The Circular RNA circPRKCI Promotes Tumor Growth in Lung Adenocarcinoma

Abstract

1Somatic copy-number variations (CNV) may drive cancer progression through both coding and 2 noncoding transcripts. However, noncoding transcripts resulting from CNV are largely unknown, 3 especially for circular RNAs. By integrating bioinformatics analyses of alerted circRNAs and 4 focal CNV in lung adenocarcinoma (LAC), we identify a proto-oncogenic circular RNA 5 (circPRKCI) from the 3q26.2 amplicon, one of the most frequent genomic aberrations in multiple 6 cancers. circPRKCI was overexpressed in LAC tissues, in part due to amplification of the 3q26.2 7 locus, and promoted proliferation and tumorigenesis of LAC. circPRKCI functioned as a sponge 8 for both miR-545 and miR-589 and abrogated their suppression of the pro-tumorigenic 9 transcription factor E2F7. Intra-tumor injection of cholesterol-conjugated siRNA specifically 10 targeting circPRKCI inhibited tumor growth in a patient-derived LAC xenograft model. In 11 summary, circPRKCI is crucial for tumorigenesis and may serve as a potential therapeutic target in 12 LAC patients. 13

circRNA meets gene amplification

“…Furthermore, they verified this finding using chromogenic in-situ hybridization (CISH) which showed that higher CISH expression of circPRKCI correlated with size and TNM stage (18). While this was an important finding, most interesting was that patients with higher CISH expression in their LAC tumors had a shorter overall survival and on multivariate analysis circPRKCI expression level is an independent poor prognostic factor (hazard ratio 2.66) (18). Prognostic factors are important in determining treatment algorithms and surveillance of patients, however, a prognostic characteristic holds much more importance when the characteristic can be acted on to alter the prognosis of the patient.…”

“…They further found circPRKCI expression was higher in larger tumors, and those with stage II-III tumors had higher circPRKCI expression than those that were stage I. Furthermore, they verified this finding using chromogenic in-situ hybridization (CISH) which showed that higher CISH expression of circPRKCI correlated with size and TNM stage (18). While this was an important finding, most interesting was that patients with higher CISH expression in their LAC tumors had a shorter overall survival and on multivariate analysis circPRKCI expression level is an independent poor prognostic factor (hazard ratio 2.66) (18).…”

“…Furthermore, circRNAs arising from CNV regions have not been identified before. The recent study by Qiu et al is the first to report the significance of circPRKCI in LAC (18). The authors eloquently identified circPRKCI as a prognosticator of LAC and elucidated the mechanism of circPRKCI, providing a potential treatment target for this lethal disease.…”

“…They initially cross referenced tumor-specific circRNAs from 5 LAC patients with common CNVs in LAC from TCGA data and found the circRNA associated with the gene protein kinase C iota (PRKCI) (18). PRKCI is located within the 3 Mb region of 3q26.2 that is frequently amplified in lung cancer (3,19).…”

“…circPRKCI was found to be overexpressed in tumor tissue compared to normal tissue with an average fold change of 6.89 (18). They further found circPRKCI expression was higher in larger tumors, and those with stage II-III tumors had higher circPRKCI expression than those that were stage I.…”