Circular RNA Has_Circ_0004277 Arouses Malignant Phenotype of Hepatocellular Carcinoma Cells and Stimulates EMT of Peripheral Cells Through Cellular Communication

Background: Circular RNAs (circRNAs) are important in the pathological process of many diseases. From accumulative evidences so far, exosomal circRNAs reflect the physiological status of donor cells and various cell reactions are induced after exosomal circRNAs are captured by recipient cells. Methods: Here, qRT-PCR was performed for detecting the circ-0004277 expression in hepatocellular carcinoma (HCC) cell lines, tissues and plasma exosomes. The influence of circ-0004277 on the proliferation and migration of hepatocellular carcinoma cells was assessed by Cell Counting Kit-8 assays, 5-ethynyl-2'-deoxyuridine assays and Transwell migration assays as well as tumor formation in nude mice. In addition, TEM was performed to indicate the size and shape of exosomes from HCC cell lines and normal liver cell line HL-7702. Findings: We found significantly up-regulated circ-0004277 in HCC cells, tissues and plasma exosomes relative to normal controls. Meanwhile, overexpressed circ-0004277 enhanced the proliferation and migration of HCC cells in vivo and in vitro. What's more, exosomes from hepatocellular carcinoma cells enhanced circ-0004277 expression of surrounding normal cells and stimulated their proliferation and migration. Furthermore, exosomal circ-0004277 stimulated the EMT of peripheral normal cells. Interpretation: Hence, our findings suggest that on the one hand circ-0004277 arouses malignant phenotype of HCC cells; on the other hand, exosomal circ-0004277 from HCC cells stimulates EMT of peripheral cells through cellular communication to further promote the invasion of HCC into normal surrounding tissues.   Funding Statement: The authors state: None.  Declaration of Interests: Authors declare that they have no competing interests. Ethics Approval Statement: All the subjects signed the written informed and the study protocol received the approval from the Ethics Committee of both Nantong University Affiliated Hospital and The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University. The study obtained the approval from the Institute Research Medical Ethics Committee of The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University and was conducted under the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.