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. 2021 Sep 27:27:1609914.
doi: 10.3389/pore.2021.1609914. eCollection 2021.

Analysis of the Expression and Prognostic Potential of a Novel Metabolic Regulator ANGPTL8/Betatrophin in Human Cancers

Fangfang Xu  1 , Dandan Tian  2 , Xiaoyang Shi  3 , Kai Sun  4 , Yuqing Chen  4
Affiliations

Analysis of the Expression and Prognostic Potential of a Novel Metabolic Regulator ANGPTL8/Betatrophin in Human Cancers

Fangfang Xu et al. Pathol Oncol Res. .

Abstract

The angiopoietin-like protein (ANGPTL) family members, except for the novel atypical member ANGPTL8/betatrophin, have been reported to participate in angiogenesis, inflammation and cancer. ANGPTL8/betatrophin is a metabolic regulator that is involved in lipid metabolism and glucose homeostasis. However, little is known about the expression and prognostic value of ANGPTL8/betatrophin in human cancers. In this study, we first conducted detailed analyses of ANGPTL8/betatrophin expression in cancer/normal samples via the Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), DriverDBv3, ENCORI and UALCAN databases. ANGPTL8/betatrophin showed high tissue specificity (enriched in the liver) and cell-type specificity (enriched in HepG2 and MCF7 cell lines). More than one databases demonstrated that the gene expression of ANGPTL8/betatrophin was significantly lower in cholangiocarcinoma (CHOL), breast invasive carcinoma (BRCA), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), uterine corpus endometrial carcinoma (UCEC), and significantly higher in kidney renal clear cell carcinoma (KIRC) compared with that in normal samples. However, the protein expression of ANGPTL8/betatrophin displayed opposite results in clear cell renal cell carcinoma (ccRCC)/KIRC. Based on the expression profiles, the prognostic value was evaluated with the GEPIA, DriverDBv3, Kaplan Meier plotter and ENCORI databases. Two or more databases demonstrated that ANGPTL8/betatrophin significantly affected the survival of KIRC, uterine corpus endometrial carcinoma (UCEC), pheochromocytoma and paraganglioma (PCPG) and sarcoma (SARC); patients with PCPG and SARC may benifit from high ANGPTL8/betatrophin expression while high ANGPTL8/betatrophin expression was associated with poor prognosis in KIRC and UCEC. Functional analyses with the GeneMANIA, Metascape and STRING databases suggested that ANGPTL8/betatrophin was mainly involved in lipid homeostasis, especially triglyceride and cholesterol metabolism; glucose homeostasis, especially insulin resistance; AMPK signaling pathway; PI3K/Akt signaling pathway; PPAR signaling pathway; mTOR signaling pathway; HIF-1 signaling pathway; autophagy; regulation of inflammatory response. ANGPTL8/betatrophin may be a promising prognostic biomarker and therapeutic target, thus providing evidence to support further exploration of its role in defined human cancers.

Keywords: ANGPTL8/betatrophin; Akt signaling; differential expression analysis; glucose homeostasis; inflammation; lipid metabolism; prognostic biomarker.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
ANGPTL8/betatrophin expression between tumor and normal samples determined by the GEPIA database. GEPIA, Gene Expression Profiling Interactive Analysis; BRCA, Breast invasive carcinoma; CHOL, Cholangiocarcinoma; *p < 0.05.
FIGURE 2
FIGURE 2
ANGPTL8/betatrophin expression between tumor and normal samples determined by the DriverDBv3 database. DriverDBv3, a database for human cancer driver gene research; BLCA, Bladder urothelial carcinoma; BRCA, Breast invasive carcinoma; CHOL, Cholangiocarcinoma; COAD, Colon adenocarcinoma; KIRC, Kidney renal clear cell carcinoma; LUAD, Lung adenocarcinoma; LUSC, Lung squamous cell carcinoma; READ, Rectum adenocarcinoma; UCEC, Uterine corpus endometrial carcinoma; *p < 0.05, **p < 0.01, ***p < 0.001 vs. normal.
FIGURE 3
FIGURE 3
ANGPTL8/betatrophin expression between tumor and normal samples determined by the ENCORI database. ENCORI, The Encyclopedia of RNA Interactomes; BRCA, Breast invasive carcinoma; UCEC, Uterine corpus endometrial carcinoma; KIRC, Kidney renal clear cell carcinoma; CHOL, Cholangiocarcinoma; STAD, Stomach adenocarcinoma; LUSC, Lung squamous cell carcinoma; KICH, Kidney chromophobe; LUAD, Lung adenocarcinoma; *p < 0.05, ***p < 0.001 vs. normal.
FIGURE 4
FIGURE 4
Comparisons of ANGPTL8/betatrophin expression profile resulted from different databases through a Venn diagram. GEPIA, Gene Expression Profiling Interactive Analysis; DriverDBv3: A database for human cancer driver gene research; ENCORI, The Encyclopedia of RNA Interactomes; CHOL, Cholangiocarcinoma; BRCA, Breast invasive carcinoma; KIRC, Kidney renal clear cell carcinoma; UCEC, Uterine corpus endometrial carcinoma; LUSC, Lung squamous cell carcinoma; LUAD, Lung adenocarcinoma; COAD, Colon adenocarcinoma; BLCA, Bladder urothelial carcinoma; READ, Rectum adenocarcinoma; KICH, Kidney chromophobe; STAD, Stomach adenocarcinoma.
FIGURE 5
FIGURE 5
Survival analysis of ANGPTL8/betatrophin in cancer patients from the GEPIA database. Both the OS and DFS survival curves of (A,B) KIRC, (C,D) LUSC, (E,F) PCPG, (G,H) SARC, (I,J) THYM, (K,L) UCS were analyzed. GEPIA, Gene Expression Profiling Interactive Analysis; OS, overall survival; DFS, disease-free survival; KIRC, kidney renal clear cell carcinoma; LUSC, Lung squamous cell carcinoma; PCPG, pheochromocytoma and paraganglioma; SARC, Sarcoma; THYM, Thymoma; UCS, Uterine carcinosarcoma.
FIGURE 6
FIGURE 6
Survival analysis of ANGPTL8/betatrophin in cancer patients from the DriverDBv3 database. Overall survival and 5-years survival of both the OS and PFI survival curves of (A–D) SARC, (E–H) KIRC were analyzed. DriverDBv3, a database for human cancer driver gene research; OS, overall survival; PFI, progression-free interval; SARC, Sarcoma; KIRC, kidney renal clear cell carcinoma.
FIGURE 7
FIGURE 7
Survival analysis of ANGPTL8/betatrophin in cancer patients from the Kaplan Meier plotter database. OS survival curves of (A) BLCA, (B) BRCA, (C) PCPG, (D) SARC, (E) KIRC, (F) UCEC were analyzed. BLCA, Bladder urothelial carcinoma; BRCA, Breast invasive carcinoma; PCPG, Pheochromocytoma and paragangliomas; SARC, Sarcoma; KIRC, Kidney renal clear cell carcinoma; UCEC, Uterine corpus endometrial carcinoma.
FIGURE 8
FIGURE 8
Survival analysis of ANGPTL8/betatrophin in cancer patients from the ENCORI database. ENCORI, The Encyclopedia of RNA Interactomes; KIRC, Kidney renal clear cell carcinoma.
FIGURE 9
FIGURE 9
Comparisons of survival analyses of ANGPTL8/betatrophin between different databases through a Venn diagram. GEPIA, Gene Expression Profiling Interactive Analysis; DriverDBv3, a database for human cancer driver gene research; ENCORI, The Encyclopedia of RNA Interactomes; KM plotter, the Kaplan Meier plotter database; KIRC, Kidney renal clear cell carcinoma; SARC, Sarcoma; PCPG, Pheochromocytoma and paragangliomas; UCEC, Uterine corpus endometrial carcinoma; UCS, Uterine carcinosarcoma; LUSC, Lung squamous cell carcinoma; THYM, Thymoma; COAD, Colon adenocarcinoma; UVM, Uveal melanoma; BLCA, Bladder urothelial carcinoma; BRCA, Breast invasive carcinoma.
FIGURE 10
FIGURE 10
PPI network analysis of ANGPTL8/betatrophin via GeneMANIA. The database identified 20 genes closely associated with ANGPTL8/betatrophin. Colors of the networks indicate the data source from publicly available biological datasets: Physical Interaction, Co-expression, Predicted, Co-localization, Genetic interaction, Pathway, Shared protein domains. Colors of the network nodes indicate the functions of enrichment genes. PPI, protein-protein interaction.
FIGURE 11
FIGURE 11
The enrichment analysis of ANGPTL8/betatrophin and the top 20 closely associated genes via Metascape. (A) Bar graph of top 10 enriched terms for ANGPTL8/betatrophin and the top 20 interacting genes, colored by p values. (B) Interactive network of 10 enriched terms colored by cluster ID where nodes that share the same cluster ID are typically close to each other.
FIGURE 12
FIGURE 12
PPI network of genes associated with ANGPTL8/betatrophin using the STRING database. PPI, protein-protein interaction; STRING, Search Tool for the Retrieval of Interacting Genes; colored nodes: query proteins and first shell of interactors; white nodes: second shell of interactors; empty nodes: proteins of unknown 3D structure; filled nodes: some 3D structure is known or predicted.
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