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

Bachmayr-Heyda A, Reiner AT, Auer K, Sukhbaatar N, Aust S, Bachleitner-Hofmann T, Mesteri I, Grunt TW, Zeillinger R, Pils D - Sci Rep (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynaecology, Molecular Oncology Group, Comprehensive Cancer Centre, Medical University of Vienna &Ludwig Boltzmann Cluster Translational Oncology, Vienna, Austria.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic model of circular and linear RNAs in proliferating and non-proliferating cells.Assumption: Circular and linear RNAs are synthesized by specific splice events in a gene (cell type and condition) dependent ratio. While linear RNAs are in a steady state of regulated synthesis and degradation, circular RNAs are much more stable. During proliferation both RNA species are evenly distributed to daughter cells. The steady state level of linear transcripts is accurately controlled and maintained by active transcription and degradation also leading to new expression of circular RNAs and resulting in constant ratios of circular to linear isoforms (lower panel). In contrast, in non-proliferating cells stable circular RNAs accumulate whereas linear transcripts are in a regulated steady state of transcription and degradation (upper panel).
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f6: Schematic model of circular and linear RNAs in proliferating and non-proliferating cells.Assumption: Circular and linear RNAs are synthesized by specific splice events in a gene (cell type and condition) dependent ratio. While linear RNAs are in a steady state of regulated synthesis and degradation, circular RNAs are much more stable. During proliferation both RNA species are evenly distributed to daughter cells. The steady state level of linear transcripts is accurately controlled and maintained by active transcription and degradation also leading to new expression of circular RNAs and resulting in constant ratios of circular to linear isoforms (lower panel). In contrast, in non-proliferating cells stable circular RNAs accumulate whereas linear transcripts are in a regulated steady state of transcription and degradation (upper panel).

Mentions: Taken together, we have reliable evidence that circRNAs are globally reduced in tumour tissues from CRC patients compared to matched normal tissues and are even more reduced in CRC cell lines. The following mechanisms could explain our data: (a) the back-splice machinery is compromised in malignant tissues; (b) the lower amount of circRNAs is a result of increasing degradation by miRNAs which are deregulated in tumour tissue; even simpler (c) circRNAs get passively thinned out by cell proliferation or vice versa accumulate in non-proliferating (starving, dormant or finally differentiated) cells (schematically outlined in Fig. 6); or (d) of course, also yet unknown mechanisms could be the reason for the results described above. For the proliferation scenario (c) the following three assumptions have to be fulfilled: (i) CircRNAs and linRNAs are processed in a gene (and cell type and condition) specific ratio. (ii) Linear transcripts are regulated by transcription and degradation and are therefore in a cell type and condition specific steady state. Although they are also – just as their circular counterparts – passively distributed to the daughter cells, thus putatively also thinned out by cell proliferation, their level is very rigorously controlled. Assuming constant environmental signals, the required levels of mRNAs are adjusted very quickly to the level before cell division also resulting in circRNA synthesis in a gene and condition specific ratio. This leads to daughter cells with the same amount (and ratio) of linear and circular RNAs compared to their mother cell. (iii) CircRNAs are more stable than linRNAs in cells, i.e. are not regulated by (general exonucleatic) degradation.


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

Bachmayr-Heyda A, Reiner AT, Auer K, Sukhbaatar N, Aust S, Bachleitner-Hofmann T, Mesteri I, Grunt TW, Zeillinger R, Pils D - Sci Rep (2015)

Schematic model of circular and linear RNAs in proliferating and non-proliferating cells.Assumption: Circular and linear RNAs are synthesized by specific splice events in a gene (cell type and condition) dependent ratio. While linear RNAs are in a steady state of regulated synthesis and degradation, circular RNAs are much more stable. During proliferation both RNA species are evenly distributed to daughter cells. The steady state level of linear transcripts is accurately controlled and maintained by active transcription and degradation also leading to new expression of circular RNAs and resulting in constant ratios of circular to linear isoforms (lower panel). In contrast, in non-proliferating cells stable circular RNAs accumulate whereas linear transcripts are in a regulated steady state of transcription and degradation (upper panel).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4306919&req=5

f6: Schematic model of circular and linear RNAs in proliferating and non-proliferating cells.Assumption: Circular and linear RNAs are synthesized by specific splice events in a gene (cell type and condition) dependent ratio. While linear RNAs are in a steady state of regulated synthesis and degradation, circular RNAs are much more stable. During proliferation both RNA species are evenly distributed to daughter cells. The steady state level of linear transcripts is accurately controlled and maintained by active transcription and degradation also leading to new expression of circular RNAs and resulting in constant ratios of circular to linear isoforms (lower panel). In contrast, in non-proliferating cells stable circular RNAs accumulate whereas linear transcripts are in a regulated steady state of transcription and degradation (upper panel).
Mentions: Taken together, we have reliable evidence that circRNAs are globally reduced in tumour tissues from CRC patients compared to matched normal tissues and are even more reduced in CRC cell lines. The following mechanisms could explain our data: (a) the back-splice machinery is compromised in malignant tissues; (b) the lower amount of circRNAs is a result of increasing degradation by miRNAs which are deregulated in tumour tissue; even simpler (c) circRNAs get passively thinned out by cell proliferation or vice versa accumulate in non-proliferating (starving, dormant or finally differentiated) cells (schematically outlined in Fig. 6); or (d) of course, also yet unknown mechanisms could be the reason for the results described above. For the proliferation scenario (c) the following three assumptions have to be fulfilled: (i) CircRNAs and linRNAs are processed in a gene (and cell type and condition) specific ratio. (ii) Linear transcripts are regulated by transcription and degradation and are therefore in a cell type and condition specific steady state. Although they are also – just as their circular counterparts – passively distributed to the daughter cells, thus putatively also thinned out by cell proliferation, their level is very rigorously controlled. Assuming constant environmental signals, the required levels of mRNAs are adjusted very quickly to the level before cell division also resulting in circRNA synthesis in a gene and condition specific ratio. This leads to daughter cells with the same amount (and ratio) of linear and circular RNAs compared to their mother cell. (iii) CircRNAs are more stable than linRNAs in cells, i.e. are not regulated by (general exonucleatic) degradation.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynaecology, Molecular Oncology Group, Comprehensive Cancer Centre, Medical University of Vienna &Ludwig Boltzmann Cluster Translational Oncology, Vienna, Austria.

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.

No MeSH data available.


Related in: MedlinePlus