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

作者全名："Zhong, Jiamin; Tian, Luyao; Gou, Yannian; Zhao, Piao; Dong, Xiangyu; Guo, Meichun; Zhao, Guozhi; Li, Aohua; Hao, Ailing; He, Tong-Chuan; Fan, Jiaming"

作者地址："[Zhong, Jiamin; Tian, Luyao; Gou, Yannian; Zhao, Piao; Dong, Xiangyu; Guo, Meichun; Li, Aohua; Hao, Ailing; Fan, Jiaming] Minist Educ, Key Lab Diagnost Med, Chongqing, Peoples R China; [Zhong, Jiamin; Tian, Luyao; Gou, Yannian; Zhao, Piao; Dong, Xiangyu; Guo, Meichun; Li, Aohua; Hao, Ailing; Fan, Jiaming] Chongqing Med Univ, Coll Lab Med, Dept Clin Biochem, 1 Med Sch Rd, Chongqing 400016, Peoples R China; [Zhong, Jiamin; Gou, Yannian; Zhao, Piao; Zhao, Guozhi; He, Tong-Chuan] Univ Chicago, Med Ctr, Dept Orthopaed Surg & Rehabil Med, Mol Oncol Lab, 5841 South Maryland Ave, MC 3079, Chicago, IL 60637 USA; [Zhao, Piao] Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing 400016, Peoples R China; [Zhao, Guozhi] Chongqing Med Univ, Affiliated Hosp 1, Dept Urol, Chongqing 400016, Peoples R China"

通信作者："Fan, JM (通讯作者)，Minist Educ, Key Lab Diagnost Med, Chongqing, Peoples R China.; Fan, JM (通讯作者)，Chongqing Med Univ, Coll Lab Med, Dept Clin Biochem, 1 Med Sch Rd, Chongqing 400016, Peoples R China.; He, TC (通讯作者)，Univ Chicago, Med Ctr, Dept Orthopaed Surg & Rehabil Med, Mol Oncol Lab, 5841 South Maryland Ave, MC 3079, Chicago, IL 60637 USA."

来源：CANCER & METABOLISM

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001024886400001

JCR分区：Q2

影响因子：5.9

年份：2023

卷号：11

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：HCC; BMP4; Smad signal pathway; Glycogen synthesis

摘要："BackgroundExcessive 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.MethodsThe 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.ResultsThe 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.ConclusionThese 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."

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