Splice variant of growth hormone-releasing hormone receptor drives esophageal squamous cell carcinoma conferring a therapeutic target

Proceedings of the National Academy of Sciences of the United States of America
Xiao XiongHao Zhang

Abstract

The extrahypothalamic growth hormone-releasing hormone (GHRH) and its cognate receptors (GHRH-Rs) and splice variants are expressed in a variety of cancers. It has been shown that the pituitary type of GHRH-R (pGHRH-R) mediates the inhibition of tumor growth induced by GHRH-R antagonists. However, GHRH-R antagonists can also suppress some cancers that do not express pGHRH-R, yet the underlying mechanisms have not been determined. Here, using human esophageal squamous cell carcinoma (ESCC) as a model, we were able to reveal that SV1, a known splice variant of GHRH-R, is responsible for the inhibition induced by GHRH-R antagonist MIA-602. We demonstrated that GHRH-R splice variant 1 (SV1) is a hypoxia-driven promoter of tumor progression. Hypoxia-elevated SV1 activates a key glycolytic enzyme, muscle-type phosphofructokinase (PFKM), through the nuclear factor kappa B (NF-κB) pathway, which enhances glycolytic metabolism and promotes progression of ESCC. The malignant actions induced by the SV1-NF-κB-PFKM pathway could be reversed by MIA-602. Altogether, our studies demonstrate a mechanism by which GHRH-R antagonists target SV1. Our findings suggest that SV1 is a hypoxia-induced oncogenic promoter which can be an alternative targe...Continue Reading

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Citations

Apr 14, 2020·Cell Biology International·Nektarios Barabutis, Agnieszka Siejka
Jun 12, 2021·Cancer Management and Research·Zodwa DlaminiAristotelis Chatziioannou
Oct 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Zhaotong CongMing-Wei Wang

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Datasets Mentioned

BETA
GSE47404

Methods Mentioned

BETA
nuclear translocation
xenograft
xenografting
Xenografts

Software Mentioned

GSEA

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