<i>Hes1</i> Is Essential in Proliferating Ductal Cell–Mediated Development of Intrahepatic Cholangiocarcinoma

Matsumori, Tomoaki; Kodama, Yuzo; Takai, Atsushi; Shiokawa, Masahiro; Nishikawa, Yoshihiro; Matsumoto, Tomonori; Takeda, Haruhiko; Marui, Saiko; Okada, Hirokazu; Hirano, Toshio; Kuwada, Takeshi; Sogabe, Yuko; Kakiuchi, Nobuyuki; Tomono, Teruko; Mima, Atsushi; Morita, Toshihiro; Ueda, Toshihisa; Tsuda, Motoyuki; Yamauchi, Yuki; Kuriyama, Katsutoshi; Sakuma, Yojiro; Ota, Yuji; Maruno, Takahisa; Uza, Norimitsu; Marusawa, Hiroyuki; Kageyama, Ryoichiro; Chiba, Tsutomu; Seno, Hiroshi

doi:10.1158/0008-5472.can-20-1161

Cited by 13 publications

(9 citation statements)

References 51 publications

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“…Notch overactivation can result in liver epithelial cell dysplasia and malignant transformation. Indeed, Notch and Hes1 have been implicated in the development of cholangiocarcinoma, and inhibition of the signaling is a potential therapeutic target for the disease 19–21 . This study confirmed that cholangiocarcinoma developing in CD also exhibited nuclear overexpression of Notch1 and Hes1 in the cells.…”

Section: Discussionsupporting

confidence: 75%

Notch‐Hes1 signaling activation in Caroli disease and polycystic liver disease

Takahashi

Sato

Yamamura

et al. 2021

Pathology International

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The Notch signaling pathway plays a key role in the morphogenesis of the biliary tree, but its involvement in cystic biliary diseases, such as Caroli disease (CD) and polycystic liver disease (PLD), has yet to be determined. Immunostaining was performed using liver sections of CD and PLD, and the results were compared with those of congenital hepatic fibrosis (CHF) and von Meyenburg complex (VMC). The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC. In addition, Notch2 and Notch3 were preferably expressed in the nuclei of biliary epithelial cells of PLD. Accordingly, the Notch effector Hes1 was highly expressed in biliary epithelial cells of CD and PLD, and the cell proliferative activity was significantly higher in CD and PLD. The expression of the Notch ligand Delta‐like 1 was significantly increased in biliary epithelial cells of CD and PLD, which may be causally associated with the nuclear overexpression of Notch1 and Hes1. These results indicate that aberrant activation of the Notch‐Hes1 signaling pathway may be responsible for the progression of biliary cystogenesis in CD and PLD.

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Section: Discussionsupporting

confidence: 75%

Notch‐Hes1 signaling activation in Caroli disease and polycystic liver disease

Takahashi

Sato

Yamamura

et al. 2021

Pathology International

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“…We then assessed the drug sensitivity scores (DSSs) for the two ICC subtypes using the above 13‐gene and 16‐ gene ZMIZ1 and YBX1 regulon, respectively, using oncoPredict ( Supporting Methods ). [ 18 ] The results showed that Vinblastine, AZD8055, Docetaxel, and BMS.754807 showed high cytotoxicity (lower DSSs) in the stress‐responding subtype (fold change < 0.25). BI.2536, Gemcitabine, Teniposide, and Mitoxantrone showed high cytotoxicity in the proliferating subtype (fold change < 0.25; Table S9 ).…”

Section: Resultsmentioning

confidence: 99%

“…[ 31 ] Seno et al reported that Hes1 plays a critical role in the induction of ICC. [ 18 ] CFL1 maintains PL‐D1 expression by repressing ubiquitin‐mediated protein degradation, thereby activating AKT signaling in HCC cells. [ 32 ] The expression levels of these three genes were positively correlated with ICC progression as observed from mouse and human single‐cell data.…”

Section: Discussionmentioning

confidence: 99%

Cellular heterogeneity and transcriptomic profiles during intrahepatic cholangiocarcinoma initiation and progression

Wang

Zhang

et al. 2022

Hepatology

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Background and Aims Intrahepatic cholangiocarcinoma (ICC) is not fully investigated, and how stromal cells contribute to ICC formation is poorly understood. We aimed to uncover ICC origin, cellular heterogeneity, and critical modulators during ICC initiation/progression, and to decipher how fibroblast and endothelial cells in the stromal compartment favor ICC progression. Approach and Results We performed single‐cell RNA sequencing (scRNA‐seq) using AKT/Notch intracellular domain–induced mouse ICC tissues at early, middle, and late stages. We analyzed the transcriptomic landscape, cellular classification and evolution, and intercellular communication during ICC initiation/progression. We confirmed the findings using quantitative real‐time PCR, western blotting, immunohistochemistry or immunofluorescence, and gene knockout/knockdown analysis. We identified stress‐responding and proliferating subpopulations in late‐stage mouse ICC tissues and validated them using human scRNA‐seq data sets. By integrating weighted correlation network analysis and protein–protein interaction through least absolute shrinkage and selection operator regression, we identified zinc finger, MIZ‐type containing 1 (Zmiz1) and Y box protein 1 (Ybx1) as core transcription factors required by stress‐responding and proliferating ICC cells, respectively. Knockout of either one led to the blockade of ICC initiation/progression. Using two other ICC mouse models (YAP/AKT, KRAS/p19) and human ICC scRNA‐seq data sets, we confirmed the orchestrating roles of Zmiz1 and Ybx1 in ICC occurrence and development. In addition, hes family bHLH transcription factor 1, cofilin 1, and inhibitor of DNA binding 1 were identified as driver genes for ICC. Moreover, periportal liver sinusoidal endothelial cells could differentiate into tip endothelial cells to promote ICC development, and this was Dll4‐Notch4‐Efnb2 signaling–dependent. Conclusions Stress‐responding and ICC proliferating subtypes were identified, and Zmiz1 and Ybx1 were revealed as core transcription factors in these subtypes. Fibroblast–endothelial cell interaction promotes ICC development.

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“…We wondered whether these two KDM6A -occupied repressors, HHEX and HES1 , act differentially in the regulation of genes that are critical to urothelium development. Therefore, we plotted the correlation between HHEX , HES1 expression, and the expression of genes associated with the term ‘regulation of developmental process’ in the normal-immortal cluster ( Figure 1 D) for primary bladder cancer [ 45 , 46 , 47 , 48 ]. This analysis revealed a striking positive and corresponding negative correlation for the expression of developmental transcription factors such as GRHL2 , GRHL3 , ZBTB7B , and TBX6 [ 49 , 50 , 51 ], and the expression of HES1 and HHEX , respectively ( Figure 4 E).…”

Section: Resultsmentioning

confidence: 99%

Differential Occupancy and Regulatory Interactions of KDM6A in Bladder Cell Lines

Özden-Yılmaz

Savaş

Bursalı

et al. 2023

Cells

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Epigenetic deregulation is a critical theme which needs further investigation in bladder cancer research. One of the most highly mutated genes in bladder cancer is KDM6A, which functions as an H3K27 demethylase and is one of the MLL3/4 complexes. To decipher the role of KDM6A in normal versus tumor settings, we identified the genomic landscape of KDM6A in normal, immortalized, and cancerous bladder cells. Our results showed differential KDM6A occupancy in the genes involved in cell differentiation, chromatin organization, and Notch signaling depending on the cell type and the mutation status of KDM6A. Transcription factor motif analysis revealed HES1 to be enriched at KDM6A peaks identified in the T24 bladder cancer cell line; moreover, it has a truncating mutation in KDM6A and lacks a demethylase domain. Our co-immunoprecipitation experiments revealed TLE co-repressors and HES1 as potential truncated and wild-type KDM6A interactors. With the aid of structural modeling, we explored how truncated KDM6A could interact with TLE and HES1, as well as RUNX and HHEX transcription factors. These structures provide a solid means of studying the functions of KDM6A independently of its demethylase activity. Collectively, our work provides important contributions to the understanding of KDM6A malfunction in bladder cancer.

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Hes1 Is Essential in Proliferating Ductal Cell–Mediated Development of Intrahepatic Cholangiocarcinoma

Abstract: Hes1 is essential in proliferating ductal cell-mediated development of intrahepatic cholangiocarcinoma.

Cited by 13 publications

References 51 publications

Notch‐Hes1 signaling activation in Caroli disease and polycystic liver disease

Notch‐Hes1 signaling activation in Caroli disease and polycystic liver disease

Cellular heterogeneity and transcriptomic profiles during intrahepatic cholangiocarcinoma initiation and progression

Differential Occupancy and Regulatory Interactions of KDM6A in Bladder Cell Lines

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