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New therapy for colorectal cancer targeting cancer metabolism through serotonin receptor HTR2B

ABSTRACT: New therapy for colorectal cancer targeting cancer metabolism through serotonin receptor HTR2B

PROVIDER: PRJNA1084766 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28242622_1.fastq.gz	Fastqsanger.gz
	SRR28242622_2.fastq.gz	Fastqsanger.gz
	SRR28242623_1.fastq.gz	Fastqsanger.gz
	SRR28242623_2.fastq.gz	Fastqsanger.gz
	SRR28242624_1.fastq.gz	Fastqsanger.gz

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Project description:Background: Aortic Stenosis (AS) is a highly prevalent disease involving physiological and structural remodeling of aortic valve, yet lacks effective medical therapy to halt its progression. Serotonin (5HT) signaling has been implicated in valvular disease. We hypothesized that AS is associated with impaired 5HT clearance due to reduced serotonin receptor (SERT) expression and increased 5HT receptor (HTR) activity. Methods: Sixty-six patients with severe AS undergoing aortic valve (AV) replacement were enrolled in the study, and samples from their explanted AV were harvested. Anatomically normal control AVs were obtained from transplant donors. Explanted AVs were collected for gene expression analysis and 5-HTTLPR genotyping. Gene expression was assessed by RT2-profiler gene array. In vivo, 8-week-old mice received 28-day Angiotensin-II (AngII) infusions ± HTR2B antagonist (LY272015) through subcutaneous Alzet osmotic-pump implants. AV structure and function were assessed via echocardiography, histology, and RNA sequencing. Human aortic valve interstitial cells (AVICs) were treated with either H2O2 or AngII ± SERT siRNAs to assess 5HT signaling and fibrotic/osteogenic markers. Results: AS patients exhibited reduced SERT and increased HTR expression. Oxidative stress in cultured human AVICs suppressed SERT and induced HTR2B expression. AngII ± SERT siRNA promoted VIC osteogenic marker expression. In mice, AngII caused AV thickening, increased velocities and gradients, and activation of fibrosis and calcification-related gene sets, including serotonin, TGFβ, Wnt/β-catenin, PI3K/Akt, and Notch pathways. Pharmacological inhibition of HTR2B preserved AV structure, normalized transvalvular velocities and pressure gradients, and reversed AngII-induced transcriptional changes. Conclusions: In human and mouse AVs, reduced SERT and elevated HTR2B signaling contribute to early-onset fibro-calcific remodeling. HTR2B inhibition by LY272015 reverses these effects, suggesting it as a potential therapeutic strategy for AS.

Project description:Introduction: Uveal melanoma (UM) is the most common type of primary intraocular tumor in the adult population. UM will propagate to the liver as the first metastatic site. Once this organ is invaded, survival becomes a matter of months for the patient as no treatment has proved effectiveness. Among the candidates from the class II gene signature, the serotonin receptor-encoding gene HTR2B appears to be the most discriminating as its expression strongly increases in the tumors of UM patients that will progress toward liver metastases. Our study aims at characterizing the molecular mechanisms that lead to this aberrant expression of HTR2B in metastatic UM cell lines.Materials and Methods: Expression of HTR2B was monitored by microarrays and validated by Western blot in a variety of UM cell lines. A 2 Kbp segment covering both the promoter and 5 '-flanking region of the HTR2B gene was cloned upstream the CAT reporter gene in the plasmid pCATbasic (to yield the -2000/HTR2B construct). Deletion mutants were generated by double digestion of the -2000/HTR2B construct with restriction enzymes and transfected, along with the parental -2000/HTR2B construct, in UM cell lines. The genomic areas of interest were 5’ end-labeled and used as probes in electrophoretic mobility shift assays (EMSAs). DMS methylation footprinting was also used to precisely position the DNA target sites for transcription factors (TFs) that bind the HTR2B regulatory regions.Results and Discussion: Transfection analyses revealed that the upstream regulatory regions of HTR2B promoter is made up of a combination of alternative positive and negative regulatory elements. Repressive regions have an abnormally elevated number of target sites for the TFs NFI. EMSA analyses provided evidence that both the NFI isoforms NFIC and NFIX could interact with the promoter and the upstream negative regulatory element from the HTR2B gene. In addition, the TF RunX1 was shown by DMS methylation interference footprinting to bind a target site from the distal silencer element.Conclusion: This project will help understand better the molecular mechanisms accounting for the abnormal expression of the HTR2B gene in uveal melanoma. In the long term, this study will allow us to identify new potential targets that could help screening patients at risk of progressing to liver metastasis formation.

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New therapy for colorectal cancer targeting cancer metabolism through serotonin receptor HTR2B

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