Abstract
BackgroundHepatocellular 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.MethodsqRT-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.ResultscircTP63 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.ConclusionOur 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.
Highlights
Hepatocellular carcinoma (HCC) is the leading cause of tumor-related death worldwide due to high morbidity and mortality, yet lacking effective biomarkers and therapies
CircTP63 is upregulated in HCC and correlated with poor prognosis To explore the clinical implication of circTP63 in HCC, total RNA was collected from 90 pairs of HCC patient tumor tissues and matched adjacent normal tissue for qRT-PCR assay
Further statistical analyses of clinicopathological features of HCC patients showed that upregulation of circTP63 was positively correlated to tumor-node-metastasis (TNM) stage, tumor differentiation, and lymph node metastasis (P < 0.05, Table 1), but there was no significant relationship between circTP63 expression and age or gender of patients
Summary
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 noncoding 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. Hepatocellular carcinoma (HCC) is the most common cause of cancer-related death worldwide in terms of high morbidity and mortality [1,2,3]. Circular RNAs (circRNAs) are a novel class of noncoding RNAs, characterized by a covalently closed loop structure without any 5′ to 3′ polarity or a polyadenylated. A novel circRNA, circTP63, was recently reported to be an oncogene in lung squamous cell carcinoma [13]. Its role in other cancer types including HCC is unknown
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