Dataset Information

Targeting Gremlin 1 Prevents Intestinal Fibrosis Progression by Inhibiting the Fatty Acid Oxidation of Fibroblast Cells.

ABSTRACT: Intestinal fibrosis is a consequence of continuous inflammatory responses that negatively affect the quality of life of patients. By screening altered proteomic profiles of mouse fibrotic colon tissues, we identified that GREM1 was dramatically upregulated in comparison to that in normal tissues. Functional experiments revealed that GREM1 promoted the proliferation and activation of intestinal fibroblast cells by enhancing fatty acid oxidation. Blocking GREM1 prevented the progression of intestinal fibrosis in vivo. Mechanistic research revealed that GREM1 acted as a ligand for VEGFR2 and triggered downstream MAPK signaling. This facilitated the expression of FAO-related genes, consequently enhancing fatty acid oxidation. Taken together, our data indicated that targeting GREM1 could represent a promising therapeutic approach for the treatment of intestinal fibrosis.

SUBMITTER: Yang Y

PROVIDER: S-EPMC8100665 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Targeting Gremlin 1 Prevents Intestinal Fibrosis Progression by Inhibiting the Fatty Acid Oxidation of Fibroblast Cells.

Yang Yang Y Zeng Qi-Shan QS Zou Min M Zeng Jian J Nie Jiao J Chen DongFeng D Gan Hua-Tian HT

Frontiers in pharmacology 20210422

Intestinal fibrosis is a consequence of continuous inflammatory responses that negatively affect the quality of life of patients. By screening altered proteomic profiles of mouse fibrotic colon tissues, we identified that GREM1 was dramatically upregulated in comparison to that in normal tissues. Functional experiments revealed that GREM1 promoted the proliferation and activation of intestinal fibroblast cells by enhancing fatty acid oxidation. Blocking GREM1 prevented the progression of intesti ...[more]

PMID: 33967807

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Project description:BackgroundBone morphogenetic proteins (BMPs) have been reported to maintain epithelial integrity and to antagonize the transforming growth factor β (TGFβ)-induced epithelial to mesenchymal transition. The expression of soluble BMP antagonists is dysregulated in cancers and interrupts proper BMP signaling in breast cancer.MethodsIn this study, we mined the prognostic role of BMP antagonists GREMLIN 1 (GREM1) in primary breast cancer tissues using in-house and publicly available datasets. We determined which cells express GREM1 RNA using in situ hybridization (ISH) on a breast cancer tissue microarray. The effects of Grem1 on the properties of breast cancer cells were assessed by measuring the mesenchymal/stem cell marker expression and functional cell-based assays for stemness and invasion. The role of Grem1 in breast cancer-associated fibroblast (CAF) activation was measured by analyzing the expression of fibroblast markers, phalloidin staining, and collagen contraction assays. The role of Grem1 in CAF-induced breast cancer cell intravasation and extravasation was studied by utilizing xenograft zebrafish breast cancer (co-) injection models.ResultsExpression analysis of clinical breast cancer datasets revealed that high expression of GREM1 in breast cancer stroma is correlated with a poor prognosis regardless of the molecular subtype. The large majority of human breast cancer cell lines did not express GREM1 in vitro, but breast CAFs did express GREM1 both in vitro and in vivo. Transforming growth factor β (TGFβ) secreted by breast cancer cells, and also inflammatory cytokines, stimulated GREM1 expression in CAFs. Grem1 abrogated bone morphogenetic protein (BMP)/SMAD signaling in breast cancer cells and promoted their mesenchymal phenotype, stemness, and invasion. Moreover, Grem1 production by CAFs strongly promoted the fibrogenic activation of CAFs and promoted breast cancer cell intravasation and extravasation in co-injection xenograft zebrafish models.ConclusionsOur results demonstrated that Grem1 is a pivotal factor in the reciprocal interplay between breast cancer cells and CAFs, which promotes cancer cell invasion. Targeting Grem1 could be beneficial in the treatment of breast cancer patients with high Grem1 expression.

Project description:Lipid accumulation is a driving force in tumor development, as it provides tumor cells with both energy and the building blocks of phospholipids for construction of cell membranes. Aberrant homeostasis of lipid metabolism has been observed in various tumors; however, the molecular mechanism has not been fully elucidated. Methods: Yin yang 1 (YY1) expression in hepatocellular carcinoma (HCC) was analyzed using clinical specimens, and its roles in HCC in lipid metabolism were examined using gain- and loss-of function experiments. The mechanism of YY1 regulation on peroxisome proliferator-activated receptor gamma coactivator-1β (PGC-1β) and its downstream genes medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD) were investigated using molecular biology and biochemical methods. The role of YY1/ PGC-1β axis in hepatocarcinogenesis was studied using xenograft experiment. Results: This study showed that YY1 suppresses fatty acid β-oxidation, leading to increase of cellular triglyceride level and lipid accumulation in HCC cells, and subsequently induction of the tumorigenesis potential of HCC cells. Molecular mechanistic study revealed that YY1 blocks the expression of PGC-1β, an activator of fatty acid β-oxidation, by directly binding to its promoter; and thus downregulates PGC-1β/MCAD and PGC1-β/LCAD axis. Importantly, we revealed that YY1 inhibition on PGC-1β occurs irrespective of the expression of hypoxia-inducible factor-1α (HIF1-α), enabling it to promote lipid accumulation under both normoxic and hypoxic conditions. Conclusion: Our study reveals the critical role of YY1/PGC-1β axis in HCC cell lipid metabolism, providing novel insight into the molecular mechanisms associated with tumor cell lipid metabolism, and a new perspective regarding the function of YY1 in tumor progression. Thus, our study provides evidences regarding the potential of YY1 as a target for lipid metabolism-based anti-tumor therapy.

Dataset Information

Targeting Gremlin 1 Prevents Intestinal Fibrosis Progression by Inhibiting the Fatty Acid Oxidation of Fibroblast Cells.

Publications

Targeting Gremlin 1 Prevents Intestinal Fibrosis Progression by Inhibiting the Fatty Acid Oxidation of Fibroblast Cells.

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