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Nuclear GAPDH is vital for hypoxia-induced hepatic stellate cell apoptosis and is indicative of aggressive hepatocellular carcinoma behavior

Authors Gong Y, Zou B, Peng S, Li P, Zhu G, Chen J, Chen J, Liu X, Zhou W, Ding L, Chen Y, Zeng L, Zhang B, Cai C, Li J

Received 20 January 2019

Accepted for publication 6 April 2019

Published 30 May 2019 Volume 2019:11 Pages 4947—4956

DOI https://doi.org/10.2147/CMAR.S202268

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 3

Editor who approved publication: Dr Chien-Feng Li


Yihang Gong,1,* Baojia Zou,1,* Siqi Peng,2 Peiping Li,1 Genglong Zhu,1 Jiafan Chen,1 Jianxu Chen,1 Xialei Liu,1 Wenying Zhou,3 Lei Ding,1 Yutong Chen,2 Linjuan Zeng,2 Baimeng Zhang,1 Chaonong Cai,1 Jian Li1

1Department of Hepatobiliary Surgery; 2Department of Oncology; 3Central Laboratory, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province 519000, People’s Republic of China

*These authors contributed equally to this work

Background/aim: Hepatic stellate cells (HSCs) are critical determinants of liver tumor behavior such as vascular invasion, cell proliferation and migration. The apoptosis of HSCs can inhibit tumor growth and contribute to repressing hepatocellular carcinoma (HCC) progression. Our study aims to investigate the impact of nuclear glyceraldehyde-3-phosphate dehydrogenase (GAPDH) on HSCs under hypoxic conditions and the association of nuclear GAPDH with HCC patient outcomes and tumor progression.
Patients and methods: Following stable cell passage, 0.3% O2 was used to induce hypoxia. Cell proliferation and apoptosis were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assays and flow cytometry, respectively. Proteins expression were detected by extracting nuclear and cytoplasmic proteins and performing Western blots. GAPDH nuclear translocation was blocked by the agent deprenyl. Immunohistochemical staining for GAPDH was investigated in 137 HCC tissue samples from our center. An analysis of the clinicopathological features, Kaplan-Meier analysis and Cox proportional hazards regression analysis were applied.
Results: MTT assays and flow cytometry analyses showed that the nuclear accumulation of GAPDH led to the apoptotic death of HSCs, while blockade of this process with deprenyl significantly decreased apoptosis. Western blots revealed that deprenyl inhibited the nuclear translocation of GAPDH. An analysis of the immunohistochemical staining of HSCs in HCC tissue samples (137) revealed that nuclear GAPDH expression was significantly positively correlated with HIF-1α expression. Overall survival (OS) and time-to-recurrence (TTR) estimated by Kaplan-Meier analyses showed that patients with high HIF-1α or low nuclear GAPDH levels in HSCs had significantly poorer prognosis compared with patients with low HIF-1α or high nuclear GAPDH expression in HSCs. Moreover, patients with combined high HIF-1α/low nuclear GAPDH expression in HSCs had the worst prognosis. The Cox regression analysis revealed that the combination of nuclear GAPDH/HIF-1α expression in HSCs was an independent prognostic factor for OS and TTR in HCC patients.
Conclusions: These findings provide a novel mechanism underlying the involvement of intranuclear GAPDH in hypoxia-induced HSCs apoptosis and a correlation between nuclear GAPDH levels and the clinical prognosis, which may prompt the development of a novel therapeutic strategy for HCC.

Keywords: apoptosis, GAPDH, HSC, HCC, hypoxia

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