Increased B3GALNT2 in hepatocellular carcinoma promotes macrophage recruitment via reducing acetoacetate secretion and elevating MIF activity

Abstract

BackgroundHepatocellular carcinoma (HCC) ranks as the sixth most prevalent cancer and the third leading cause of tumor-related death, so it is urgently needed to discover efficient markers and targets for therapy. β-1,3-N-acetylgalactosaminyltransferase II (B3GALNT2) belongs to the β-1,3-glycosyltransferases (b3GT) family and has been reported to regulate development of both normal and tumor tissues. However, studies on the functions of B3GALNT2 in cancer are quite limited. Here we investigated the potential role of B3GALNT2 in HCC progression.MethodsWestern blot, qPCR, and immunohistochemistry assays were performed to quantify the relative expression of B3GALNT2 in HCC. The functions of B3GALNT2 in tumor progression were evaluated in HCC cell lines and nude mice. Metabolomics analysis was applied to detect alternatively expressed small molecules. Enzyme activity assays were employed to determine the tautomerase activity of macrophage inhibitory factor (MIF).ResultsFor expression analysis, higher levels of B3GALNT2 were observed in tumor tissues compared with adjacent normal tissues, and upregulation of B3GALNT2 correlated with increased tumor size and worse overall survival. Changing levels of B3GALNT2 did not influence cell viability in vitro but promoted tumor growth via enhancing macrophage recruitment in vivo. Furthermore, acetoacetate was identified as a key molecule in B3GALNT2-mediated macrophage recruitment. Mechanistically, B3GALNT2 downregulated expression of enzymes involved in acetoacetate-related metabolism, and reduction of acetoacetate revived MIF activity, thus promoting macrophage recruitment.ConclusionsThis study evaluated B3GALNT2 as a tumor marker in HCC and revealed functions of B3GALNT2 in metabolic transformation and microenvironmental remodeling in HCC. Mechanistically, B3GALNT2 reduced expression of some metabolic enzymes and thus downregulated levels of secreted acetoacetate. This relieved the activity of MIF and enhanced macrophage recruitment to promote tumor growth.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0595-3) contains supplementary material, which is available to authorized users.

Dysregulation of Ketone Body Metabolism Is Associated With Poor Prognosis for Clear Cell Renal Cell Carcinoma Patients

“…This is the first step of ketone body degradation (39). Downregulation of BDH2 gene expression in liver cancer causes decreased secretion of acetoacetate, leading to inability to prevent recruitment of tumor-associated macrophage, a step in oncogenic transformation (40). On the other hand, in acute myeloid leukemia (AML) patients BDH2 functions as an anti-apoptotic factor, high expression of which serves as an unfavorable prognostic factor in this disease (41).…”

Downregulation of exosomal CLEC3B in hepatocellular carcinoma promotes metastasis and angiogenesis via AMPK and VEGF signals

“…The images were obtained by Nikon eclipse Ti-s microscope (Tokyo, Japan) and assessed by two investigators who had no knowledge of the patients’ clinical data to exclude subjectivity. For IHC results assessment, a previous scoring method was used [31]. Composite expression score (CES) with full range from 0 to 12 was performed to show the staining intensity and frequency of positive cells.…”

Destabilization of macrophage migration inhibitory factor by 4‐IPP reduces NF‐κB/P‐TEFb complex‐mediated c‐Myb transcription to suppress osteosarcoma tumourigenesis

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