UDP-sugar accumulation drives hyaluronan synthesis in breast cancer.

Abstract

Increased uptake of glucose, a general hallmark of malignant tumors, leads to an accumulation of intermediate metabolites of glycolysis. We investigated whether the high supply of these intermediates promotes their flow into UDP-sugars, and consequently into hyaluronan, a tumor-promoting matrix molecule. We quantified UDP-N-Acetylglucosamine (UDP-GlcNAc) and UDP-glucuronic acid (UDP-GlcUA) in human breast cancer biopsies, the levels of enzymes contributing to their synthesis, and their association with the hyaluronan accumulation in the tumor. The content of UDP-GlcUA was 4 times, and that of UDP-GlcNAc 12 times higher in the tumors as compared to normal glandular tissue obtained from breast reductions. The surge of UDP-GlcNAc correlated with an elevated mRNA expression of glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), one of the key enzymes in the biosynthesis of UDP-GlcNAc, and the expression of GFAT1 was also elevated. The contents of both UDP-sugars strongly correlated with tumor hyaluronan levels. Interestingly, hyaluronan content did not correlate with the mRNA levels of the hyaluronan synthases (HAS1-3), thus emphasizing the role of the UDP-sugar substrates of these enzymes. The UDP-sugars showed a trend to higher levels in ductal vs. lobular cancer subtypes. The results reveal for the first time a dramatic increase of UDP-sugars in breast cancer, and suggest that their high supply drives the accumulation of hyaluronan, a known promoter of breast cancer and other malignancies. In general, the study shows how the disturbed glucose metabolism typical for malignant tumors can influence cancer microenvironment through UDP-sugars and hyaluronan.

• Authors: Sanna Oikari, Tiia Kettunen, Satu Tiainen, Jukka Häyrinen, Amro Masarwah, Mazen Sudah, Anna Sutela, Ritva Vanninen, Markku Tammi, Päivi Auvinen
• Journal: Matrix biology : journal of the International Society for Matrix Biology (Matrix Biol) Vol. 67 Pg. 63-74 (04 2018) ISSN: 1569-1802 [Electronic] Netherlands
• PMID: 29331336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Uridine Diphosphate Glucuronic Acid
• Uridine Diphosphate N-Acetylglucosamine
• Hyaluronic Acid
• Hyaluronan Synthases
• GFPT1 protein, human
• GFPT2 protein, human
• Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)

Topics

• Adult
• Aged
• Aged, 80 and over
• Breast Neoplasms (genetics, metabolism)
• Case-Control Studies
• Female
• Gene Expression Regulation, Neoplastic
• Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) (genetics)
• Humans
• Hyaluronan Synthases (genetics)
• Hyaluronic Acid (metabolism)
• Middle Aged
• Up-Regulation
• Uridine Diphosphate Glucuronic Acid (metabolism)
• Uridine Diphosphate N-Acetylglucosamine (metabolism)
• Young Adult