2. Academic Validation
  3. BMP4 upregulates glycogen synthesis through the SMAD/SLC2A1 (GLUT1) signaling axis in hepatocellular carcinoma (HCC) cells

BMP4 upregulates glycogen synthesis through the SMAD/SLC2A1 (GLUT1) signaling axis in hepatocellular carcinoma (HCC) cells

  • Cancer Metab. 2023 Jul 13;11(1):9. doi: 10.1186/s40170-023-00310-6.
Jiamin Zhong 1 2 3,  Luyao Tian 1 2,  Yannian Gou 1 2 3,  Piao Zhao 1 2 3 4,  Xiangyu Dong 1 2,  Meichun Guo 1 2,  Guozhi Zhao 3 5,  Aohua Li 1 2,  Ailing Hao 1 2,  Tong-Chuan He 6,  Jiaming Fan 7 8
Affiliations

Affiliations

  • 1 Ministry of Education Key Laboratory of Diagnostic Medicine, Chongqing, China.
  • 2 Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, No. 1 Medical School Road, Yuzhong District, Chongqing, 400016, China.
  • 3 Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3079, Chicago, IL, 60637, USA.
  • 4 Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 5 Department of Urology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 6 Molecular Oncology Laboratory, Department of Orthopaedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3079, Chicago, IL, 60637, USA. [email protected].
  • 7 Ministry of Education Key Laboratory of Diagnostic Medicine, Chongqing, China. [email protected].
  • 8 Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, No. 1 Medical School Road, Yuzhong District, Chongqing, 400016, China. [email protected].
PMID: 37443106 DOI: 10.1186/s40170-023-00310-6
Abstract

Background: Excessive hepatic glycogen accumulation benefits tumorigenesis and Cancer cell survival. We previously reported that BMP4 has the strongest ability to promote glycogenesis among the 14 BMPs in hepatocytes and augmented hepatocellular carcinoma (HCC) cell survival under hypoxia and hypoglycemia conditions by promoting the glycolysis pathway. However, the mechanism underlying BMP4's effect on glycogenesis in HCC remains elusive.

Methods: The expression of BMP4 and SLC2A1 were acquired by analyzing the TCGA-LIHC dataset, as well as by immunohistochemical analysis of the 40 pairs of human HCC samples and para-tumor tissues. Gene expressions were detected by qPCR, immunoflurorescence staining, and Western blotting. Overexpression and silencing of BMP4 were accomplished through adenoviruses Ad-B4 and Ad-siB4 Infection. Hepatic glycogen was detected by PAS staining. SLC2A1 (GLUT1) function was blocked by the inhibitor BAY-876. ChIP assay was used to determine the binding of SMADs to the promoter region of SLC2A1 in HCC cells. Lastly, the in vivo effect of BMP4-regulated SLC2A1 on HCC tumor growth was assessed in a xenograft model of HCC.

Results: The elevated expression of BMP4 in HCC tumor tissues was highly correlated with hepatic glycogen accumulation in clinical samples. SLC2A1 was highly expressed in HCC tumor tissue and correlated with clinical stage and prognosis. Exogenous BMP4 augmented glycogen accumulation and upregulated the expression of glycogen synthesis-related genes in Huh7 and HepG2 cells, both of which were effectively blunted by SLC2A1inhibitor BAY-876. In mechanism, BMP4 activated SMAD5 to regulate the promoter of SLC2A1to enhance its expression. The in vivo xenograft experiments revealed that BMP4 promoted glycogen accumulation and tumor growth, which were effectively diminished by BAY-876.

Conclusion: These results demonstrate that BMP4 upregulates glycogen synthesis through the SMAD/SLC2A1 (GLUT1) signaling axis in HCC cells, which may be exploited as novel therapeutic targets for HCC treatment.

Keywords

BMP4; Glycogen synthesis; HCC; SLC2A1; Smad signal pathway.

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