CircTP63 Promotes Hepatocellular Carcinoma Progression by Sponging miR-155-5p and Upregulating ZBTB18

Abstract

Background: Hepatocellular carcinoma (HCC) is the leading cause of tumor-related death worldwide due to high morbidity and mortality, yet still lacking biomarkers and therapies. Circular RNAs (circRNAs) are a group of non-coding RNAs that regulate gene expression through interacting with miRNAs, implicating in the tumorigenesis and progression. A novel circRNA, circTP63, was reported to be an oncogene in HCC. However, its role in HCC remains unclear.Methods: qRT-PCR was used to assess the mRNA levels of CircTP63 in 90 pairs of tumor and adjacent normal tissues from HCC patients, one human normal hepatic epithelial cell line and HCC cell lines. CCK-8, colony formation, transwell, and flow cytometry assays were performed to detect the cellular function of circTP63/miR-155-5p/ZBTB18 in HCC cells. Bioinformatic analysis, RNA pull-down and luciferase assays were used to determine the interaction among circTP63/miR-155-5p/ZBTB18. Results: circTP63 was significantly upregulated in HCC tissues and cell lines. High circTP63 expression is closely associated with the tumor stages, lymph node metastasis, and poor prognosis of HCC patients. Functionally, knockdown of circTP63 inhibited cell proliferation, migration, invasion, and promoted cell apoptosis of HCC. Meanwhile, overexpression of circTP63 enhanced HCC progression. Mechanically, circTP63 was a sponge of miR-155-5p to facilitate the ZBTB18 expression, and the ZBTB18 expression in HCC tissues was negatively associated with the survival rate of HCC patients. Furthermore, the reduced tumor-promoting effect on HCC cells induced by knockdown of circTP63 can be reversed by miR-155-5p inhibitor or ZBTB18 overexpression. Conclusion: Our data highlight a critical circTP63-miR-155-5p-ZBTB18 regulatory network involved in the HCC progression, gaining mechanistic insights into the function of CircRNAs in HCC progression, and providing effective biomarkers and therapeutic targets for HCC treatment.

A peptide translated from circPPP1R12A promotes the malignancy of non‐small cell lung cancer cells through AKT signaling pathway

“…CircPPP1R12A expression in A549 and H1299 cells was upregulated after Lv‐circPPP1R12A transfection (Figure 1C). Circular RNAs play a crucial part in the malignant phenotype of cancer cells, such as proliferation, invasion and migration 21–24 . For example, hsa_circ_0020095 enhances colon cancer proliferation, invasion and migration 24 .…”

“…Circular RNAs play a crucial part in the malignant phenotype of cancer cells, such as proliferation, invasion and migration. [21][22][23][24] For example, hsa_circ_0020095 enhances colon cancer proliferation, invasion and migration. 24 Hsa_circ_0022160 accelerates esophageal squamous cell proliferation, migration and invasion.…”

The function and regulation network mechanism of circRNA in liver diseases

“…It is showed that circRNA is closely associated with the recurrence-free survival (RFS) and OS of HCC by univariate and multivariate Cox regression analysis, dysregulated circRNA might be used as a prognostic factor for the selection of rational treatment regimens for HCC, due to circRNA shows stable conserved and high specificity in different tissues even the stages of disease [129]. For instance, hsa_ circ_0128298 [130], circLARP4 [131], circTP63 [132], circBIRC6 [133], hsa_circ_104348 [134] and circZNF566 [135], etc., were overexpressed in HCC tissues and cell lines. Kaplan-Meier survival analysis showed that HCC patients with circRNA high expression and had shorter overall survival than those with low expression.…”

“…In addition, hsa_circ_0128298 [130], circLARP4 [131] and circBIRC6 [133] were testified to be the independent prognostic factors of OS by multivariate Cox regression analysis. Moreover, studies have found that high expression of hsa_circ_0128298 was associated with vascular cancer embolus, LNM and organ metastasis; overexpression of circTP63 [132] was related to TNM stage, tumor differentiation, and LNM; circLARP4 [131] and circ-ZNF566 [135] were associated with clinicopathological features, including tumor differentiation, tumor size and TNM stage, etc., circ-BIRC6 [133] was associated with TNM stage and MVI in HCC tissues; hsa_circ_104348 [134] expression level was related to tumor size, LNM as well as TNM. Besides, univariate and multivariate Cox regression analysis showed circZKSCAN1 was an independent prognostic factor of OS and RFS by binding FMRP, and the combination of circZKSCAN1 and CCAR1 could improve the prognostic value of HCC [136].…”