumulate in non-proliferating cells.

The emerging role and clinical implication of human exonic circular RNA

“…Cancer Bachmayr-Heyda and colleagues were the first to report a global reduction of circRNA abundance in colorectal cancer cell lines and cancer tissues compared to normal tissues, and they discovered a negative correlation between global circular RNA abundance and proliferation. 42 Further study by RNAseq analyses of normal and cancerous tissues identified a large number of circRNA candidates. 16 Among these candidates, many were differently expressed between normal and cancerous tissues, suggesting a potential role of circRNA in cancer.…”

Circular RNA participates in the carcinogenesis and the malignant behavior of cancer

“…And the abnormality of gene expression and biological behavior observed in cancer cells may be considered the result of deregulated circRNA function. 11,38 Interestingly, the versatility of circRNA expression mainly lies in post-transcriptional regulation, which is frequently achieved by RNA-RNA interactions. 24 CircRNAs, together with some other ceRNAs, are believed to serve as microRNA reservoirs, but with much more binding sites, which enable the circRNAs to specialize in harboring microRNAs.…”

“…A circular RNA encoded as Hsa_circ_002059 has already been determined to be significantly downregulated in gastric cancer. 37,38 In addition, several circRNAs are considered responsible for the malignant biological behavior of cancer cells. Thus, in this review, we mainly discuss the roles of circRNAs in cancer tissues by engaging in regulation of microRNA.…”

Repetitive elements regulate circular RNA biogenesis

“…The expression of circular RNAs has recently been reported to generally decrease in human cancers 53 and increase as flies age, 47 suggesting that their expression can be drastically altered and potentially contribute to pathological states. However, the biological functions of most circular RNAs are still completely unclear.…”