Original contributionPIGU overexpression adds value to TNM staging in the prognostic stratification of patients with hepatocellular carcinoma☆,☆☆
Introduction
Hepatocellular carcinoma (HCC) is a major public health problem, with more than 700 000 new cases and deaths occurring yearly worldwide, and China alone accounts for approximately 50% [1]. Because of a low rate of early diagnosis and lack of treatment options in the advanced stage, the prognosis of HCC remains poor [2]. HCC tends to be heterogeneous, both clinically and biologically, with different outcomes and treatment responses even in patients with the same TNM stage [3]. Therefore, identification of molecular biomarkers that accurately predict clinical outcomes could be of substantial aid in better patient stratification and may even lead to novel targeted therapies in specific subsets of patients.
Glycosylphosphatidylinositol (GPI) membrane anchoring of proteins is a widespread phenomenon that specifically tethers proteins to lipid bilayers [4]. This posttranslational glycolipid modification is introduced into proteins via GPI transamidase (GPI-T), which contains 5 known subunits, namely, phosphatidylinositol glycan anchor biosynthesis class K, phosphatidylinositol glycan anchor biosynthesis class T, glycosylphosphatidylinositol anchor attachment 1 (GPAA1), phosphatidylinositol glycan anchor biosynthesis class S, and phosphatidylinositol glycan anchor biosynthesis class U (PIGU) [5]. Overexpression of one or more GPI-T subunits has been reported in various tumors, such as breast cancer, ovarian cancer, and uterine cancer, indicating that GPI-T itself may be tumorigenic [6], [7]. PIGU, a hydrophobic protein that is essential for GPI-T activity, has been reported to be the first oncogenic GPI-T subunit [8]. PIGU is overexpressed in bladder cancer, breast cancer, and lymphoma. In bladder cancer, PIGU exerts its oncogenic role via increasing GPI-T activity and anchoring substrate proteins such as urokinase plasminogen activator surface receptor (UPAR) [9]. Genome-wide association studies analysis showed that PIGU polymorphism is associated with an increased susceptibility to cutaneous melanoma [10]. Moreover, researchers discovered that the presence of a reciprocal balanced translocation event between asparagine-linked glycosylation protein 5 homolog (ALG5) and PIGU can give rise to 2 novel gene fusions (ALG5-PIGU and PIGU-ALG5), implicating PIGU as a potential oncogene in prostate cancer [11]. Nevertheless, the expression profile, clinical importance, and biological role of PIGU in HCC are unclear and need further exploration.
In the present study, we investigated the expression profile of GPI-T in HCC tissues and provided the first evidence that PIGU is the most significantly overexpressed GPI-T subunit in HCC tissues at both the RNA and protein levels. Using Kaplan-Meier analysis, subgroup analysis, and Cox proportional hazards regression models, we then comprehensively explored the prognostic impact of overexpressed PIGU in HCC patients in 2 independent HCC cohorts. Furthermore, based on the constructed nomogram, we proposed a risk score combining PIGU expression with the standard TNM staging system and provided a more powerful tool for prognostic stratification of HCC patients. We also investigated the potential functional role of PIGU in HCC by performing bioinformatic analysis, indicating that PIGU may be involved in cell cycle–related biological processes.
Section snippets
Patients and tissue specimens
Forty paired fresh-frozen HCCs and adjacent nontumor tissue samples used in quantitative real-time polymerase chain reaction (qRT-PCR) were randomly collected from HCC patients who had underwent hepatectomy at Peking Union Medical College Hospital (PUMCH; Beijing, China) between 2010 and 2014. All samples were collected immediately after resection of the tumors and then stored in liquid nitrogen.
One hundred sixty-six HCC, 31 paratumor, and 36 normal liver tissue samples were used in tissue
PIGU is the most significantly overexpressed GPI-T subunit in HCC
First, we searched the TCGA database to identify the expression profile of the GPI-T complex genes in HCC. We found that almost all 5 GPI-T subunits tended to be up-regulated in HCC tissues compared with paratumor tissues, and PIGU was the most significant overexpressed subunit (Fig. 1A and B). To further examine the expression pattern of the GPI-T subunits, we performed qRT-PCR in clinical HCC samples. The results confirmed that PIGU was consistently overexpressed in HCC tissues (Fig. 1C). We
Discussion
Existing studies have shown that the expression and prognostic significance of PIGU in HCC remain unknown. This study represents the first investigation of dysregulated PIGU expression and its prognostic impact on HCC patients. Our results indicated that PIGU was the most significantly overexpressed GPI-T complex gene in HCC tissues and that HCC patients with high PIGU expression had a poorer survival. Moreover, our study revealed that the nomogram-based risk score, which incorporated PIGU
Author contributions
X. He and J. Cao designed the research. J. Cao, P. Wang, and J. Chen performed the research. J. Cao analyzed the data. X. He and J. Cao wrote the manuscript.
Supplementary data
The following are the supplementary data to this article.
References (19)
- et al.
Hepatocellular carcinoma
Lancet
(2012) - et al.
Profiling the expression pattern of GPI transamidase complex subunits in human cancer
Mod Pathol
(2008) - et al.
Global cancer statistics, 2012
CA Cancer J Clin
(2015) - et al.
Hepatocellular carcinoma: clinical frontiers and perspectives
Gut
(2014) - et al.
The glycosylphosphatidylinositol anchor: a complex membrane-anchoring structure for proteins
Biochemistry
(2008) - et al.
GPI-anchor remodeling: potential functions of GPI-anchors in intracellular trafficking and membrane dynamics
Biochim Biophys Acta
(1821) - et al.
GPI transamidase and GPI anchored proteins: oncogenes and biomarkers for cancer
Crit Rev Biochem Mol Biol
(2013) - et al.
Human PIG-U and yeast Cdc91p are the fifth subunit of GPI transamidase that attaches GPI-anchors to proteins
Mol Biol Cell
(2003) - et al.
CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer
Nat Med
(2004)
Cited by (14)
PIGU promotes hepatocellular carcinoma progression through activating NF-κB pathway and increasing immune escape
2020, Life SciencesCitation Excerpt :Among them, PIGU has been reported to participate in the recognition of long-chain fatty acids in GPI and play a role in promoting cancer progression by increasing the activity of GPI-T [7,9]. It is reported that PIGU was overexpressed in HCC, and overexpression of PIGU was an independent predictor of poor survival in HCC patients [10]. The findings indicated that PIGU plays a vital role in the development of HCC, but the functions and regulatory mechanisms of PIGU in HCC are still unknown.
Prognostic value and oncogene function of heterogeneous nuclear ribonucleoprotein A1 overexpression in HBV-related hepatocellular carcinoma
2019, International Journal of Biological MacromoleculesCitation Excerpt :There is an urgent medical demand to develop treatment strategies that can improve the treatment outcome of HCC [3]. Therefore, the identification of molecular biomarkers that predict the prognosis of clinical treatment may be of substantial help in the development of patient treatment strategies, and may even lead to new targeted therapies in specific patients [4]. Hepatitis B virus (HBV) is reported to be one of the major risk factors for the development and progression of HCC.
PIGT promotes cell growth, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking
2024, Journal of Translational MedicineThe Prognostic Significance and Potential Mechanism of Ferroptosis-Related Genes in Hepatocellular Carcinoma
2022, Frontiers in GeneticsSystemic characterization of the SLC family genes reveals SLC26A6 as a novel oncogene in hepatocellular carcinoma
2021, Translational Cancer Research
- ☆
Competing interests: The authors declare that there are no conflicts of interest.
- ☆☆
Funding/Support: This work was supported by CAMS Initiative for Innovative Medicine (CAMS-I2M) (2017-12M-4-003) and the National Natural Science Foundation of China (81372578, to X. D. H.).
- 1
J. Cao, P. Wang, and J. Chen contributed equally to this work.