HBx regulates fatty acid oxidation to promote hepatocellular carcinoma survival during metabolic stress

Wang, Ming Da; Wu, Han; Huang, Shuai; Zhang, Hui‐Lu; Qin, Chen-Jie; Zhao, Lan‐Juan; Fu, Gongbo; Zhou, Xu; Wang, Xianming; Tang, Liang; Wen, Wen; Yang, Wen; Tang, Shanhua; Cao, Dan; Guo, Linna; Zeng, Min; Wu, Mengchao; Yan, He‐Xin; Wang, Hongyang

doi:10.18632/oncotarget.6817

Cited by 63 publications

(63 citation statements)

References 53 publications

(55 reference statements)

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“…These results confirm our previous hypothesis that more malignant tumors are usually characterized by a more modular expression pattern of cancer-associated genes [8,9]. We predict that higher modularity increases the fitness of tumors because metabolic networks are typically under increased stress in HCC tumor cells [34].…”

Section: One Interesting Phenomena Is a Non-monotonic Relation Betweesupporting

confidence: 91%

Modularity of the metabolic gene network as a prognostic biomarker for hepatocellular carcinoma

Jia

et al. 2017

Preprint

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Abnormal metabolism is an emerging hallmark of cancer. Cancer cells utilize both aerobic glycolysis and oxidative phosphorylation (OXPHOS) for energy production and biomass synthesis. Understanding the metabolic reprogramming in cancer can help design therapies to target metabolism and thereby to improve prognosis. We have previously argued that more malignant tumors are usually characterized by a more modular expression pattern of cancer-associated genes. In this work, we analyzed the expression patterns of metabolism genes in terms of modularity for 371 hepatocellular carcinoma (HCC) samples from the Cancer Genome Atlas (TCGA). We found that higher modularity significantly correlated with glycolytic phenotype, later tumor stages, higher metastatic potential, and cancer recurrence, all of which contributed to poorer overall prognosis. Among patients that recurred, we found the correlation of greater modularity with worse prognosis during early to mid-progression. Furthermore, we developed metrics to calculate individual modularity, which was shown to be predictive of cancer recurrence and patients' survival and therefore may serve as a prognostic biomarker. Our overall conclusion is that more aggressive HCC tumors, as judged by decreased host survival probability, had more modular expression patterns of metabolic genes. These results may be used to identify cancer driver genes and for drug design.

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Section: One Interesting Phenomena Is a Non-monotonic Relation Betweesupporting

confidence: 91%

Modularity of the metabolic gene network as a prognostic biomarker for hepatocellular carcinoma

Jia

et al. 2017

Preprint

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“…In addition, cancer cells have their own ways to adapt to metabolic deprivation. [6][7][8] One study reported that nutrient deprivation can induce the Warburg effect, thereby indicating the role of the Warburg effect in helping cancer cells to overcome metabolic stress. 9 Otto Warburg first discovered that even with normal concentrations of oxygen, cancer cells prefer anaerobic breakdown of glucose over mitochondrial oxidative phosphorylation to generate energy, and this phenomenon is known as the "Warburg effect".…”

Section: Introductionmentioning

confidence: 99%

Pim1 supports human colorectal cancer growth during glucose deprivation by enhancing the Warburg effect

et al. 2018

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Cancer cells metabolize glucose mainly by glycolysis and are well adapted to metabolic stress. Pim1 is an oncogene that promotes colorectal cancer (CRC) growth and metastasis, and its expression is positively correlated with CRC progression. However, the mechanism underlying Pim1 overexpression during CRC progression and the role of Pim1 in CRC metabolism remains unclear. In the present study, we discovered that Pim1 expression was significantly upregulated in response to glucose deprivation‐induced metabolic stress by AMP‐activated protein kinase signaling. Pim1 promoted CRC cell proliferation in vitro and tumorigenicity in vivo. Clinical observations showed that Pim1 expression was higher in CRC tissues than in adjacent normal tissues. Pim1 overexpression in CRC tissues not only predicted CRC prognosis in patients but also showed a positive relationship with 18F‐fluorodeoxyglucose uptake. Further in vitro experiments showed that Pim1 promoted the Warburg effect and that Pim1 expression was positively correlated with hexokinase 2 and lactate dehydrogenase A expression. Pim1‐silenced cells were more vulnerable to glucose starvation, and Pim1‐induced tumor proliferation or tolerance to glucose starvation was attenuated by blocking the Warburg effect. In conclusion, glucose deprivation is one of the mechanisms that leads to elevated Pim1 expression in CRC, and Pim1 upregulation ensures CRC growth in response to glucose deprivation by facilitating the Warburg effect in a compensatory way.

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“…In response to viral infections, glycolysis may be increased or decreased, with beneficial results for viruses, for example, in the case of herpes simplex virus 1 and adenovirus infections (Abrantes et al, 2012;Thai et al, 2014). Studies found that HBV infection modulated host liver metabolic pathways, resulting in upregulation of glucose metabolism (e.g., gluconeogenesis, aerobic oxidation of glucose, and pentose phosphate pathway; Liu et al, 2015;Shin et al, 2011) and lipid metabolism (e.g., fatty acids, phospholipids, and cholesterol biosynthesis; Chen, Liang, Ou, Goldstein, & Brown, 2004;M. D. Wang et al, 2016;Yang et al, 2008).…”

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confidence: 99%

AMPK and Akt/mTOR signalling pathways participate in glucose‐mediated regulation of hepatitis B virus replication and cellular autophagy

Wang

Lin

Kemper

et al. 2019

Cellular Microbiology

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A growing consensus indicates that host metabolism plays a vital role in viral infections.Hepatitis B virus (HBV) infection occurs in hepatocytes with active glucose metabolism and may be regulated by cellular metabolism. We addressed the question whether and how glucose regulates HBV replication in hepatocytes. The low glucose concentration at 5 mM significantly promoted HBV replication via enhanced transcription and autophagy when compared with higher glucose concentrations (10 and 25 mM). At low glucose concentration, AMPK activity was increased and led to ULK1 phosphorylation at Ser 555 and LC3-II accumulation. By contrast, the mTOR pathway was activated by high glucose concentrations, resulting in reduced HBV replication. mTOR inhibition by rapamycin reversed negative effects of high glucose concentrations on HBV replication, suggesting that low glucose concentration promotes HBV replication by stimulating the AMPK/mTOR-ULK1-autophagy axis. Consistently, we found that glucose transporters inhibition using phloretin also enhanced HBV replication via increased AMPK/mTOR-ULK1-induced autophagy. Surprisingly, the glucose analogue 2-deoxy-D-glucose reduced HBV replication through activating the Akt/mTOR signalling pathway also at the low glucose concentrations. Our study reveals that glucose is an important factor for the HBV life cycle by regulating HBV transcription and posttranscriptional steps of HBV replication via cellular autophagy.

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HBx regulates fatty acid oxidation to promote hepatocellular carcinoma survival during metabolic stress

Cited by 63 publications

References 53 publications

Modularity of the metabolic gene network as a prognostic biomarker for hepatocellular carcinoma

Modularity of the metabolic gene network as a prognostic biomarker for hepatocellular carcinoma

Pim1 supports human colorectal cancer growth during glucose deprivation by enhancing the Warburg effect

AMPK and Akt/mTOR signalling pathways participate in glucose‐mediated regulation of hepatitis B virus replication and cellular autophagy

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