The role of circular RNAs (circRNAs) in tumors is becoming increasingly apparent. Recently, circHIPK3, one circular RNA of HIPK3 gene has been found to play an important role in tumor growth and progression, but its role in lung cancer has not been elucidated.
Late in June, a research group co-chaired by Associate Professor Chen Guoan of the School of Medicine at Southern University of Science and Technology (SUSTech) published an article in international journal Autophagy (IF 11.1) entitled “Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKα signaling in STK11 mutant lung cancer.” The paper sought to reveal the role of circHIPK3 in lung cancer and the new mechanism of regulating the autophagic pathway.
CircRNAs are covalently-closed, single-stranded transcripts derived from pre-mRNAs. Discovered in the 1970s, they were then regarded as a rare product arising from mRNA splicing errors. Their abundance in human cells has recently been clarified by RNA-seq analysis, and they appear to have a significant role in tumorigenesis and development. CircRNAs can be divided into 4 different categories based on their origin. CircRNAs derived from exons are the most widely studied, with other types including ciRNAs derived from introns, ElciRNAs derived from a combination of exons and introns, as well as group I and II ribozymes. Multiple hypotheses have been proposed regarding the biogenesis of circRNAs, among which alternative splicing, reverse complementary intronic sequence paring, or RNA binding protein regulation being the most accepted ones. Understanding of circRNA function however remains incomplete but it is well accepted that circRNAs can act as microRNA sponges to regulate gene expression and may have diagnostic or therapeutic potential.
This study shows that silencing circHIPK3 can significantly inhibit the proliferation, invasion and metastasis of lung cancer cells, and lead to autophagy. Mechanistically, the team found that autophagy was induced upon loss of circHIPK3 via the MIR124-3p-STAT3-PRKAA/AMPKa axis in STK11 mutant lung cancer cell lines (A549 and H838). Silencing STAT3 or knocking MIR124-3p mimic could reproduce autophagy induction. In addition, they also found that circHIPK3 and linHIPK3 have antagonistic effects on autophagy regulation. Therefore, the ratio of circHIPK3 to linHIPK3 (C:L ratio) may reflect the autophagic intensity of cancer cells. The team discovered that a high C:L ratio (>0.49) suggested a poor prognosis, which was more pronounced in advanced non-small cell lung cancer. These results suggest that circHIPK3 is a key molecule of autophagy regulation in some lung cancers. As an oncogene and autophagy regulatory gene of lung cancer, circHIPK3 may further become a prognostic marker and even have potential therapeutic value.
Taken together, the results provide clinical significance for the oncogenic circHIPK3 and revealed its role in autophagy regulation. Autophagy is induced upon circHIPK3 silencing via MIR124-3p-STAT3-PRKAA pathway and is dependent on STK11 status. Upregulation of the ratio between circHIPK3 and linHIPK3 may hold treatment potential in NSCLC patients.
Dr. Xiuyuan Chen of Peking University People’s Hospital is the first author and Professor Wang Jun is a co-author of the paper. The co-authors include the University of Michigan Medical School, the First Affiliated Hospital of Xinjiang Medical University, the Affiliated Hospital of Guangdong Medical University and the First & Second Affiliated Hospital of Xi’an Jiaotong University.
This work was supported in part by the National Institutes of Health, the University of Michigan’s Cancer Center Support Grant, University of Michigan’s Cancer Center Thoracic Oncology Program Research Grant, University of Michigan Department of Surgery RAC grant and the China Scholarship Council (CSC) funding .