Wang Jiantao, Che Jinbiao
Department of Hepatobiliary Surgery, Yantaishan Hospital, Jiefang Road, Zhifu District, Yantai, 264000, Shandong Province, China.
Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, Shandong Province, China.
Cancer Cell Int. 2021 Mar 8;21(1):156. doi: 10.1186/s12935-021-01753-x.
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.
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.
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.
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.
肝细胞癌（HCC）由于高发病率和死亡率，是全球肿瘤相关死亡的主要原因，但缺乏有效的生物标志物和治疗方法。环状RNA（circRNAs）是一类非编码RNA，通过与微小RNA（miRNAs）相互作用来调节基因表达，参与肿瘤的发生和发展。一种新的环状RNA，circTP63，据报道在肝癌中是一种致癌基因。然而，其在肝癌中的作用仍不清楚。
采用qRT-PCR检测90对肝癌患者肿瘤组织和癌旁正常组织、1种人正常肝上皮细胞系和肝癌细胞系中CircTP63的mRNA水平。进行CCK-8、集落形成、Transwell和流式细胞术检测，以检测circTP63/miR-155-5p/ZBTB18在肝癌细胞中的细胞功能。建立肝癌异种移植小鼠模型，评估circTP63的体内作用。采用生物信息学分析、RNA下拉和荧光素酶检测来确定circTP63/miR-155-5p/ZBTB18之间的相互作用。
circTP63在肝癌组织和细胞系中显著上调。circTP63高表达与肝癌患者的肿瘤分期、淋巴结转移及预后不良密切相关。在功能上，敲低circTP63可抑制肝癌细胞的增殖、迁移、侵袭，并促进细胞凋亡。同时，circTP63的过表达促进了肝癌的进展。机制上，circTP63是miR-155-5p的海绵，促进ZBTB18的表达，肝癌组织中ZBTB18的表达与肝癌患者的生存率呈负相关。此外，挽救实验表明，敲低circTP63对肝癌细胞的促肿瘤作用降低可被miR-155-5p抑制剂或ZBTB18过表达逆转。
我们的数据突出了一个关键的circTP63-miR-155-5p-ZBTB18调控网络参与肝癌进展，为环状RNA在肝癌进展中的功能提供了机制性见解，并为肝癌治疗提供了有效的生物标志物和治疗靶点。
