Original article
Serum level of ANGPTL4 as a potential biomarker in renal cell carcinoma

https://doi.org/10.1016/j.urolonc.2016.12.017Get rights and content

Highlights

  • Serum ANGPTL4 levels were significantly higher in patients with RCC than the controls.

  • Serum ANGPTL4 levels were closely associated with tumor stages of the patients with RCC.

  • Serum ANGPTL4 levels can distinguish patients with RCC from the healthy controls.

  • Serum ANGPTL4 levels were correlated with the prognosis of patients with RCC.

Abstract

Objectives

This study aimed to determine the serum levels of angiopoietin-like 4 (ANGPTL4) in patients with renal cell carcinoma (RCC) and explore its potential as a biomarker.

Materials and methods

Blood samples were taken from 110 patients with RCC, 66 healthy controls, and patients with other solid tumors. Serum ANGPTL4 levels were measured using the enzyme-linked immunosorbent assay, and their correlation with clinical characteristics was further analyzed. Received operating characteristic (ROC) curves, Kaplan-Meier curves, and log-rank analyses were used to evaluate diagnostic and prognostic significance.

Results

Serum ANGPTL4 levels were significantly higher in patients with RCC compared with healthy controls and patients with other types of cancers (P<0.0001) and associated with sex, Fuhrman grades, metastasis states, and tumor node metastasis stages (P<0.05), but not with age, tumor size, and histological types (P>0.05). The ROCs/area under the ROC curve analysis indicated an area under the ROC curve of 0.844 (sensitivity = 0.691; specificity = 0.939) and 0.725 (sensitivity = 0.909; specificity = 0.568), respectively, to distinguish patients with RCC from healthy controls and those with metastasis from those without metastasis. The survival analysis revealed that patients with low serum ANGPTL4 had longer progression-free survival compared with those with high serum ANGPTL4 (P = 0.033).

Conclusion

The present study suggested that the elevated serum ANGPTL4 level might be a novel diagnostic and prognostic biomarker for patients with RCC.

Introduction

Renal cell carcinoma (RCC), the most common type of kidney cancer, accounts for approximately 2% to 3% of all malignancies [1]. It is the leading secondary cause of death among all types of urologic tumors [1]. Although the number of patients diagnosed with RCC is increasing over the years, many patients (25%–30%) nevertheless have distant metastases at diagnosis. In approximately 30% of the remaining patients, the disease will progress with metastasis [2]. To date, surgery is still the most effective treatment for local RCC. However, prognosis remains poor for advanced and metastatic RCCs because of low sensitivity to chemotherapy and radiotherapy [3], [4]. It is, therefore, of great importance to find the biomarkers for early diagnosis and to develop more effective systemic therapies for progressive disease.

Angiopoietin-like protein 4 (ANGPTL4), also known as hepatic fibrinogen/angiopoietin-related protein, fasting-induced adipose factor, or peroxisome proliferator-activated receptor-c angiopoietin-related gene, is a circulating glycoprotein that structurally belongs to the angiopoietin/ANGPTL family [5]. Human ANGPTL4 protein consists of 406 amino acids with a signal peptide directing secretion, an amino-terminal coiled-coil domain, a linker, and a carboxy-terminal fibrinogen-like domain [6]. ANGPTL4 has been reported to exhibit distinct biological functions, and the most studied function of ANGPTL4 is its effects in regulating lipid metabolism, particularly as an inhibitor of lipoprotein lipase activity [7], [8], [9], [10]. Recent studies have concentrated on the roles of ANGPTL4 in tumor progression in various cancers; however, the effects of ANGPTL4 in human cancers remain controversial. The overexpression of ANGPTL4 can promote tumorigenesis, angiogenesis, tumor invasion, and metastasis [11], [12], [13], [14], [15]. On the contrary, ANGPTL4 has antimetastatic effects on tumor cells through inhibiting vascular permeability, motility, and invasiveness [5] or through attenuating endothelial cell adhesion, migration, and sprouting [16].

Increased levels of ANGPTL4 mRNA have been demonstrated in RCC compared with the nontumor tissues [14], [15]. However, no study has investigated the clinical significance of serum ANGPTL4 levels in RCC. In this study, the serum levels of ANGPTL4 were measured in patients with RCC, healthy controls, and patients with other types of solid tumor using an enzyme-linked immunosorbent assay (ELISA), and the association between the clinical characteristics of RCC and serum ANGPTL4 levels was analyzed.

Section snippets

Patients and specimens

Blood samples were taken from 110 patients with RCC before surgery and 66 healthy controls. Patients with other cancers were evaluated regarding marker specificity, including 34 with bladder cancer, 30 with breast cancer, 21 with gastrointestinal cancer, and 21 with lung adenocarcinoma. All of the serum samples were harvested before surgery or treatment from Tianjin Medical University Cancer Institute and Hospital between July 2010 and August 2014. All samples were collected, aliquoted, and

Serum ANGPTL4 was up-regulated in patients with RCC

Serum ANGPTL4 levels were detected in patients with RCC and healthy controls. A total of 176 participants were enrolled in this study. The serum levels of ANGPTL4 in patients with RCC (n = 110) and healthy controls (n = 66) were assessed using ELISA. The serum levels of ANGPTL4 in the 2 groups are shown in Fig. 1. Compared with the control patients, ANGPTL4 was highly expressed in patients with RCC. The mean expression level of ANGPTL4 in patients with RCC was twice of that in control patients.

Discussion

RCC is a common urologic malignancy characterized by a high frequency of local invasion and distant metastasis; most patients with RCC are diagnosed at an advanced stage. Lack of reliable biomarkers to detect metastases and predict survival is a challenge worthy of study. Noninvasive blood-based biomarkers can be used to guide treatment decisions, monitor response to therapy, and detect the early recurrence of disease. Some potential biomarkers have been reported in the previous literature [18]

Ethical approval

All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki Declaration ethical standards and approved by the Research Ethics Committee of Tianjin Medical University Cancer Institute and Hospital.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References (31)

  • X. Na et al.

    Overproduction of vascular endothelial growth factor related to von Hippel-Lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 alpha expression in renal cell carcinomas

    J Urol

    (2003)
  • T. Robal et al.

    Fatty acids bind tightly to the N-terminal domain of angiopoietin-like protein 4 and modulate its interaction with lipoprotein lipase

    J Biol Chem

    (2012)
  • B. Ljungberg

    Prognostic markers in renal cell carcinoma

    Curr Opin Urol

    (2007)
  • H.T. Cohen et al.

    Renal-cell carcinoma

    N Engl J Med

    (2005)
  • A. Galaup et al.

    Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness

    Proc Natl Acad Sci U S A

    (2006)
  • Cited by (0)

    This work was supported by research grants from the National Natural Science Foundation of China (Nos. 81502519 and 81201653), and the Natural Science Foundation of Tianjin City, China (16JCYBJC26000).

    1

    Dong Dong and Li Jia contributed equally to this work.

    View full text