PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis

Hong, Xuehui; Song, Ran; Song, Huiwen; Zheng, Tongsen; Wang, Jiabei; Liang, Yingjian; Qi, Shuyi; Lu, Zhao-Yang; Song, Xuan; Jiang, Hongchi; Liu, Lianxin; Zhang, Zhiyong

doi:10.1136/gutjnl-2013-305302

Cited by 101 publications

(98 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Meanwhile, genes that are associated with the production and utilization of antioxidants, including NADPH, glutathione, and thioredoxin, have been implicated in HCC. Glucose 6 phosphate dehydrogenase, a critical enzyme in the pentose phosphate pathway generating NADPH, has been shown to be overexpressed in HCC in a PTEN-dependent manner (41). Overexpression of thioredoxin and thioredoxin-related REDOX molecules, glutaredoxin and peroxiredoxin, was documented in HCC and was associated with increased proliferative output, aggressive clinicopathologic parameters, presence of metastasis, and poor prognosis in HCC patients (42,43).…”

Section: Discussionmentioning

confidence: 99%

NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma

Lai

Chiu

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Hepatocellular carcinoma (HCC) lacks effective curative therapy. Hypoxia is commonly found in HCC. Hypoxia elicits a series of protumorigenic responses through hypoxia-inducible factor-1 (HIF1). Better understanding of the metabolic adaptations of HCC cells during hypoxia is essential to the design of new therapeutic regimen.Experimental Design: Expressions of genes involved in the electron transport chain (ETC) in HCC cell lines (20% and 1% O 2 ) and human HCC samples were analyzed by transcriptome sequencing. Expression of NDUFA4L2, a less active subunit in complex I of the ETC, in 100 pairs of HCC and nontumorous liver tissues were analyzed by qRT-PCR. Student t test and KaplanMeier analyses were used for clinicopathologic correlation and survival studies. Orthotopic HCC implantation model was used to evaluate the efficiency of HIF inhibitor.Results: NDUFA4L2 was drastically overexpressed in human HCC and induced by hypoxia. NDUFA4L2 overexpression was closely associated with tumor microsatellite formation, absence of tumor encapsulation, and poor overall survival in HCC patients. We confirmed that NDUFA4L2 was HIF1-regulated in HCC cells. Inactivation of HIF1/NDUFA4L2 increased mitochondrial activity and oxygen consumption, resulting in ROS accumulation and apoptosis. Knockdown of NDUFA4L2 markedly suppressed HCC growth and metastasis in vivo. HIF inhibitor, digoxin, significantly suppressed growth of tumors that expressed high level of NDUFA4L2.Conclusions: Our study has provided the first clinical relevance of NDUFA4L2 in human cancer and suggested that HCC patients with NDUFA4L2 overexpression may be suitable candidates for HIF inhibitor treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma

Lai

Chiu

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…The development and progression of HCC is a complicated process that involves the deregulation of multiple genes that are essential for cell biological processes (14,15). Previously, a distinct choline transporter called the SLC44A1-5 family was shown to be present in various human cancer cells (16).…”

Section: Discussionmentioning

confidence: 99%

Knockdown by shRNA identifies SLC44A5 as a potential therapeutic target in hepatocellular carcinoma

Peng

Ren

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Hepatocellular carcinoma (HCC) has been ranked the second leading cause of cancer-associated mortality in China and the third leading cause of cancer-associated mortality worldwide. A number of previous studies investigating SLC44A5 have revealed important biological insight and disease-specific functions. Therefore, the present study investigated the expression of SLC44A5 in HCC tissues and cell lines, and assessed the effect of SLC44A5 on the viability, cell cycle, apoptosis and invasion of HCC cell lines. The mRNA expression of SLC44A5 in 35 HCC tissues was significantly higher compared with that in 35 normal tissues. The protein expression of SLC44A5 was notably high in MHCC-97H and SMMC-7721 cells compared with that in four other HCC cell lines. Knockdown of SLC44A5 using short hairpin RNA inhibited cell viability and arrested the cells in G1 of the cell cycle by reducing the expression of cell cycle markers, proliferating cell nuclear antigen and cyclin-dependent kinase 2 in MHCC-97H and SMMC-7721 cells. Furthermore, SLC44A5 knockdown cells also exhibited cell apoptosis by reducing the expression levels of apoptosis markers, caspase-3 and caspase-9 in MHCC-97H and SMMC-7721 cells, and suppressed invasion. The present results suggested that SLC44A5 is involved in HCC carcinogenesis and progression in HCC, indicating that SLC44A5 may be a molecular target in cancer therapy.

show abstract

“…Ex vivo imaging showed that lung metastasis was found in 0 of 6 mice and 1 of 6 mice in the 2 MTHFD1L-knockdown groups as opposed to its occurrence in 5 of 6 mice from the NTC group ( Figure 8B). Histological analysis suggested that tumors derived phate pathway (PPP), was overexpressed in HCC owing to the inactivation of PTEN (33). Malic enzymes were overexpressed in human HCC (34) and were found to be repressed by p53 in osteosarcoma cells (35).…”

Section: Inhibition Of the Folate Cycle Represses Hcc Growth And Sensmentioning

confidence: 99%

Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma

Lee¹,

Xu²,

Chiu³

et al. 2017

Journal of Clinical Investigation

115

106

View full text Add to dashboard Cite

PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis

Abstract: These results establish the counteraction between PTEN and Tcl1 as a key mechanism that regulates the PPP and suggest that targeting the PTEN/Tcl1/hnRNPK/G6PD axis could open up possibilities for therapeutic intervention and improve the prognosis of patients with HCC.

Cited by 101 publications

References 25 publications

NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma

NDUFA4L2 Fine-tunes Oxidative Stress in Hepatocellular Carcinoma

Knockdown by shRNA identifies SLC44A5 as a potential therapeutic target in hepatocellular carcinoma

Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma

Contact Info

Product

Resources

About