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  • Ovid Technologies (Wolters Kluwer Health)  (4)
  • Sangro, Bruno  (4)
  • 1
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    Dual Targeting of G9a and DNA Methyltransferase‐1 for the Treatment of Experimental Cholangiocarcinoma
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Hepatology Vol. 73, No. 6 ( 2021-06), p. 2380-2396
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    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 73, No. 6 ( 2021-06), p. 2380-2396
    Abstract: Cholangiocarcinoma (CCA) is a devastating disease often detected at advanced stages when surgery cannot be performed. Conventional and targeted systemic therapies perform poorly, and therefore effective drugs are urgently needed. Different epigenetic modifications occur in CCA and contribute to malignancy. Targeting epigenetic mechanisms may thus open therapeutic opportunities. However, modifications such as DNA and histone methylation often coexist and cooperate in carcinogenesis. We tested the therapeutic efficacy and mechanism of action of a class of dual G9a histone‐methyltransferase and DNA‐methyltransferase 1 (DNMT1) inhibitors. Approach and Results Expression of G9a , DNMT1 , and their molecular adaptor, ubiquitin‐like with PHD and RING finger domains‐1 ( UHRF1 ), was determined in human CCA. We evaluated the effect of individual and combined pharmacological inhibition of G9a and DNMT1 on CCA cell growth. Our lead G9a/DNMT1 inhibitor, CM272, was tested in human CCA cells, patient‐derived tumoroids and xenograft, and a mouse model of cholangiocarcinogenesis with hepatocellular deletion of c‐Jun‐N‐terminal‐kinase (Jnk)‐1/2 and diethyl‐nitrosamine (DEN) plus CCl 4 treatment (Jnk Δhepa + DEN + CCl 4 mice). We found an increased and correlative expression of G9a , DNMT1 , and UHRF1 in CCAs. Cotreatment with independent pharmacological inhibitors G9a and DNMT1 synergistically inhibited CCA cell growth. CM272 markedly reduced CCA cell proliferation and synergized with Cisplatin and the ERBB‐targeted inhibitor, Lapatinib. CM272 inhibited CCA tumoroids and xenograft growth and significantly antagonized CCA progression in Jnk Δhepa + DEN + CCl 4 mice without apparent toxicity. Mechanistically, CM272 reprogrammed the tumoral metabolic transcriptome and phenotype toward a differentiated and quiescent status. Conclusions Dual targeting of G9a and DNMT1 with epigenetic small molecule inhibitors such as CM272 is a potential strategy to treat CCA and/or enhance the efficacy of other systemic therapies.
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.31642
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1472120-X
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  • 2
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    Splicing Factor SLU7 Prevents Oxidative Stress‐Mediated Hepatocyte Nuclear Factor 4α Degradation, Preserving Hepatic Differentiation and Protecting From Liver Damage
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Hepatology Vol. 74, No. 5 ( 2021-11), p. 2791-2807
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    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 74, No. 5 ( 2021-11), p. 2791-2807
    Abstract: Hepatocellular dedifferentiation is emerging as an important determinant in liver disease progression. Preservation of mature hepatocyte identity relies on a set of key genes, predominantly the transcription factor hepatocyte nuclear factor 4α (HNF4α) but also splicing factors like SLU7. How these factors interact and become dysregulated and the impact of their impairment in driving liver disease are not fully understood. Approach and Results Expression of SLU7 and that of the adult and oncofetal isoforms of HNF4α , driven by its promoter 1 (P1) and P2, respectively, was studied in diseased human and mouse livers. Hepatic function and damage response were analyzed in wild‐type and Slu7 ‐haploinsufficient/heterozygous ( Slu7+/− ) mice undergoing chronic (CCl 4 ) and acute (acetaminophen) injury. SLU7 expression was restored in CCl 4 ‐injured mice using SLU7‐expressing adeno‐associated viruses (AAV‐SLU7). The hepatocellular SLU7 interactome was characterized by mass spectrometry. Reduced SLU7 expression in human and mouse diseased livers correlated with a switch in HNF4α P1 to P2 usage. This response was reproduced in Slu7+/− mice, which displayed increased sensitivity to chronic and acute liver injury, enhanced oxidative stress, and marked impairment of hepatic functions. AAV‐SLU7 infection prevented liver injury and hepatocellular dedifferentiation. Mechanistically we demonstrate a unique role for SLU7 in the preservation of HNF4α1 protein stability through its capacity to protect the liver against oxidative stress. SLU7 is herein identified as a key component of the stress granule proteome, an essential part of the cell’s antioxidant machinery. Conclusions Our results place SLU7 at the highest level of hepatocellular identity control, identifying SLU7 as a link between stress‐protective mechanisms and liver differentiation. These findings emphasize the importance of the preservation of hepatic functions in the protection from liver injury.
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.32029
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1472120-X
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  • 3
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    Online Resource
    The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Hepatology Vol. 69, No. 4 ( 2019-04), p. 1632-1647
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 69, No. 4 ( 2019-04), p. 1632-1647
    Abstract: Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ’s function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha‐naphthyl‐isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up‐regulated. Importantly, Areg–/– mice showed aggravated liver injury after BDL and ANIT administration compared to Areg+/+ mice. Recombinant AREG protected from ANIT and BDL‐induced liver injury and reduced BA‐triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and, interestingly, cholestyramine feeding reduced postprandial Areg up‐regulation in both tissues. Most interestingly, Areg–/– mice displayed high hepatic cholesterol 7 α‐hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg–/– mice, and recombinant AREG down‐regulated Cyp7a1 mRNA in hepatocytes. On the other hand, BAs promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr–/– mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA‐FXR through activation of suppressor of cytokine signaling‐3 (SOC3). Conclusion: AREG‐EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.30348
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1472120-X
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  • 4
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    Serum Metabolites as Diagnostic Biomarkers for Cholangiocarcinoma, Hepatocellular Carcinoma, and Primary Sclerosing Cholangitis
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Hepatology Vol. 70, No. 2 ( 2019-08), p. 547-562
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 70, No. 2 ( 2019-08), p. 547-562
    Abstract: Early and differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and hepatocellular carcinoma (HCC) by noninvasive methods represents a current clinical challenge. The analysis of low‐molecular‐weight metabolites by new high‐throughput techniques is a strategy for identifying biomarkers. Here, we have investigated whether serum metabolome can provide useful biomarkers in the diagnosis of iCCA and HCC and could discriminate iCCA from HCC. Because primary sclerosing cholangitis (PSC) is a risk factor for CCA, serum metabolic profiles of PSC and CCA have also been compared. The analysis of the levels of lipids and amino acids in the serum of patients with iCCA, HCC, and PSC and healthy individuals (n = 20/group) showed differential profiles. Several metabolites presented high diagnostic value for iCCA versus control, HCC versus control, and PSC versus control, with areas under the receiver operating characteristic curve (AUC) greater than those found in serum for the nonspecific tumor markers carbohydrate antigen 19‐9 (CA 19‐9) and alpha‐fetoprotein (AFP), commonly used to help in the diagnosis of iCCA and HCC, respectively. The development of an algorithm combining glycine, aspartic acid, SM(42:3), and SM(43:2) permitted to accurately differentiate in the diagnosis of both types of tumors (biopsy‐proven). The proposed model yielded 0.890 AUC, 75% sensitivity, and 90% specificity. Another algorithm by combination of PC(34:3) and histidine accurately permitted to differentiate PSC from iCCA, with an AUC of 0.990, 100% sensitivity, and 70% specificity. These results were validated in independent cohorts of 14‐15 patients per group and compared with profiles found in patients with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Conclusion: Specific changes in serum concentrations of certain metabolites are useful to differentiate iCCA from HCC or PSC, and could help in the early diagnosis of these diseases.
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.30319
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1472120-X
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