Ductular reaction promotes intrahepatic angiogenesis through Slit2–Roundabout 1 signaling

Coll, Mar; Ariño, Sílvia; Martínez-Sánchez, Celia; García-Pras, Ester; Gallego, Javier González; Moles, Anna; Aguilar-Bravo, Beatriz; Blaya, Delia; Vallverdú, Julia; Rubio-Tomás, Teresa; Lozano, Juan José; Pose, Elisa; Graupera, Isabel; Fernández-Vidal, Andrea; Pol, Albert; Bataller, Ramón; Geng, Jason; Ginès, Pere; Fernández, Mercedes; Sancho‐Bru, Pau

doi:10.1002/hep.32140

Cited by 26 publications

(24 citation statements)

References 37 publications

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“…Several studies have shown that ROBO1 has important functions in angiogenesis. The activation of ROBO1 in vascular endothelial cells promoted angiogenesis ( 29 ). Furthermore, in human renal glomerular endothelial cells, the activation of SLIT2/ROBO1 signaling may contribute to angiogenesis through the PI3K/Akt/VEGF pathway ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

ROBO1 p.E280* Loses the Inhibitory Effects on the Proliferation and Angiogenesis of Wild-Type ROBO1 in Cholangiocarcinoma by Interrupting SLIT2 Signal

et al. 2022

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BackgroundCholangiocarcinoma (CCA) remains one of the most lethal malignancies with an increasing incidence globally. Through whole-exome sequencing of 67 CCA tissues, we identified new mutated genes in CCA, including MACF1, METTL14, ROBO1, and so on. The study was designed to explore the effects and mechanism of ROBO1 wild type (ROBO1WT) and ROBO1E280* mutation on the progression of CCA.MethodsWhole-exome sequencing was performed to identify novel mutations in CCAs. In vitro and in vivo experiments were used to examine the function and mechanism of ROBO1WT and ROBO1E280* in cholangiocarcinoma. A tissue microarray including 190 CCA patients and subsequent analyses were performed to indicate the clinical significance of ROBO1.ResultsThrough whole-exome sequencing, we identified a novel CCA-related mutation, ROBO1E280*. ROBO1 was downregulated in CCA tissues, and the downregulation of ROBO1 was significantly correlated with poor prognosis. ROBO1WT suppressed the proliferation and angiogenesis of CCA in vitro and in vivo, while ROBO1E280* lost the inhibitory effects. Mechanically, ROBO1E280* translocated from the cytomembrane to the cytoplasm and interrupted the interaction between SLIT2 and ROBO1. We identified OLFML3 as a potential target of ROBO1 by conducting RNA-Seq assays. OLFML3 expression was downregulated by ROBO1WT and recovered by ROBO1E280*. Functionally, the silence of OLFML3 inhibited CCA proliferation and angiogenesis and was sufficient to repress the loss-of-function role of ROBO1E280*.ConclusionsThese results suggest that ROBO1 may act as a tumor suppressor and potential prognostic marker for CCA. ROBO1E280* mutation is a loss-of-function mutation, and it might serve as a candidate therapeutic target for CCA patients.

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Section: Discussionmentioning

confidence: 99%

ROBO1 p.E280* Loses the Inhibitory Effects on the Proliferation and Angiogenesis of Wild-Type ROBO1 in Cholangiocarcinoma by Interrupting SLIT2 Signal

et al. 2022

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“…1 C). The atypical cells exhibited severe dysplasia, with an increased nuclear-cytoplasmic ratio and enlarged nuclei with hyperploidization 16 , 17 accompanied by fat deposition, ductular reaction 18 and fibrosis in zone 3 (the centrilobular region), as evaluated using Masson’s trichrome staining (blue staining, Fig. 1 C).…”

Section: Resultsmentioning

confidence: 99%

A maternal high-fat diet induces fetal origins of NASH-HCC in mice

Takiyama

Sera

Nakamura

et al. 2022

Sci Rep

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Maternal overnutrition affects offspring susceptibility to nonalcoholic steatohepatitis (NASH). Male offspring from high-fat diet (HFD)-fed dams developed a severe form of NASH, leading to highly vascular tumor formation. The cancer/testis antigen HORMA domain containing protein 1 (HORMAD1), one of 146 upregulated differentially expressed genes in fetal livers from HFD-fed dams, was overexpressed with hypoxia-inducible factor 1 alpha (HIF-1alpha) in hepatoblasts and in NASH-based hepatocellular carcinoma (HCC) in offspring from HFD-fed dams at 15 weeks old. Hypoxia substantially increased Hormad1 expression in primary mouse hepatocytes. Despite the presence of three putative hypoxia response elements within the mouse Hormad1 gene, the Hif-1alpha siRNA only slightly decreased hypoxia-induced Hormad1 mRNA expression. In contrast, N-acetylcysteine, but not rotenone, inhibited hypoxia-induced Hormad1 expression, indicating its dependency on nonmitochondrial reactive oxygen species production. Synchrotron-based phase-contrast micro-CT of the fetuses from HFD-fed dams showed significant enlargement of the liver accompanied by a consistent size of the umbilical vein, which may cause hypoxia in the fetal liver. Based on these findings, a maternal HFD induces fetal origins of NASH/HCC via hypoxia, and HORMAD1 is a potential therapeutic target for NASH/HCC.

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“…Slit2, known as a profibrotic and proangiogenic factor in the liver (29)(30)(31)(32) Animals, all males, were housed in a temperaturecontrolled, specific pathogen-free environment, on a 12-hour light-dark cycle, with free access to chow and water. Abcb4 -/mice and their wildtype Abcb4 +/+ littermates were bred, using Abcb4 +/heterozygous mice on an FVB/N genetic background (FVB.129P2-Abcb4tm1Bor/J) provided by Sanofi R&D (Chilly-Mazarin, France).…”

Section: Discussionmentioning

confidence: 99%

“…Slit2, known as a profibrotic and proangiogenic factor in the liver (29)(30)(31)(32), is a prototypical gene of PMSC/PMSC-MF signature. From the present data, we may postulate that following liver injury, SLIT2, produced by proliferating PMSCs/PMSC-MFs, promotes the formation of new vessels and the survival of HSC-MFs.…”

Section: Discussionmentioning

confidence: 99%

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Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis

et al. 2022

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Ductular reaction promotes intrahepatic angiogenesis through Slit2–Roundabout 1 signaling

Cited by 26 publications

References 37 publications

ROBO1 p.E280* Loses the Inhibitory Effects on the Proliferation and Angiogenesis of Wild-Type ROBO1 in Cholangiocarcinoma by Interrupting SLIT2 Signal

ROBO1 p.E280* Loses the Inhibitory Effects on the Proliferation and Angiogenesis of Wild-Type ROBO1 in Cholangiocarcinoma by Interrupting SLIT2 Signal

A maternal high-fat diet induces fetal origins of NASH-HCC in mice

Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis

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