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One stone, two birds: circACTN4, a nexus for a coordinated activation of Hippo and Wnt/β-catenin pathways in cholangiocarcinoma

  • Corentin Louis
    Affiliations
    Inserm, Univ Rennes 1, UMR_S 1242, COSS (Chemistry, Oncogenesis Stress Signaling), Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
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  • Cédric Coulouarn
    Correspondence
    Corresponding author. Address: Inserm UMR_S 1242, "Chemistry, Oncogenesis, stress, Signaling" (COSS), Centre de Lutte contre le Cancer Eugène Marquis, Rue de la Bataille Flandres Dunkerque, Bat D, F-35042 Rennes, France. Tel.: +33-2-2323-3881
    Affiliations
    Inserm, Univ Rennes 1, UMR_S 1242, COSS (Chemistry, Oncogenesis Stress Signaling), Centre de Lutte contre le Cancer Eugène Marquis, Rennes, France
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Published:October 12, 2021DOI:https://doi.org/10.1016/j.jhep.2021.10.002

      Keywords

      See Article, pages 135–147
      Cholangiocarcinomas (CCAs) are a group of tumors arising along the hepatobiliary tree. CCA is a rare cancer, but its incidence has been increasing over the last decade. CCA is associated with a poor prognosis and limited effective therapeutic options.
      • Banales J.M.
      • Marin J.J.G.
      • Lamarca A.
      • Rodrigues P.M.
      • Khan S.A.
      • Roberts L.R.
      • et al.
      Cholangiocarcinoma 2020: the next horizon in mechanisms and management.
      Innovative strategies are therefore urgently needed to identify novel therapeutic targets and clinically relevant biomarkers to ultimately improve the survival of patients with CCA.
      • Banales J.M.
      • Marin J.J.G.
      • Lamarca A.
      • Rodrigues P.M.
      • Khan S.A.
      • Roberts L.R.
      • et al.
      Cholangiocarcinoma 2020: the next horizon in mechanisms and management.
      Circular RNAs (circRNAs) are splicing products that form a continuous loop by joining the 3’ extremity of a downstream exon with the 5’ extremity of an upstream exon. Although circRNAs are mainly outlined for their ability to sponge microRNAs (miRNAs) and RNA binding proteins (RBPs), their modes of action remain largely unknown.
      • Kristensen L.S.
      • Andersen M.S.
      • Stagsted L.V.W.
      • Ebbesen K.K.
      • Hansen T.B.
      • Kjems J.
      The biogenesis, biology and characterization of circular RNAs.
      Recently, circRNAs have emerged as new regulatory molecules that contribute to human carcinogenesis and hold promise as biomarkers.
      • Kristensen L.S.
      • Andersen M.S.
      • Stagsted L.V.W.
      • Ebbesen K.K.
      • Hansen T.B.
      • Kjems J.
      The biogenesis, biology and characterization of circular RNAs.
      However, very few studies have reported on the role of deregulated circRNAs in CCA so far.
      • Li D.
      • Tang Z.
      • Gao Z.
      • Shen P.
      • Liu Z.
      • Dang X.
      Circular RNA CDR1as exerts oncogenic properties partially through regulating MicroRNA 641 in cholangiocarcinoma.
      • Merdrignac A.
      • Angenard G.
      • Allain C.
      • Petitjean K.
      • Bergeat D.
      • Bellaud P.
      • et al.
      A novel transforming growth factor beta-induced long noncoding RNA promotes an inflammatory microenvironment in human intrahepatic cholangiocarcinoma.
      • Merdrignac A.
      • Papoutsoglou P.
      • Coulouarn C.
      Long noncoding RNAs in cholangiocarcinoma.
      • Xu Y.
      • Gao P.
      • Wang Z.
      • Su Z.
      • Liao G.
      • Han Y.
      • et al.
      Circ-LAMP1 contributes to the growth and metastasis of cholangiocarcinoma via miR-556-5p and miR-567 mediated YY1 activation.
      • Xu Y.
      • Leng K.
      • Yao Y.
      • Kang P.
      • Liao G.
      • Han Y.
      • et al.
      A circular RNA, cholangiocarcinoma-associated circular RNA 1, contributes to cholangiocarcinoma progression, induces angiogenesis, and disrupts vascular endothelial barriers.
      Notably, an increased expression of circ-CCAC1 has been identified by circRNA expression profiling in tumor tissues and bile-resident extracellular vesicles (EVs) from patients with CCA.
      • Xu Y.
      • Leng K.
      • Yao Y.
      • Kang P.
      • Liao G.
      • Han Y.
      • et al.
      A circular RNA, cholangiocarcinoma-associated circular RNA 1, contributes to cholangiocarcinoma progression, induces angiogenesis, and disrupts vascular endothelial barriers.
      CCA-delivered exosomal circ-CCAC1 was reported to be transferred to endothelial cells to disrupt endothelial barriers and induce angiogenesis.
      • Xu Y.
      • Leng K.
      • Yao Y.
      • Kang P.
      • Liao G.
      • Han Y.
      • et al.
      A circular RNA, cholangiocarcinoma-associated circular RNA 1, contributes to cholangiocarcinoma progression, induces angiogenesis, and disrupts vascular endothelial barriers.
      Mechanistically, circ-CCAC1 increased cell permeability by sequestering enhancer of zeste homolog 2 (EZH2) in the cytoplasm, thereby increasing SH3GL2 expression to suppress intercellular junction proteins.
      • Xu Y.
      • Leng K.
      • Yao Y.
      • Kang P.
      • Liao G.
      • Han Y.
      • et al.
      A circular RNA, cholangiocarcinoma-associated circular RNA 1, contributes to cholangiocarcinoma progression, induces angiogenesis, and disrupts vascular endothelial barriers.
      Besides this well-designed functional study, most of the published reports highlighting circRNAs in CCA solely focused on the clinical relevance of their expression. Thus, a comprehensive analysis of their functional role in the gene regulatory networks contributing to CCA onset and progression has barely been addressed. In addition, 80-90% of reports focused on the sponging capacity of circRNAs as a mechanism of action. We would like to point out that circRNAs are more than simple sponges for miRNAs. Indeed, emerging data from the literature demonstrate that circRNAs take an active role in complex transcriptional and post-transcriptional regulatory systems.
      In this issue of Journal of Hepatology, Chen and colleagues illustrate this concept by investigating the function and the clinical relevance of circular RNA ACTN4 (circACTN4) in intrahepatic CCA (iCCA). They demonstrate that circACTN4 is induced in iCCA and promotes proliferation and invasion of tumor cells in vitro and in vivo. Importantly, the study implies circACTN4 as a signaling nexus that enables the coordinated activation of Hippo and Wnt/β-catenin pathways, notably by acting on different targets in the cytoplasm and the nucleus (Fig. 1). Indeed, circACTN4 is reported i) in the cytoplasm, to sponge miR-424-5p, which could target the oncogenic transcriptional coactivator Yes-associated protein 1 (YAP1) from the Hippo pathway and ii) in the nucleus, to recruit the Y-box binding protein 1 (YBX1) transcription factor to initiate the transcription of Frizzled-7 (FZD7), a positive regulator of the Wnt/β-catenin signaling pathway.
      • Chen Q.
      • Wang H.
      • Li Z.
      • Li F.
      • Liang L.
      • Zou Y.
      • et al.
      Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription.
      CircACTN4 is also shown to favor the interaction between YAP1 and β-catenin and their nuclear accumulation, which ultimately leads to CCA cell growth and metastasis (Fig. 1). Thus, this study demonstrates how circRNAs can act as sponges for miRNAs and as scaffolds to locate transcription factors to the nucleus. The data suggest that the specific location of circRNAs within the cells could play a significant role in controlling gene expression. Overall, the study by Chen and colleagues unraveled circRNAs as intracellular nodes acting simultaneously in the cytoplasm and in the nucleus through specific regulatory processes. However, this study raises unanswered questions. Notably, the dynamic regulation of circRNAs shuttling between the nucleus and the cytoplasm, in relationship to their mode of action, is an important feature which remains to be elucidated. In addition, whether or not circACTN4 acts as a scaffold by interacting with DNA and/or other co-factors to recruit YBP1 to the promoter of FZD7 remains to be determined.
      Figure thumbnail gr1
      Fig. 1Squaring the circle: emerging roles of circRNAs in CCA.
      In this issue of Journal of Hepatology, Chen and colleagues report the role and the clinical relevance of circACTN4 in CCA.
      • Chen Q.
      • Wang H.
      • Li Z.
      • Li F.
      • Liang L.
      • Zou Y.
      • et al.
      Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription.
      The study demonstrates that circACTN4 is induced in CCA and exhibits specific but complementary functions depending on its subcellular localization. Thus, in the cytoplasm circACTN4 acts as a sponge sequestrating miR-424-5p and therefore preventing the degradation of YAP1, from the Hippo pathway. In the nucleus, circACTN4 recruits YBX1 to initiate FZD7 transcription and contributes to activate the Wnt/β-catenin pathway. Altogether, the coordinated activation of Wnt/β-catenin and Hippo signaling pathways by circACTN4 contributes to CCA cell growth and metastasis.
      The mechanisms regulating the spatial localization of circRNAs are poorly understood, although this parameter is probably of special importance in determining their activity. The reason why intron-containing circRNAs are restricted to the nucleus (to act as transcriptional regulators) while exonic circRNAs are enriched in the cytoplasm (to operate as post-transcriptional regulators by sponging miRNAs and/or RBPs) is unclear.
      • Chen L.L.
      The expanding regulatory mechanisms and cellular functions of circular RNAs.
      Several reports explored possible mechanisms whereby circRNAs could shuttle from the nucleus to the cytoplasm. One of them described an evolutionarily conserved pathway that controls the nuclear export of circRNAs depending on the length of the transcripts. Hence, long (>800 nt) or short circRNAs could be translocated to the cytoplasm with the assistance of UAP56 or URH49, respectively.
      • Huang C.
      • Liang D.
      • Tatomer D.C.
      • Wilusz J.E.
      A length-dependent evolutionarily conserved pathway controls nuclear export of circular RNAs.
      Wang and colleagues described a nuclear export process specific for a circular repeat containing intron. They identified a NXF1:NXT1-related active process regulating the level of intronic circRNAs in the cytoplasm.
      • Wang S.
      • Latallo M.J.
      • Zhang Z.
      • Huang B.
      • Bobrovnikov D.G.
      • Dong D.
      • et al.
      Nuclear export and translation of circular repeat-containing intronic RNA in C9ORF72-ALS/FTD.
      Another study pinpointed N6-methyladenosine (m6A) epitranscriptomic modifications favoring the export of circNSUN2 to the cytoplasm.
      • Chen R.X.
      • Chen X.
      • Xia L.P.
      • Zhang J.X.
      • Pan Z.Z.
      • Ma X.D.
      • et al.
      N(6)-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis.
      These studies highlight the importance of better characterizing the mechanisms regulating circRNA spatial localization to better understand the underlying molecular mechanisms involved in CCA progression. In the future, the modulation of such transport mechanisms could be considered as an option to modulate circRNA availability and activity.
      When it comes to circRNAs, most studies describe a cytoplasmic circRNA sequestrating a couple of miRNAs, which are therefore not available to inhibit their predicted target genes. However, it is becoming obvious from emerging functional studies that investigating the molecular mode of action of circRNAs should not be considered through a unique axis. Indeed, several reports, including the one from Chen and colleagues in this issue of Journal of Hepatology,
      • Chen Q.
      • Wang H.
      • Li Z.
      • Li F.
      • Liang L.
      • Zou Y.
      • et al.
      Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription.
      established that circRNAs could operate in a multi-layered coordinated fashion, by acting at different levels on several gene regulatory networks. The ability of a single circRNA to concomitantly sponge miRNAs in the cytoplasm and to recruit RBPs in the nucleus to mediate RNA Pol II transcription has been also reported in gastric cancer.
      • Fang J.
      • Hong H.
      • Xue X.
      • Zhu X.
      • Jiang L.
      • Qin M.
      • et al.
      A novel circular RNA, circFAT1(e2), inhibits gastric cancer progression by targeting miR-548g in the cytoplasm and interacting with YBX1 in the nucleus.
      Hence, circFAT1 exerts tumor suppressive actions by regulating the miR-548g/RUNX1 axis in the cytoplasm and by targeting YBX1 in the nucleus to inhibit its activity.
      • Fang J.
      • Hong H.
      • Xue X.
      • Zhu X.
      • Jiang L.
      • Qin M.
      • et al.
      A novel circular RNA, circFAT1(e2), inhibits gastric cancer progression by targeting miR-548g in the cytoplasm and interacting with YBX1 in the nucleus.
      However, the process regulating circFAT1 spatial localization is unknown.
      • Fang J.
      • Hong H.
      • Xue X.
      • Zhu X.
      • Jiang L.
      • Qin M.
      • et al.
      A novel circular RNA, circFAT1(e2), inhibits gastric cancer progression by targeting miR-548g in the cytoplasm and interacting with YBX1 in the nucleus.
      Factors regulating RNA circularization, such as QKI5 RBP, could also act at a post-transcriptional level to competitively regulate the level of canonical and back-splicing. That competition could be explained by a shared spliceosome machinery for intron and exon definition and back-splicing.
      • Conn S.J.
      • Pillman K.A.
      • Toubia J.
      • Conn V.M.
      • Salmanidis M.
      • Phillips C.A.
      • et al.
      The RNA binding protein quaking regulates formation of circRNAs.
      ,
      • Li X.
      • Liu S.
      • Zhang L.
      • Issaian A.
      • Hill R.C.
      • Espinosa S.
      • et al.
      A unified mechanism for intron and exon definition and back-splicing.
      Although initially viewed as non-coding RNAs, growing evidence indicates that circRNAs could also be translated, notably by cap-independent mechanisms that rely on the internal ribosome entry site and m6A modifications.
      • Di Timoteo G.
      • Dattilo D.
      • Centron-Broco A.
      • Colantoni A.
      • Guarnacci M.
      • Rossi F.
      • et al.
      Modulation of circRNA metabolism by m(6)A modification.
      Characterizing the function of circRNA-derived peptides is still in its infancy, but several reports described a role as protein baits.
      • Zhao H.
      • Zhou Q.
      • Li X.
      Protein bait hypothesis: circRNA-encoded proteins competitively inhibit cognate functional isoforms.
      An original mode of action of circβ-catenin (a circRNA derived from β-catenin) has recently been reported.
      • Liang W.C.
      • Wong C.W.
      • Liang P.P.
      • Shi M.
      • Cao Y.
      • Rao S.T.
      • et al.
      Translation of the circular RNA circbeta-catenin promotes liver cancer cell growth through activation of the Wnt pathway.
      Circβ-catenin differs from its cognate mRNA by a new stop codon generated by the circularization junction. Thus, circβ-catenin is translated into a 370-amino acid β-catenin isoform which acts as a decoy. Indeed, this shorter isoform can stabilize full-length β-catenin by antagonizing GSK3β-induced β-catenin phosphorylation and degradation, leading to Wnt/β-catenin pathway activation and promotion of tumor cell growth.
      • Liang W.C.
      • Wong C.W.
      • Liang P.P.
      • Shi M.
      • Cao Y.
      • Rao S.T.
      • et al.
      Translation of the circular RNA circbeta-catenin promotes liver cancer cell growth through activation of the Wnt pathway.
      In breast cancer, circSMARCA5 was shown to combine several of the functions described above. Indeed, circSMARCA5 binds its parental gene locus forming an R-loop with DNA and regulates concomitantly the splicing machinery and transcriptional pausing, leading to the production of a non-functional truncated SMARCA5 protein.
      • Xu X.
      • Zhang J.
      • Tian Y.
      • Gao Y.
      • Dong X.
      • Chen W.
      • et al.
      CircRNA inhibits DNA damage repair by interacting with host gene.
      Eventually, growing evidence suggests that circRNAs act as important cellular regulators with various modes of action. However, how many functions a single circRNA can fulfill needs to be determined. This is a fundamental point to address before thinking of the clinical translation of circRNAs as therapeutic targets, as suggested by Chen and colleagues for circACTN4.
      Chen and colleagues reported in this issue of Journal of Hepatology that increased expression of circACTN4 in iCCA tissues was associated with worse survival.
      • Chen Q.
      • Wang H.
      • Li Z.
      • Li F.
      • Liang L.
      • Zou Y.
      • et al.
      Circular RNA ACTN4 promotes intrahepatic cholangiocarcinoma progression by recruiting YBX1 to initiate FZD7 transcription.
      Although, the prognostic potential of numerous circRNAs has already been described, none have been validated for clinical use. Nonetheless, circRNAs have attracted substantial interest owing to their presence in body fluids (e.g. serum, plasma, saliva), circulating either freely or encapsulated in EVs, particularly in exosomes (100-200 nm EVs).
      • Li Y.
      • Zheng Q.
      • Bao C.
      • Li S.
      • Guo W.
      • Zhao J.
      • et al.
      Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis.
      Moreover, circRNAs display an expanded half-life compared to linear RNAs, suggesting they could challenge the sensitivity and specificity of standard biomarkers. Thus, measuring the level of circulating circRNAs in liquid biopsies represents an appealing alternative to tissue biopsies.
      • Li Y.
      • Zheng Q.
      • Bao C.
      • Li S.
      • Guo W.
      • Zhao J.
      • et al.
      Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis.
      Taken collectively, the study by Chen and colleagues provides an elegant example of how circRNAs could contribute to a coordinated activation of signaling pathways involved in CCA progression. Along with other pioneering studies in the field, it highlights the promising potential of circRNAs as therapeutic targets and clinically relevant biomarkers. Nevertheless, the field is still in its infancy, with many unanswered questions, notably regarding the exact functions and modes of action of circRNAs in the gene regulatory network, and how they contribute to tumor progression. Integrating coding and non-coding RNA profiles could lead to a comprehensive picture of circRNA/miRNA/mRNA networks and to a better understanding of the underlying molecular mechanisms involved in CCA tumorigenesis.

      Financial support

      CC is supported by Inserm , Université de Rennes 1 , Ligue Contre le Cancer (CD22, CD35, CD85), INCa , and ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé) dans le cadre du Plan cancer (Non-coding RNA in cancerology: fundamental to translational) and Fondation ARC pour la recherche sur le cancer . CL is supported by a PhD fellowship from Université de Rennes 1 and Fondation ARC pour la recherche sur le cancer .

      Authors' contributions

      All authors contributed equally to the intellectual content of the manuscript. All authors wrote the initial draft and contributed significantly to the final version.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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