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Hepatic stellate cell stearoyl co-A desaturase activates leukotrien B4 receptor 2-β-catanin cascade to promote liver tumorigenesis.

ABSTRACT: Hepatocellular carcinoma (HCC) is the 3rd most deadly malignancy. Activated hepatic stellate cells (aHSC) give rise to cancer-associated fibroblasts in HCC and are considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase-2 (Scd2) in aHSC globally suppresses nuclear CTNNB1 and YAP1 in tumors and tumor microenvironment and prevents liver tumorigenesis in male mice. Tumor suppression is associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). Genetic or pharmacological inhibition of LTB4R2, recapitulates CTNNB1 and YAP1 inactivation and tumor suppression in culture and in vivo. Single cell RNA sequencing identifies a subset of tumor-associated aHSC expressing Cyp1b1 but no other 12-HHTrE biosynthetic genes. aHSC release 12-HHTrE in a manner dependent on SCD and CYP1B1 and their conditioned medium reproduces the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC are detected in proximity of LTB4R2-positive HCC cells and the growth of patient HCC organoids is blunted by LTB4R2 antagonism or knockdown. Collectively, our findings suggest aHSC-initiated 12-HHTrE-LTB4R2-CTNNB1-YAP1 pathway as a potential HCC therapeutic target.

ORGANISM(S): Mus musculus

PROVIDER: GSE230843 | GEO | 2023/04/30

REPOSITORIES: GEO

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Hepatic stellate cell-derived oxylipin activates leukotrine B4 receptor 2-β-catenin-YAP1 cascade to promote liver tumorigenesis

Project description:Hepatocellular carcinoma (HCC) is the 3rd most deadly malignancy due to limited therapeutic options. Activated hepatic stellate cells (aHSC) give rise to major cancer-associated myofibroblasts in HCC and considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase (Scd) in aHSC globally suppressed nuclear β-catenin (CTNNB1) and YAP1 in the tumor microenvironment and prevented liver tumorigenesis in mice. Tumor suppression was associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). LTB4R2 ablation and pharmacological inhibition, recapitulated CTNNB1 and YAP1 inactivation and tumor suppression in vivo and in culture. Single cell RNA sequencing identified a unique subset of tumor-associated aHSC expressing Cyp1b1 but no other 12-HHTrE biosynthetic genes. aHSC released 12-HHTrE in a manner dependent on SCD and their conditioned medium reproduced the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC were detected in proximity of LTB4R2-positive cancer cells in human HCC and the growth of patient HCC organoids was blunted by LTB4R2 antagonism or knockdown. Collectively, our research identified a novel aHSC-initiated 12-HHTrE-LTB4R2-CTNNB-YAP1 pathway as a potential HCC therapeutic target.

2023-03-13 | GSE193980 | GEO

Breast cancer cell MCF7+CYP1B1-AS1 LC-MS/MS

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2023-10-24 | PXD037317 | Pride

β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma

Project description:We study the role of CTNNB1 in immune escape in HCC.

2019-06-13 | GSE125336 | GEO

Bulk transcriptomic analysis of two models of zebrafish beta-catenin-driven HCC

Project description:Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. β-catenin has dual cellular functions as a component of the Wnt signaling pathway and adherens junctions. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in 1) a small number of hepatocytes in early development; or 2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. Ingenuity Pathway Analysis of differentially expressed genes in the Cre-lox HCC model revealed that “Cancer” and “Liver Tumor” categories were significantly altered, indicating transcriptional similarities with human HCC and other vertebrate HCC models. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca, and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.

2019-09-27 | GSE137787 | GEO

Single-cell transcriptomic analysis of two models of zebrafish beta-catenin-driven HCC

2019-09-27 | GSE137784 | GEO

PRRX1 deficiency induces mesenchymal-epithelial transition through PITX2/miR-200-dependent SLUG/CTNNB1 regulation in hepatocellular carcinoma

Project description:Metastasis is a major obstacle to better prognosis in patients with hepatocellular carcinoma (HCC). Mesenchymal-epithelial transition (MET) is the driving force for metastatic colonization in which E-cadherin reexpression is a critical procedure. It has been reported that the loss of paired-related homeobox transcription factor 1 (PRRX1) is required for cancer cell metastasis in vivo. However, the role of PRRX1 in MET and how its downregulation triggers E-cadherin reexpression are unknown. In this study, we performed a systematic, mechanistic study regarding the role of PRRX1 in MET of HCC. We observed PRRX1 downregulation in HCC tissues which correlated with early metastasis and short overall survival time. Overexpression of PRRX1 induced EMT, but did not promote metastasis formation, while knockdown of PRRX1 promoted metastasis and colonization of circulating HCC cells as shown in in situ liver tumor model and colonization model. PRRX1 protein levels reversely correlated with E-cadherin levels in HCC cell lines. PRRX1 knockdown promoted E-cadherin reexpression and cell proliferation, inhibited cell invasion and migration. The microarray results showed that PRRX1 deficiency regulated extracellular matrix (ECM) interaction, focal adhesion, TGF-β signaling and cancer pathways. PRRX1 knockdown upregulated PITX2 (paired like homeodomain 2) and inhibited CTNNB1 (catenin beta 1) and SLUG. Silencing of PITX2 reversed CTNNB1 and SLUG inhibition and E-cadherin reexpression. PITX2 upregulation increased miR-200a and miR-200b/429, which further inhibited the transcription of CTNNB1 and SLUG, respectively, thus abrogating the inhibitory effect on E-cadherin. In conclusion, our data showed that the downregulation of PRRX1 induced E-cadherin reexpression through PITX2/miR-200a/CTNNB1 and PITX2/miR-200b/429/SLUG pathway, making PRRX1 a novel prognostic factor for HCC.

2020-04-18 | GSE148851 | GEO

A novel kinase inhibitor for b-catenin mutant hepatocellular carcinoma [Cut&Run]

Project description:We screened HCC organoids to identify a CTNNB1-mutant HCC selective small molecule (WNTinib), with MOA depending on reactivation of cytoplasmic EZH2, leading to its nuclear translocation and selective transcriptional block of WNT targets

2023-05-03 | GSE213515 | GEO

Transcriptomic characterization of Hepatocellular Carcinoma with CTNNB1 mutation

Project description:We report transcritomic characterization of changes in CTNNB1 mutation positive HCCs in comparison to paratumoral tissues 4 pair of HCC and paratumoral liver tissues are sequenced and compared

2014-08-15 | E-GEOD-55048 | biostudies-arrayexpress

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Project description:Hippo pathway is evolutionarily well conserved. All core components of the pathway identified to date have one or more mammalian orthologs, including MST1/2 (Hippo), SAV1 (Salvador, also known as WW45), LATS1/2 (Warts), MOB1 (Mats), YAP1 and its paralog WWTR1 (also known as TAZ) (Yorkie), and TEAD1/2/3/4 (Scalloped). Ectopic over-expression of YAP1 in mouse liver led to develop hepatocellular carcinoma (HCC). HCC is the third most common cause of cancer-related death in the world, and accounts for an estimated 600,000 deaths annually. Lack of molecular classification and clinical heterogeneity of this malignant disease hampered the development of standardized treatment. To investigate roles of Hippo pathway in liver carcinogenesis, we generated liver-specific Mst1/2 -/- and Sav1 -/- mouse models and collected gene expression data from them. Our study provided new understanding on molecular characteristics of HCC. Sav1 and Mst1/2 Knockout models

2014-08-23 | E-GEOD-32510 | biostudies-arrayexpress

MUTHEC

Project description:We analyzed 801 primary HCC developed in 720 patients. Samples were collected from 1992 to 2016 in three French tertiary liver centers in patients treated by liver resection, liver transplantation (surgical samples) and in patients treated by radiofrequency ablation and with advanced HCC treated by non-curative therapies (tumor biopsies). All samples obtained from surgical samples or tumor biopsy were immediately frozen in liquid nitrogen and stored at -80°C prior extraction. We assessed mRNA expression by quantitative RT-PCR in a subset of 757 liver tumor samples. 517 to 782 HCC, according to the gene considered, were sequenced for 30 driver genes (TERT, TP53, CTNNB1, AXIN1, PIK3CA, ARID1A, ARID2, RPS6KA3, NFE2L2, CDKN2A, IL6ST, BRAF, STAT3, HNF1A, JAK1, KRAS, GNAS, KEAP1, IRF2, HRAS, NRAS, TSC2, APOB, TSC1, ALB, CDKN1A, MAP1B, SETD2, ATM and MLL2).

2019-04-05 | GSE129322 | GEO

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