Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 4/2016

01-08-2016 | Translational Research and Biomarkers

Neurotrophin Receptor-Interacting Melanoma Antigen-Encoding Gene Homolog is Associated with Malignant Phenotype of Gastric Cancer

Authors: Mitsuro Kanda, MD, PhD, Dai Shimizu, MD, Tsutomu Fujii, MD, PhD, FACS, Haruyoshi Tanaka, MD, Yuri Tanaka, MD, Kazuhiro Ezaka, MD, Masahiro Shibata, MD, Hideki Takami, MD, PhD, Ryoji Hashimoto, MD, Satoshi Sueoka, MD, Naoki Iwata, MD, PhD, Daisuke Kobayashi, MD, PhD, Chie Tanaka, MD, PhD, Suguru Yamada, MD, PhD, FACS, Goro Nakayama, MD, PhD, Hiroyuki Sugimoto, MD, PhD, Masahiko Koike, MD, PhD, Michitaka Fujiwara, MD, PhD, Yasuhiro Kodera, MD, PhD, FACS

Published in: Annals of Surgical Oncology | Special Issue 4/2016

Login to get access

Abstract

Background

Identification of novel molecules implicated in the malignancy of gastric cancer (GC) is key to the development of personalized treatments and the improvement of patient outcome. Neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE) regulates apoptosis and metastasis via interactions with various genes. This study aimed to evaluate the function and clinical significance of NRAGE in GC.

Methods

The expression of NRAGE and its putative interacting genes apoptosis antagonizing transcription factor (AATF), p75 neurotrophin receptor (p75NTR), and proliferating cell nuclear antigen (PCNA) were determined in GC cell lines using reverse transcription-polymerase chain reaction (RT-PCR). The effect of NRAGE knockdown by small interfering RNA (siRNA) on GC cell behavior also was evaluated. In addition, NRAGE expression was determined in 179 pairs of resected gastric tissues.

Results

Expression of NRAGE mRNA positively correlated with that of AATF, and NRAGE knockdown significantly decreased the proliferation, migration, and invasion of GC cells. The mean level of NRAGE mRNA expression was significantly higher in GC tissues than in corresponding adjacent normal tissues. The expression patterns of NRAGE mRNA and protein were closely correlated. A stepwise elevation in NRAGE mRNA expression in GC tissues was observed with increasing Union for International Cancer Control (UICC) stage. High NRAGE expression in GCs was associated with shortened recurrence-free survival and identified as an independent prognostic factor (hazard ratio, 1.83; 95 % CI, 1.12–3.02, p = 0.017).

Conclusions

The results indicate that NRAGE represents a putative oncogene associated with a malignant phenotype of GC. In GC, NRAGE may serve as a predictive biomarker and a target of molecular therapy.
Appendix
Available only for authorised users
Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMed
2.
Kanda M, Kobayashi D, Tanaka C, et al. Adverse prognostic impact of perioperative allogeneic transfusion on patients with stage II/III gastric cancer. Gastric Cancer. 2016;19:255–63.CrossRefPubMed
3.
4.
5.
Resende C, Thiel A, Machado JC, Ristimaki A. Gastric cancer: basic aspects. Helicobacter. 2011;16(Suppl 1):38–44.CrossRefPubMed
6.
McLean MH, El-Omar EM. Genetics of gastric cancer. Nat Rev Gastroenterol Hepatol. 2014;11:664–74.CrossRefPubMed
7.
Duraes C, Almeida GM, Seruca R, Oliveira C, Carneiro F. Biomarkers for gastric cancer: prognostic, predictive or targets of therapy? Virchows Arch. 2014;464:367–78.CrossRefPubMed
8.
Kanda M, Nomoto S, Oya H, et al. Decreased expression of prenyl diphosphate synthase subunit 2 correlates with reduced survival of patients with gastric cancer. J Exp Clin Cancer Res. 2014;33:88.CrossRefPubMedPubMedCentral
9.
Barker PA, Salehi A. The MAGE proteins: emerging roles in cell cycle progression, apoptosis, and neurogenetic disease. J Neurosci Res. 2002;67:705–12.CrossRefPubMed
10.
Sang M, Wang L, Ding C, et al. Melanoma-associated antigen genes: an update. Cancer Lett. 2011;302:85–90.CrossRefPubMed
11.
Wang X, Gao X, Xu Y. MAGED1: molecular insights and clinical implications. Ann Med. 2011;43:347–55.CrossRefPubMed
12.
Oya H, Kanda M, Takami H, et al. Overexpression of melanoma-associated antigen D4 is an independent prognostic factor in squamous cell carcinoma of the esophagus. Dis Esophagus. 2015;28:188–95.CrossRefPubMed
13.
Du Q, Zhang Y, Tian XX, Li Y, Fang WG. MAGE-D1 inhibits proliferation, migration, and invasion of human breast cancer cells. Oncol Rep. 2009;22:659–65.PubMed
14.
Yang Q, Ou C, Liu M, Xiao W, Wen C, Sun F. NRAGE promotes cell proliferation by stabilizing PCNA in a ubiquitin-proteasome pathway in esophageal carcinomas. Carcinogenesis. 2014;35:1643–51.CrossRefPubMed
15.
Salehi AH, Roux PP, Kubu CJ, et al. NRAGE, a novel MAGE protein, interacts with the p75 neurotrophin receptor and facilitates nerve growth factor-dependent apoptosis. Neuron. 2000;27:279–88.CrossRefPubMed
16.
Matluk N, Rochira JA, Karaczyn A, Adams T, Verdi JM. A role for NRAGE in NF-kappaB activation through the non-canonical BMP pathway. BMC Biol. 2010;8:7.CrossRefPubMedPubMedCentral
17.
Xue XY, Liu ZH, Jing FM, Li YG, Liu HZ, Gao XS. Relationship between NRAGE and the radioresistance of esophageal carcinoma cell line TE13R120. Chin J Cancer. 2010;29:900–6.CrossRefPubMed
18.
Passananti C, Fanciulli M. The anti-apoptotic factor Che-1/AATF links transcriptional regulation, cell cycle control, and DNA damage response. Cell Div. 2007;2:21.CrossRefPubMedPubMedCentral
19.
Chu CS, Xue B, Tu C, et al. NRAGE suppresses metastasis of melanoma and pancreatic cancer in vitro and in vivo. Cancer Lett. 2007;250:268–75.CrossRefPubMed
20.
21.
Lee D, Lee GK, Yoon KA, Lee JS. Pathway-based analysis using genome-wide association data from a Korean non-small cell lung cancer study. PLoS One. 2013;8:e65396.CrossRefPubMedPubMedCentral
22.
Kanda M, Shimizu D, Nomoto S, et al. Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer. Gastric Cancer. 2015;18:288–96.CrossRefPubMed
23.
Sobin LH, Gospodarowicz MK, Wittekind C. International Union against cancer; TNM classification of malignant tumors. 7th ed. New York: Wiley-Blackwell; 2009.
24.
Kanda M, Kodera Y, Sakamoto J. Updated evidence on adjuvant treatments for gastric cancer. Expert Rev Gastroenterol Hepatol. 2015;9:1–12.CrossRef
25.
Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357:1810–20.CrossRefPubMed
26.
Kanda M, Mizuno A, Fujii T, et al. Tumor infiltrative pattern predicts sites of recurrence after curative gastrectomy for stages 2 and 3 gastric cancer. Ann Surg Oncol. 2016;23:1934–40.CrossRefPubMed
27.
Kanda M, Shimizu D, Nomoto S, et al. Clinical significance of expression and epigenetic profiling of TUSC1 in gastric cancer. J Surg Oncol. 2014;110:136–44.CrossRefPubMed
28.
Kanda M, Nomoto S, Oya H, et al. The expression of melanoma-associated antigen D2 both in surgically resected and serum samples serves as clinically relevant biomarker of gastric cancer progression. Ann Surg Oncol. 2016;23(Suppl 2):214–21.CrossRef
29.
Kanda M, Sugimoto H, Nomoto S, et al. Clinical utility of PDSS2 expression to stratify patients at risk for recurrence of hepatocellular carcinoma. Int J Oncol. 2014;45:2005–12.PubMed
30.
Kanda M, Shimizu D, Fujii T, et al. Function and diagnostic value of Anosmin-1 in gastric cancer progression. Int J Cancer. 2016;138:721–30.CrossRefPubMed
31.
Kanda M, Shimizu D, Tanaka H, et al. Metastatic pathway-specific transcriptome analysis identifies MFSD4 as a putative tumor suppressor and biomarker for hepatic metastasis in patients with gastric cancer. Oncotarget. 2016;7:13667–79.PubMedPubMedCentral
32.
33.
Masuda Y, Sasaki A, Shibuya H, Ueno N, Ikeda K, Watanabe K. Dlxin-1, a novel protein that binds Dlx5 and regulates its transcriptional function. J Biol Chem. 2001;276:5331–8.CrossRefPubMed
34.
Williams ME, Strickland P, Watanabe K, Hinck L. UNC5H1 induces apoptosis via its juxtamembrane region through an interaction with NRAGE. J Biol Chem. 2003;278:17483–90.CrossRefPubMed
35.
Lai SS, Xue B, Yang Y, et al. Ror2-Src signaling in metastasis of mouse melanoma cells is inhibited by NRAGE. Cancer Genet. 2012;205:552–62.CrossRefPubMed
Metadata
Title
Neurotrophin Receptor-Interacting Melanoma Antigen-Encoding Gene Homolog is Associated with Malignant Phenotype of Gastric Cancer
Authors
Mitsuro Kanda, MD, PhD
Dai Shimizu, MD
Tsutomu Fujii, MD, PhD, FACS
Haruyoshi Tanaka, MD
Yuri Tanaka, MD
Kazuhiro Ezaka, MD
Masahiro Shibata, MD
Hideki Takami, MD, PhD
Ryoji Hashimoto, MD
Satoshi Sueoka, MD
Naoki Iwata, MD, PhD
Daisuke Kobayashi, MD, PhD
Chie Tanaka, MD, PhD
Suguru Yamada, MD, PhD, FACS
Goro Nakayama, MD, PhD
Hiroyuki Sugimoto, MD, PhD
Masahiko Koike, MD, PhD
Michitaka Fujiwara, MD, PhD
Yasuhiro Kodera, MD, PhD, FACS
Publication date
01-08-2016
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue Special Issue 4/2016
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-016-5375-0

Other articles of this Special Issue 4/2016

Annals of Surgical Oncology 4/2016 Go to the issue

Hepatobiliary Tumors

Significance of Vascular Resection and Reconstruction in Surgery for Hilar Cholangiocarcinoma: With Special Reference to Hepatic Arterial Resection and Reconstruction

Hepatobiliary Tumors

Aggressive Hemihepatectomy Combined with Resection and Reconstruction of Middle Hepatic Vein for Intrahepatic Cholangiocarcinoma

Author Disclosure Summary

Japanese Society of Gastroenterological Surgery Article Series Disclosure Index

Gastrointestinal Oncology

Expression of PD-L1 and HLA Class I in Esophageal Squamous Cell Carcinoma: Prognostic Factors for Patient Outcome

Gastrointestinal Oncology

Feasibility of Laparoscopic Radical Gastrectomy for Gastric Cancer of Clinical Stage II or Higher: Early Outcomes in a Phase II Study (KUGC04)

Hepatobiliary Tumors

Vascularity of Intrahepatic Cholangiocarcinoma on Computed Tomography is Predictive of Lymph Node Metastasis