Details

Autor(en) / Beteiligte

• Oikari, Sanna
• Kettunen, Tiia
• Tiainen, Satu
• Häyrinen, Jukka
• Masarwah, Amro
• Sudah, Mazen
• Sutela, Anna
• Vanninen, Ritva
• Tammi, Markku
• Auvinen, Päivi

Titel

UDP-sugar accumulation drives hyaluronan synthesis in breast cancer

Ist Teil von

• Matrix biology, 2018-04, Vol.67, p.63-74

Ort / Verlag

Netherlands: Elsevier B.V

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. •This is the first quantitative assay of UDP-sugars in malignant human breast tumors•Several-fold increases of UDP-sugars take place in breast cancer•UDP-GlcNAc increase is most drastic, likely due to the elevated expression of GFAT2•Hyaluronan content correlates with UDP-sugars but not with HAS1–3 mRNA levels•Glucose flux into UDP-sugars offers a new mechanistic insight into tumor hyaluronan accumulation