June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Gene expression signature associated with hypoxia in human uveal melanoma cells
Author Affiliations & Notes
  • Hua Yang
    Emory Eye Center, Atlanta, Georgia, United States
  • Stefan Kaluz
    Neurosurgery, Emory University, Atlanta, Georgia, United States
  • Satoru Osuka
    Neurosurgery, University of Alabama at Birmingham, Alabama, United States
  • Margaret Offermann
    OncoSpherix, Georgia, United States
  • Erwin Van Meir
    Neurosurgery, University of Alabama at Birmingham, Alabama, United States
  • Hans E Grossniklaus
    Emory Eye Center, Atlanta, Georgia, United States
  • Footnotes
    Commercial Relationships   Hua Yang None; Stefan Kaluz None; Satoru Osuka None; Margaret Offermann OncoSpherix, Code E (Employment), OncoSpherix, Code O (Owner), OncoSpherix, Code P (Patent); Erwin Van Meir OncoSpherix, Code E (Employment), OncoSpherix, Code O (Owner), OncoSpherix, Code P (Patent); Hans Grossniklaus Aura Biosciences , Code C (Consultant/Contractor)
  • Footnotes
    Support  SBIR 1 R43 CA254756-01A1, RPB.
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 875. doi:
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      Hua Yang, Stefan Kaluz, Satoru Osuka, Margaret Offermann, Erwin Van Meir, Hans E Grossniklaus; Gene expression signature associated with hypoxia in human uveal melanoma cells . Invest. Ophthalmol. Vis. Sci. 2023;64(8):875.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : A tumor hypoxic microenvironment arising from tumor cell overgrowth may be associated with resistance to chemotherapy and result in a poor clinical outcome due in large part to activation of hypoxia inducible factor 1 (HIF-1) and induction of genes that aid in tumor survival and spread. Uveal melanoma (UM) exhibits hypoxia during tumor growth and vascularization. The purpose of this study is to examine the transcriptomic changes of human uveal melanoma associated with hypoxia and further investigate the mechanisms of 64B, a HIF1-α inhibitor, in suppression of UM.

Methods : RNA-sequencing was performed after the human UM cell line 92.1 was cultured with 10 µM 64B or vehicle solution in normoxia vs hypoxia (1% O2) for 8 hours. The data mapping sequencing reads were quantified for expression levels of transcripts. Genes that were differentially expressed between normoxia and hypoxia were selected based on meeting both P<=0.05 using student t-test and fold change >=2.

Results : 2,130 out of a total of 58,289 transcripts exhibited differential expression in normoxic vs hypoxic conditions (P<=0.05). Under hypoxia, 116 transcripts showed a ≥2-fold increase, including 12 transcripts that were only expressed under hypoxia, 14 transcripts (5 genes, 5 pseudogenes and 4 non-coding RNAs) with ≥10-fold increase, and 26 genes with a 5 to 10-fold increase. When cells were cultured under hypoxia, an 8-hour treatment with 64B reversed hypoxia-induced upregulation of all 5 genes that had a 10-fold increase including 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4, hypoxia 4146 ± 407 vs normoxia 248 ± 32, p=0.009; hypoxia control 4146 ± 407 vs hypoxia 64B 357 ± 156, p=0.01; normoxia control 248 ± 32 vs normoxia 64B 186 ± 29, p=0.02). PFKFB4 is essential for the survival of cancer cells under hypoxic conditions, as PFKFB4 increases the amount of fructose 2,6-bisphosphate and ATP. An additional 4 genes with 10-fold change in response to hypoxia (Izumo Sperm-Oocyte Fusion 1, ectoplasmic specialization protein, Neurexophilin 4, Stanniocalcin 1) were decreased by 64B in hypoxia.

Conclusions : Hypoxia causes alteration of gene expression in cultured human UM 92.1 cells. Our finding on gene hypoxia signature in cultured UM cells may be beneficial for further evaluation of hypoxia in the pathogenesis of UM and guide combinatorial hypoxia-mediated therapeutic strategies in uveal melanoma.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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