Molecular Cancer Fan Zusen/Tian Yong and others discover new potential therapeutic targets for hepatocellular carcinoma

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Due to its high recurrence rate and heterogeneity of iNature, hepatocellular carcinoma (HCC) is one of the most difficult to treat tumors in the world
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Hepatocarcinoma initiating cells, also known as cancer stem cells (CSC), play a key role in resistance to typical therapies and high tumor initiation potential
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However, the role of the new circular RNA (circRNA) circIPO11 in maintaining the starting cells of liver cancer is still elusive
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On October 14, 2021, Fan Zusen, Tian Yong and Wang Yanying of the Institute of Biophysics of the Chinese Academy of Sciences published an online publication in Molecular Cancer (IF=27.
40) entitled "Circular RNA circIPO11 drives self-renewal of liver cancer initiating cells via Hedgehog signaling "In the research paper, this study identified highly conserved circRNAs in humans and mice from three primary HCC samples through the circRNA array
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The study found that CircIPO11 is highly expressed in HCC tumor tissues and liver CSC
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CircIPO11 is necessary for liver CSC self-renewal maintenance to initiate HCC development
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In terms of mechanism, circIPO11 recruits TOP1 to the GLI1 promoter to trigger its transcription, thereby activating Hedgehog signaling
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In addition, GLI1 is also highly expressed in HCC tumor tissues and liver CSC, and the expression level of TOP1 is positively correlated with the metastasis, recurrence and survival of HCC patients
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In addition, circIPO11 knockout in mice inhibited the progression of chemically induced liver cancer
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In summary, the results of this study indicate that circIPO11 drives the self-renewal of liver CSCs and promotes the spread of HCC by activating the Hedgehog signaling pathway
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Antisense oligonucleotides (ASO) targeting circIPO11 combine with TOP1 inhibitor camptothecin (CPT) to exert a synergistic anti-tumor effect
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Therefore, circIPO11 and Hedgehog signaling pathway may provide new potential targets for the treatment of HCC patients
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Hepatocellular carcinoma (HCC) is the main type of primary liver cancer and the second leading cause of cancer-related deaths worldwide
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Due to its increasing morbidity and mortality, liver cancer has become an increasingly serious global health care problem
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Effective treatment methods for liver cancer are limited.
Traditional surgical resection, radiotherapy and chemotherapy are prone to disease recurrence, and the prognosis is poor
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New treatment methods come from a better understanding of HCC tumorigenesis
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The two main biological characteristics of HCC are high recurrence rate and heterogeneity
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Studies have shown that a group of stem/progenitor cells called cancer initiating cells or cancer stem cells (CSC) can contribute to tissue hierarchy and lead to heterogeneity
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Unlike bulk tumor cells, these CSCs show the ability to self-renew, differentiate, and form new tumors, leading to resistance to traditional treatments and a high recurrence rate of HCC
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Recently, a large number of cell surface markers have been identified to isolate liver CSCs, such as CD13, CD133, CD90 and EpCAM
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However, the mechanism that maintains the self-renewal of liver CSC is still elusive
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CSC is similar to embryonic or adult tissue stem cells because they rely on the activation of highly conserved stem signaling pathways to maintain their self-renewal and regeneration
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More and more evidence shows that changes in stem signaling pathways, including Hedgehog (Hh), Wnt and Notch signaling pathways, can promote tumor occurrence and progression
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It is worth noting that abnormal activation of these pathways in stem cells may cause uncontrolled cell proliferation and abnormal differentiation, leading to tumorigenesis
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In addition, their reactivation can induce tumor reprogramming, leading to the appearance of the CSC phenotype
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These dry pathways also contribute to the occurrence and recurrence of liver cancer
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Two surface markers, CD13 and CD133, were used to isolate a rare subpopulation from HCC cells, and CD13+CD133+ cells were defined as liver CSC and CD13-CD133- cells as non-CSC
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In addition, several long non-coding RNAs (lncRNA) can regulate the self-renewal of liver CSCs through Wnt and BMP signaling
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Circular RNA (circRNA) is a type of single-stranded covalently closed RNA produced by reverse splicing derived from pre-mRNA (pre-mRNA)
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As a new type of non-coding RNA, some circRNAs are highly conserved among species and have cell-specific and tissue-specific characteristics
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Recent studies have shown that some specific circRNAs accumulated in the brain are conserved from humans to fruit flies
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Because RNaseR is difficult to degrade and lacks polyadenylation (poly A) tails compared to linear RNA, circRNA is rarely detected in next-generation RNA sequencing (RNA-seq) analysis that is usually rich in poly(A) + RNA
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So far, most of the well-characterized circRNAs have been identified and a database has been established
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 The function of circRNA in a wide range of biological processes has been elucidated through a variety of mechanisms
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Emerging research shows that some circRNAs are related to neuropsychiatric diseases, innate immune response, hematopoiesis and cell proliferation
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Interestingly, circ-CDYL, especially up-regulated in the early stage of HCC, can be used as a potential biomarker for early monitoring of liver cancer
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However, whether circRNAs are involved in the regulation of liver CSC self-renewal is largely unknown
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The ability of circRNAs to regulate gene expression makes them potential drug targets
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Targeting circLONP2 through antisense oligonucleotides (ASO) shows excellent therapeutic effects on colorectal cancer
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However, whether circRNAs can be used as drug candidates for liver cancer is still worth exploring
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DNA topoisomerase relaxes supercoiled DNA by introducing transient DNA breaks, and plays an important role in chromatin dynamics, transcription, replication, DNA damage repair, and genome stability
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For example, topoisomerase 1 (TOP1) binds to a DNA substrate to form a TOP1 cleavage complex (TOP1cc), which causes transient DNA nicks to relax supercoiled DNA
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Camptothecin (CPT) and its derivatives inhibit TOP1 by binding at the enzyme-DNA interface to block the reconnection of TOP1cc
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Previous studies have shown that inhibition of topoisomerase can increase the chemosensitivity of HCC cells
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However, how topoisomerases play a role in liver CSC remains unclear
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Here, the study identified a conserved circRNA circIPO11 (derived from the IPO11 gene transcript, circbase symbol hsa_circ_0007915) that is highly expressed in tumor tissues and liver CSC
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CircIPO11 binds to TOP1 to initiate GLI1 transcription and activate Hh signaling to maintain the self-renewal of liver CSC
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In addition, the combined administration of circIPO11's ASO and TOP1 inhibitor CPT has an effective therapeutic effect on HCC tumors
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Reference message: https://molecular-cancer.
biomedcentral.
com/articles/10.
1186/s12943-021-01435-2