Theranostics 2019; 9(3):796-810. doi:10.7150/thno.28992 This issue Cite

Research Paper

LINC01554-Mediated Glucose Metabolism Reprogramming Suppresses Tumorigenicity in Hepatocellular Carcinoma via Downregulating PKM2 Expression and Inhibiting Akt/mTOR Signaling Pathway

Yin-Li Zheng1*, Lei Li1*, Yong-Xun Jia2, Bao-Zhu Zhang1,3, Jiang-Chao Li4, Ying-Hui Zhu1, Meng-Qing Li1, Jiao-Zi He5, Ting-Ting Zeng1, Xiao-Jiao Ban1, Yun-Fei Yuan1, Yan Li1✉, Xin-Yuan Guan1,5✉

1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510062, China
2. Department of Clinical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
3. The People's Hospital of Baoan Shenzhen, The Affiliated Baoan Hospital of Southern Medical University, Shenzhen 518101, China
4. Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China
5. Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
*These authors contributed equally to this work.

Citation:
Zheng YL, Li L, Jia YX, Zhang BZ, Li JC, Zhu YH, Li MQ, He JZ, Zeng TT, Ban XJ, Yuan YF, Li Y, Guan XY. LINC01554-Mediated Glucose Metabolism Reprogramming Suppresses Tumorigenicity in Hepatocellular Carcinoma via Downregulating PKM2 Expression and Inhibiting Akt/mTOR Signaling Pathway. Theranostics 2019; 9(3):796-810. doi:10.7150/thno.28992. https://www.thno.org/v09p0796.htm
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Abstract

Graphic abstract

Background and Aims: Cancer cells prefer aerobic glycolysis to maintain growth advantages, but the role of long non-coding RNAs (lncRNAs) in glycometabolism still remains unclear. Here we identified one cytoplasmic lncRNA LINC01554 as a significantly downregulated lncRNA in hepatocellular carcinoma (HCC) and aimed to investigate its role in cellular glucose metabolism in the development and progression of HCC.

Methods: Quantitative real-time PCR was used to determine the expression level of LINC01554. Downregulation of LINC01554 by miR-365a at transcriptional level was assessed by luciferase reporter assay. Subcellular fractionation assay and RNA fluorescence in situ hybridization were performed to detect the subcellular localization of LINC01554. RNA pull-down assay, mass spectrometry, and RNA immunoprecipitation assay were used to identify the underlying molecular mechanisms. The tumor-suppressive function of LINC01554 was determined by both in vitro assay and nude mice xenograft model.

Results: LINC01554 was frequently downregulated in HCC, which was significantly associated with tumor invasion (P = 0.005), tumor size (P = 0.041), tumor staging (P = 0.023) and shorter survival (P = 0.035) of HCC patients. Luciferase reporter assay unraveled that LINC01554 was negatively regulated by miR-365a. Subcellular fractionation assay and RNA FISH revealed the cytoplasmic predominance of LINC01554 in MIHA cells and HCC clinical samples. Ectopic expression of LINC01554 inhibited HCC cell growth, colony formation in soft agar, foci formation, and tumor formation in nude mice. LINC01554 promoted the ubiquitin-mediated degradation of PKM2 and inhibited Akt/mTOR signaling pathway to abolish aerobic glycolysis in HCC cells. Further study found that LINC01554-knockout could effectively reverse the tumor-suppressive effect of LINC01554.

Conclusions: Our results identify LINC01554 as a novel tumor suppressor in HCC and unravel its underlying molecular mechanism in reprogramming cellular glucose metabolism. LINC01554 could possibly serve as a novel prognostic biomarker and provide the rationale for HCC therapy.

Keywords: HCC, LINC01554, Aerobic Glycolysis, PKM2, Akt


Citation styles

APA
Zheng, Y.L., Li, L., Jia, Y.X., Zhang, B.Z., Li, J.C., Zhu, Y.H., Li, M.Q., He, J.Z., Zeng, T.T., Ban, X.J., Yuan, Y.F., Li, Y., Guan, X.Y. (2019). LINC01554-Mediated Glucose Metabolism Reprogramming Suppresses Tumorigenicity in Hepatocellular Carcinoma via Downregulating PKM2 Expression and Inhibiting Akt/mTOR Signaling Pathway. Theranostics, 9(3), 796-810. https://doi.org/10.7150/thno.28992.

ACS
Zheng, Y.L.; Li, L.; Jia, Y.X.; Zhang, B.Z.; Li, J.C.; Zhu, Y.H.; Li, M.Q.; He, J.Z.; Zeng, T.T.; Ban, X.J.; Yuan, Y.F.; Li, Y.; Guan, X.Y. LINC01554-Mediated Glucose Metabolism Reprogramming Suppresses Tumorigenicity in Hepatocellular Carcinoma via Downregulating PKM2 Expression and Inhibiting Akt/mTOR Signaling Pathway. Theranostics 2019, 9 (3), 796-810. DOI: 10.7150/thno.28992.

NLM
Zheng YL, Li L, Jia YX, Zhang BZ, Li JC, Zhu YH, Li MQ, He JZ, Zeng TT, Ban XJ, Yuan YF, Li Y, Guan XY. LINC01554-Mediated Glucose Metabolism Reprogramming Suppresses Tumorigenicity in Hepatocellular Carcinoma via Downregulating PKM2 Expression and Inhibiting Akt/mTOR Signaling Pathway. Theranostics 2019; 9(3):796-810. doi:10.7150/thno.28992. https://www.thno.org/v09p0796.htm

CSE
Zheng YL, Li L, Jia YX, Zhang BZ, Li JC, Zhu YH, Li MQ, He JZ, Zeng TT, Ban XJ, Yuan YF, Li Y, Guan XY. 2019. LINC01554-Mediated Glucose Metabolism Reprogramming Suppresses Tumorigenicity in Hepatocellular Carcinoma via Downregulating PKM2 Expression and Inhibiting Akt/mTOR Signaling Pathway. Theranostics. 9(3):796-810.

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