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 lacking effective 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. HCC xenograft mice models were established to assess the in vivo effect of circTP63. 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, rescued assays revealed that 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.

CircTP63 promotes cell proliferation and invasion by regulating EZH2 via sponging miR-217 in gallbladder cancer

“…Another study shows that circular RNA circTP63 enhances estrogen receptor-positive breast cancer progression and malignant behaviors through the miR-873-3p/FOXM1 axis [ 13 ]. In hepatocellular carcinoma (HCC), circTP63 is significantly upregulated in HCC tissues and cell lines, and circTP63 overexpression promotes tumor progression by sponging miR-155-5p and upregulating ZBTB18 expression [ 14 ]. However, its role in GBC progression remains unknown.…”

CircANTXR1 Contributes to the Malignant Progression of Hepatocellular Carcinoma by Promoting Proliferation and Metastasis

“…In HCC-related studies, circTP63 was found to be upregulated in HCC, and was considered to be a tumor promoter to accelerate HCC proliferation and metastasis via the miR-155-5p/ZBTB18 network. 21 On the contrary, Ma et al reported that circ_0014717 was downregulated in HCC, which could suppress HCC growth and metastasis by reducing BTG2 through sponging miR-668-3p. 22 Here, we screened a new circRNA, circANTXR1.…”

CircUCK2 promotes hepatocellular carcinoma development by upregulating UCK2 in a mir-149-5p-dependent manner

“…CircEPB41L2 exerted a carcinogenic role in HCC through interacting directly with miR-590-5p [ 22 ]. CircTP63 was conspicuously enhanced in HCC tissues and cells and accelerated HCC progression via miR-155-5p/ZBTB18 regulatory network [ 23 ]. The analysis of GSE94508 dataset showed circUCK2, a splicing form of UCK2, is highly expressed in HCC tissues.…”