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Angiopoietin-Like Protein 2 Acts as a Novel Biomarker for Diagnosis and Prognosis in Patients with Esophageal Cancer

Annals of Surgical Oncology volume 22, pages 2585–2592 (2015)Cite this article

Abstract

Background

Angiopoietin-like protein 2 (ANGPTL2) mediates chronic inflammation. Tumor cell-derived ANGPTL2 promotes tumor invasion and angiogenesis. Overexpression of ANGPTL2 in tumor cells is associated with tumor progression and has been recognized in lung, breast, colon, and gastric cancer. However, to our knowledge the functional and clinical significance of ANGPTL2 expression has not been investigated in patients with esophageal cancer (EC).

Methods

First, in vitro assays were performed for functional analysis of ANGPTL2 using small interfering RNA. Next, ANGPTL2 expression in EC tissues (n = 71) was evaluated by immunohistochemistry (IHC in patients with EC (n = 71). Finally, serum ANGPLT2 levels from patients with EC (n = 71) and healthy controls (n = 35) were evaluated using enzyme-linked immunosorbent assay.

Results

Knockdown of ANGPTL2 expression decreased the proliferative, invasive, and migration capacity in EC cell lines. ANGPTL2 expression in EC tissues was significantly elevated in patients with a high T stage, squamous cell carcinoma, and high TNM stage. Patients with high ANGPTL2 expression had significantly poorer overall and disease-free survival than those with low expression. Furthermore, high ANGPTL2 expression in EC tissues was an independent predictive marker for a poor prognosis. On the other hand, the serum ANGPTL2 level in patients with EC was significantly higher than that in healthy controls, and allowed for highly accurate discrimination between patients with and without EC. However, no significant association between serum ANGPTL2 levels and clinicopathological findings was observed in patients with EC.

Conclusions

We have demonstrated novel evidence for the clinical significance of ANGPTL2 as a biomarker in patients with EC.

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Abbreviations

ANGPTL2:

angiopoietin-like protein 2

EC:

esophageal cancer

siRNA:

small interfering RNA

ESCC:

esophageal squamous cell carcinoma

EAD:

esophageal adenocarcinoma

IHC:

immunohistochemistry

GC:

gastric cancer

CRC:

colorectal cancer

cDNA:

complementary DNA

qRT-PCR:

quantitative real-time polymerase chain reaction

ELISA:

enzyme-linked immunosorbent assay

OS:

overall survival

DFS:

disease-free survival

ROC:

receiver operating characteristic

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Disclosure

Shozo Ide, Yuji Toiyama, Tadanobu Shimura, Mikio Kawamura, Hiromi Yasuda, Susumu Saigusa, Masaki Ohi, Koji Tanaka, Yasuhiko Mohri, and Masato Kusunoki have nothig to disclose.

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Affiliations

  1. Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan

    Shozo Ide MD, Yuji Toiyama PhD, MD, Tadanobu Shimura PhD, MD, Mikio Kawamura PhD, MD, Hiromi Yasuda PhD, MD, Susumu Saigusa PhD, MD, Masaki Ohi PhD, MD, Koji Tanaka PhD, MD, Yasuhiko Mohri PhD, MD & Masato Kusunoki PhD, MD

Authors
  1. Shozo Ide MD
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  2. Yuji Toiyama PhD, MD
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  3. Tadanobu Shimura PhD, MD
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  4. Mikio Kawamura PhD, MD
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  5. Hiromi Yasuda PhD, MD
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  6. Susumu Saigusa PhD, MD
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  7. Masaki Ohi PhD, MD
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  8. Koji Tanaka PhD, MD
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  9. Yasuhiko Mohri PhD, MD
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  10. Masato Kusunoki PhD, MD
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Corresponding author

Correspondence to Yuji Toiyama PhD, MD.

Electronic supplementary material

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10434_2014_4315_MOESM1_ESM.tif

Extent of ANGPTL2 IHC staining.Representative photomicrographs obtained from immunohistochemicalstaining to analyze ANGPTL2 expression in primary esophageal cancer (EC) tissue specimens (original magnification, ×100). Scores for extent of ANGPTL2 staining in EC: 0%: 0, (a) 1–25%: 1, (b) 26–50%: 2, (c) 51–75%: 3, and (d) 76–100%: 4 (TIFF 3916 kb)

10434_2014_4315_MOESM2_ESM.tif

Intensity of ANGPTL2IHC staining.Representative photomicrographs obtained from immunohistochemicalstaining to analyze ANGPTL2 expression in primary esophageal cancer (EC) tissue specimens (original magnification, ×100). Scores for intensity of ANGPTL2 staining in EC: (a) no staining: 0, (b) weak staining: 1, (c) moderate staining: 2, and (d) strong staining: 3 (TIFF 3912 kb)

10434_2014_4315_MOESM3_ESM.tif

Expression and knockdown of ANGPTL2 in EC cell lines.(a)Relative quantification of ANGPTL2 mRNA expression in six esophageal cancer (EC) cell lines based on the 2-⊿Ct method. (b, c) Expression of ANGPTL2 in TE1 and TE2 after siRNA transfection (2-⊿Ct method). (d, e) ANGPTL2 expression in TE1 and TE3 at 48 hours after siRNA transfection as evaluated by ELISA. Control: negative-control siRNA-treated cells, si: ANGPTL2 siRNA-treated cells (TIFF 238 kb)

Supplementary material 4 (DOCX 16 kb)

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Ide, S., Toiyama, Y., Shimura, T. et al. Angiopoietin-Like Protein 2 Acts as a Novel Biomarker for Diagnosis and Prognosis in Patients with Esophageal Cancer. Ann Surg Oncol 22, 2585–2592 (2015). https://doi.org/10.1245/s10434-014-4315-0

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  • DOI: https://doi.org/10.1245/s10434-014-4315-0

Keywords

  • Esophageal Cancer
  • Esophageal Squamous Cell Carcinoma
  • National Comprehensive Cancer Network
  • Poor Overall Survival
  • Esophageal Cancer Cell