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.
Highlights
Betatrophin, known as hepatocellular carcinoma-associated protein TD26, lipasin, refeeding induced fat and liver (RIFL), atypical angiopoietin-like protein 8 (ANGPTL8) or C19orf80 [1,2,3], is a newly identified secreted metabolic regulator predominantly expressed in the human liver
Gene symbols for ANGPTL8/betatrophin identified in each database were shown in Table 1 and tumor abbreviations were listed in Supplementary Table S1
The results of the Pathology Atlas showed that ANGPTL8/betatrophin was enriched in liver cancer across 17 cancer types (Supplementary Figure S4)
Summary
Betatrophin, known as hepatocellular carcinoma-associated protein TD26, lipasin, refeeding induced fat and liver (RIFL), atypical angiopoietin-like protein 8 (ANGPTL8) or C19orf80 [1,2,3], is a newly identified secreted metabolic regulator predominantly expressed in the human liver. Previous studies have shown that ANGPTL8/betatrophin is involved in the regulation of both lipid metabolism and glucose homeostasis [3,4,5,6]. It is well known that cancer cells change their metabolism to support rapid proliferation and expansion; abnormal lipid and glucose metabolism has been found to be involved in a variety of cancers [7,8,9,10,11]. The angiopoietin-like protein (ANGPTL) family consists of eight members, ANGPTL1-8. We do not know whether the atypical ANGPTL family member ANGPTL8/betatrophin plays a role in human cancers
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