Int J Biol Sci 2019; 15(9):1771-1786. doi:10.7150/ijbs.35094

Research Paper

Combined Aberrant Expression of NDRG2 and LDHA Predicts Hepatocellular Carcinoma Prognosis and Mediates the Anti-tumor Effect of Gemcitabine

Yan Guo1*, Xi'an Li1*, Xiang Sun2*, Jiancai Wang1, Xu Yang1, Xin Zhou1, Xinping Liu1, Wenchao Liu3, Jianlin Yuan4, Libo Yao1, Xia Li1, Lan Shen1✉

1. The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China;
2. Department of Prosthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
3. Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China;
4. Department of Urology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China;
* These authors contributed equally to this work.

Abstract

The Warburg effect is one of the important hallmarks of cancer. The activation of oncogene and inactivation of tumor suppressor gene contribute to the enhancement of glycolytic enzymes and the Warburg effect. The N-myc downstream regulated gene 2 (NDRG2) is a tumor suppressor gene and is frequently lost in various types of cancer. However, little is known about glycolytic function and therapeutic value of NDRG2 in hepatocellular carcinoma (HCC). In this study, we found that NDRG2 and lactate dehydrogenase A (LDHA) were aberrantly expressed in HCC and were closely related to the Warburg effect. The correlation between NDRG2 and LDHA expression predicted HCC prognosis and the clinical response to chemotherapy. NDRG2 expression was significantly decreased while LDHA expression was increased in HCC specimens. NDRG2 and LDHA expression was significantly correlated with differentiation status, vascular invasion, and TNM stage of HCC. NDRG2 inhibited LDHA expression, the Warburg effect and the growth of HCC cells. Furthermore, NDRG2 mediated gemcitabine-induced inhibition of LDHA expression and the Warburg effect in HCC cells. Taken together, our data suggest that NDRG2 plays an important role in inhibiting the Warburg effect and the malignant growth of HCC via LDHA. NDRG2 combined with LDHA might be powerful prognostic biomarkers and targets for chemotherapy treatment of HCC.

Keywords: Warburg effect, NDRG2, LDHA, gemcitabine, hepatocellular carcinoma

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How to cite this article:
Guo Y, Li X, Sun X, Wang J, Yang X, Zhou X, Liu X, Liu W, Yuan J, Yao L, Li X, Shen L. Combined Aberrant Expression of NDRG2 and LDHA Predicts Hepatocellular Carcinoma Prognosis and Mediates the Anti-tumor Effect of Gemcitabine. Int J Biol Sci 2019; 15(9):1771-1786. doi:10.7150/ijbs.35094. Available from http://www.ijbs.com/v15p1771.htm