Circular RNA hsa_circ_0004277 Stimulates Malignant Phenotype of Hepatocellular Carcinoma and Epithelial-Mesenchymal Transition of Peripheral Cells

Abstract

Accumulating evidence shows that exosomal circRNAs reflect the physiological status of donor cells, and various cell reactions are induced after exosomal circRNAs are captured by recipient cells. In this study, qRT-PCR was performed to detect circ-0004277 expression in hepatocellular carcinoma (HCC) cell lines, tissues, and plasma exosomes. The effects of circ-0004277 on the proliferation and migration of HCC cells were assessed by cell counting, 5-ethynyl-2′-deoxyuridine assays, Transwell migration assays, and tumor formation in nude mice. We found that circ-0004277 was significantly upregulated in HCC cells, tissues, and plasma exosomes compared to that in normal controls. Overexpression of circ-0004277 enhanced the proliferation, migration, and epithelial-mesenchymal transition (EMT) of HCC cells in vivo and in vitro. Furthermore, exosomes from HCC cells enhanced circ-0004277 expression in surrounding normal cells and stimulated EMT progression. ZO-1, a tight junction adapter protein, was downregulated in HCC tissues. In conclusion, our findings suggest that circ-0004277 promotes the malignant phenotype of HCC cells via inhibition of ZO-1 and promotion of EMT progression. In addition, 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.

The functional roles, cross-talk and clinical implications of m6A modification and circRNA in hepatocellular carcinoma

“…circ_0004277 was significantly upregulated in HCC cells, tissues and plasma exosomes. Exosomal circ_0004277 from HCC cells enhanced the circ_0004277 expression in surrounding normal cells through cellular communication, thus stimulating EMT process and promoting the invasion of HCC cells 160 . In addition, the expression of exosomal circZNF652 was upregulated in the serum of HCC patients and was closely associated with the proliferation, migration, invasion and glycolysis of HCC cells, suggesting that it might become a novel biomarker for predicting the malignant characteristics of HCC 161 .…”

Circular RNAs in Hepatocellular Carcinoma: Emerging Functions to Clinical Significances

“…The increased expression of exosomal circ-0004277 in HCC presents good diagnostic value because its area under the curve (AUC), sensitivity, and specificity are 0.816, 58.3% and 96.7%, respectively. Those results demonstrated that exosomal circ-0004277 might be a useful diagnostic biomarker and therapeutic target for HCC patients (129).…”

Roles and mechanisms of exosomal non-coding RNAs in human health and diseases

“…236 Exosomal circ-0004277 plays a role in inducing malignant phenotype of HCC by suppressing expression of ZO-1 and increasing tumor cell progression, migration, and EMT. 237 In addition, the level of serum exosomal CircPTGR1 is upregulated in HCC patients and plays a role in facilitating tumor metastasis by targeting miR449a/MET pathway. 238 Overexpression of exosomal has-circ-0039411 increases secretion of matrix metallopeptidase 2 (MMP2) by sponging miR-136-5p.…”