Transcription of the Human 5-Hydroxytryptamine Receptor 2B (HTR2B) Gene Is under the Regulatory Influence of the Transcription Factors NFI and RUNX1 in Human Uveal Melanoma.

Manel Benhassine,Sylvain Guérin

doi:10.3390/ijms19103272

Manel Benhassine, Sylvain Guérin

Open Access

https://doi.org/10.3390/ijms19103272

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Abstract

Because it accounts for 70% of all eye cancers, uveal melanoma (UM) is therefore the most common primary ocular malignancy. In this study, we investigated the molecular mechanisms leading to the aberrant expression of the gene encoding the serotonin receptor 2B (HTR2B), one of the most discriminating among the candidates from the class II gene signature, in metastatic and non-metastatic UM cell lines. Transfection analyses revealed that the upstream regulatory region of the HTR2B gene contains a combination of alternative positive and negative regulatory elements functional in HTR2B− but not in HTR23B+ UM cells. We demonstrated that both the transcription factors nuclear factor I (NFI) and Runt-related transcription factor I (RUNX1) interact with regulatory elements from the HTR2B gene to either activate (NFI) or repress (RUNX1) HTR2B expression in UM cells. The results of this study will help understand better the molecular mechanisms accounting for the abnormal expression of the HTR2B gene in uveal melanoma.

Highlights

Uveal melanoma (UM), with an incidence of 4 to 6 affected individuals per million in the United States [1], accounts for 70% of all eye cancers, which makes it the most observed ocular malignancy among the adult population
Gene profiling on microarrays was first exploited in order to monitor the expression of the four candidates (HTR2B, CDH1, RAB31 and ECM1) that belong to the uveal melanoma (UM) class II gene signature in a variety of UM cell lines cultured at low passage (P1 to P16)
The highest normalized level of Hydroxytryptamine receptor 2B (HTR2B) expression was observed in the UM cell lines T142 (RNS: 0.0205), T151 (RNS: 0.3661) and T157 (RNS: 0.0134), whereas the lowest levels were observed in T97, T98, T108, T111, T128, T131, T132, and T143 cells

Summary

Introduction

Uveal melanoma (UM), with an incidence of 4 to 6 affected individuals per million in the United States [1], accounts for 70% of all eye cancers, which makes it the most observed ocular malignancy among the adult population. The serotonin receptor HTR2B belongs to a larger family of proteins that comprises seven sub-families (HTR1 to HTR7) [6]. When it binds its ligand serotonin (5-HT), HTR2B activates the G proteins GNAQ, GNA11 and GNA13, and participates in the development and cell proliferation and survival through the activation of a few signal transduction pathways such as the phospholipase C (PLC), Janus kinase/Signal Transducer and Activator of Transcription proteins (JAK/STAT), Receptor Tyrosin Kinase (RTK)/Phosphatidylinositol-4,5-bisphos- phate-3-kinase (PI3K)/Extracellular signal-Regulated Kinase (ERK)/mammalian target of rapamycin (mTOR) and RAF/Mitogen activated protein Kinase Kinase (MEK)/ERK pathways [6,7,8,9,10]. Excess serotonin signaling that results from the overexpression of the HTR2B receptor was found to cause the formation of irregularly shaped eyes that are inappropriately positioned and oriented in Xenopus embryos [19]

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