Journal Article

Circular RNA circIPO11 drives self-renewal of liver cancer initiating cells via Hedgehog signaling

Wang, Yanying, He, Luyun, Lu, Tiankun, Liu, Nian, Wang, Jianyi, Fan, Zusen, Zhu, Xiaoxiao, Tian, Yong, Zhang, Jiahang, He, Lei, Gu, Yang

2021

Overview

Background Hepatocellular carcinoma (HCC) is one of the most intractable tumors in the world due to its high rate of recurrence and heterogeneity. Liver cancer initiating cells also called cancer stem cells (CSCs) play a critical role in resistance against typical therapy and high tumor-initiating potential. However, the role of the novel circular RNA (circRNA) circIPO11 in the maintenance of liver cancer initiating cells remains elusive. Methods CircRNAs highly conserved in humans and mice were identified from 3 primary HCC samples by circRNA array. The expression and function of circIPO11 were further evaluated by Northern blot, limiting dilution xenograft analysis, chromatin isolation by RNA purification-PCR assay (ChIRP) and HCC patient-derived tumor cells (PDC) models. CircIpo11 knockout (KO) mice were generated by a CRISPR/Cas9 technology. Results CircIPO11 is highly expressed in HCC tumor tissues and liver CSCs. CircIPO11 is required for the self-renewal maintenance of liver CSCs to initiate HCC development. Mechanistically, circIPO11 recruits TOP1 to GLI1 promoter to trigger its transcription, leading to the activation of Hedgehog signaling. Moreover, GLI1 is also highly expressed in HCC tumor tissues and liver CSCs, and TOP1 expression levels positively correlate with the metastasis, recurrence and survival of HCC patients. Additionally, circIPO11 knockout in mice suppresses the progression of chemically induced liver cancer development. Conclusion Our findings reveal that circIPO11 drives the self-renewal of liver CSCs and promotes the propagation of HCC via activating Hedgehog signaling pathway. Antisense oligonucleotides (ASOs) against circIPO11 combined with TOP1 inhibitor camptothecin (CPT) exert synergistic antitumor effect. Therefore, circIPO11 and the Hedgehog signaling pathway may provide new potential targets for the treatment of HCC patients.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animal models / Animals / Antibodies / Antisense oligonucleotides / Antitumor activity / beta Karyopherins - genetics / Biomarkers, Tumor / Biomedical and Life Sciences / Biomedicine / Camptothecin / cancer initiating cell / Cancer Research / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / Cell culture / Cell growth / Cell Line, Tumor / Cell Self Renewal - genetics / Cell self-renewal / Chromatin / circIPO11 / Circular RNA / CRISPR / Development and progression / Disease Models, Animal / Disease Susceptibility / Diseases / Gene Dosage / Gene expression / Gene Expression Regulation, Neoplastic / Hedgehog protein / Hedgehog Proteins - metabolism / Hedgehog signaling / Hepatocellular carcinoma / Hepatocytes / Humans / Immunohistochemistry / Laboratory animals / Liver cancer / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / Metastases / Mice / Mice, Knockout / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Oncology / Patients / Promoter Regions, Genetic / Relapse / Ribonucleic acid / RNA / RNA polymerase / RNA, Circular / Self-renewal / Signal Transduction / Stem cell transplantation / Stem cells / Transcription activation / Transplantation / Tumor cells / Tumors / Xenografts