The emerging role of the tricarboxylic acid cycle (TCA) in Uveal melanoma
Zahra Souri1 *, Martine .J. Jager2
- Department of Cell and Molecular Biology and Microbiology, Biological Science and Technology, University of Isfahan, Iran
- Department of Ophthalmology, LUMC, Leiden, The Netherlands
Abstract: Uveal Melanoma (UM) is an intraocular malignancy that originates from the pigment-producing cells of the eye (iris, ciliary body and the choroid). Studies have shown that UM tumours are metabolically heterogeneous.
The tricarboxylic acid cycle (TCA) cycle is a metabolic pathway that occurs in the mitochondria and generates energy for cells. TCA has been shown to be associated with oncogenesis and inflammatory processes in different cancers.
We study the expression of the most important components of the TCA cycle in UM tumours with regard to BAP1 expression and investigate the possible associations between this metabolic pathway with inflammation.
Methods: The expression of CS, IDH1, IDH2, IDH3A, IDH3G, OGDH, DLST, SDHA, SDHC, MDHA, SLC25A1, SLC25A12 and the inflammatory markers HLA-A, HLA-B, CD8 and CD68 was determined using an Illumina HT12V4 array in 64 primary UM. Immunohistochemical staining was performed for the detection of BAP1 status.
Results: CS (One out of two probes P = 0.01, P = 0.06), IDH1 (both probes P = 0.01, P = 0.04), SLC25A1 (P = 0.03) and SLC25A12 (P = 0.01) expression was positively associated with BAP1 status while IDH2 (P = 0.001), IDH3A (P = 0.05), IDH3B (two out of three probes P = 0.005, P = 0.04, P = 1), IDH3G (both probes P = 0.01, P = 0.001), OGDH (both probes P = 0.005, P = 0.001), DLST (P = 0.001), SDHA (both probes P = 0.002, P = 0.001), SDHC (one out of two probes P = 0.001, P = 0.08) and MDH2 (P = 0.001), were negatively associated with BAP1 status. Moreover, CS and SLC25A1 showed a negative correlation with HLA class I and tumour infiltrate markers while IDH2, IDH3G, OGDH, DLST, SDHA, SDHB, SDHC, MDH1 and MDH2 were positively correlated.
Conclusion: The TCA cycle has been identified as a potent immune modulator in cancers. We find that components of the TCA cycle are differentially expressed among prognostically-good BAP1-positive vs prognostically-bad BAP1-negative UM tumours and additionally show association with inflammatory characteristics HLA Class I and tumour-infiltrated leukocytes. As inflammation plays a major role in the progression of UM, targeting the TCA cycle may serve as a putative strategy to reduce malignant transformation and inflammation in this disease.
