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Published in: Journal of Experimental & Clinical Cancer Research 1/2014

Open Access 01-12-2014 | Research

Dihydropyrimidinase-like 3 facilitates malignant behavior of gastric cancer

Authors: Mitsuro Kanda, Shuji Nomoto, Hisaharu Oya, Dai Shimizu, Hideki Takami, Soki Hibino, Ryoji Hashimoto, Daisuke Kobayashi, Chie Tanaka, Suguru Yamada, Tsutomu Fujii, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2014

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Abstract

Background

Gastric cancer (GC) remains to have a poor prognosis via diverse process of cancer progression. Dihydropyrimidinase-like 3 (DPYSL3) is a cell adhesion molecule that has been reported to be involved in the metastatic process of tumor cells. The aim of this study was to identify a novel clinically-relevant biomarker of GC.

Methods

Expression analysis of DPYSL3 mRNA and protein levels was conducted using GC cell lines and 238 pairs of surgically resected gastric tissues. Correlations between expression status of DPYSL3 and clinicopathological parameters were investigated.

Results

DPYSL3 mRNA expression levels positively correlated with those of potentially interacting genes (VEGF, FAK and EZR) in GC cell lines. GC tissues from tumors with distant metastases (stage IV cancer) showed elevated expression levels of DPYSL3 mRNA. The DPYSL3 staining intensity in immunochemical staining was consistent with the mRNA expression patterns in GC tissues. High DPYSL3 mRNA expression in GCs was significantly associated with more malignant phenotypes and was an independent prognostic factor. Moreover, patients with high DPYSL3 mRNA expression had a significantly shorter recurrence free survival after curative resection. In subgroup analysis based on tumor histology, similar tendency was observed between patients with differentiated and undifferentiated GCs.

Conclusions

Expression status of DPYSL3 in GC tissues may represent a promising biomarker for the malignant behavior of GC.
Appendix
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Literature
1.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322/caac.20107.CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61: 69-90. 10.3322/caac.20107.CrossRefPubMed
2.
go back to reference Ivanova T, Zouridis H, Wu Y, Cheng LL, Tan IB, Gopalakrishnan V, Ooi CH, Lee J, Qin L, Wu J, Lee M, Rha SY, Huang D, Liem N, Yeoh KG, Yong WP, Teh BT, Tan P: Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. Gut. 2013, 62: 22-33. 10.1136/gutjnl-2011-301113.CrossRefPubMed Ivanova T, Zouridis H, Wu Y, Cheng LL, Tan IB, Gopalakrishnan V, Ooi CH, Lee J, Qin L, Wu J, Lee M, Rha SY, Huang D, Liem N, Yeoh KG, Yong WP, Teh BT, Tan P: Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer. Gut. 2013, 62: 22-33. 10.1136/gutjnl-2011-301113.CrossRefPubMed
3.
go back to reference Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, Yang YH, Sano T, Yang HK, Zhang X, Park SR, Fujii M, Kang YK, Chen LT: Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol. 2013, 14: e535-547. 10.1016/S1470-2045(13)70436-4.CrossRefPubMed Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, Yang YH, Sano T, Yang HK, Zhang X, Park SR, Fujii M, Kang YK, Chen LT: Management of gastric cancer in Asia: resource-stratified guidelines. Lancet Oncol. 2013, 14: e535-547. 10.1016/S1470-2045(13)70436-4.CrossRefPubMed
5.
go back to reference Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE: Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol. 2006, 24: 2903-2909. 10.1200/JCO.2005.05.0245.CrossRefPubMed Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE: Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol. 2006, 24: 2903-2909. 10.1200/JCO.2005.05.0245.CrossRefPubMed
6.
go back to reference Steeg PS: Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer. 2003, 3: 55-63. 10.1038/nrc967.CrossRefPubMed Steeg PS: Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer. 2003, 3: 55-63. 10.1038/nrc967.CrossRefPubMed
7.
go back to reference Kanda M, Nomoto S, Okamura Y, Hayashi M, Hishida M, Fujii T, Nishikawa Y, Sugimoto H, Takeda S, Nakao A: Promoter hypermethylation of fibulin 1 gene is associated with tumor progression in hepatocellular carcinoma. Mol Carcinog. 2011, 50: 571-579. 10.1002/mc.20735.CrossRefPubMed Kanda M, Nomoto S, Okamura Y, Hayashi M, Hishida M, Fujii T, Nishikawa Y, Sugimoto H, Takeda S, Nakao A: Promoter hypermethylation of fibulin 1 gene is associated with tumor progression in hepatocellular carcinoma. Mol Carcinog. 2011, 50: 571-579. 10.1002/mc.20735.CrossRefPubMed
8.
go back to reference Gonzalez CA, Agudo A: Carcinogenesis, prevention and early detection of gastric cancer: where we are and where we should go. Int J Cancer. 2012, 130: 745-753. 10.1002/ijc.26430.CrossRefPubMed Gonzalez CA, Agudo A: Carcinogenesis, prevention and early detection of gastric cancer: where we are and where we should go. Int J Cancer. 2012, 130: 745-753. 10.1002/ijc.26430.CrossRefPubMed
9.
go back to reference Janjigian YY, Kelsen DP: Genomic dysregulation in gastric tumors. J Surg Oncol. 2013, 107: 237-242. 10.1002/jso.23263.CrossRefPubMed Janjigian YY, Kelsen DP: Genomic dysregulation in gastric tumors. J Surg Oncol. 2013, 107: 237-242. 10.1002/jso.23263.CrossRefPubMed
10.
go back to reference Jang BG, Kim WH: Molecular pathology of gastric carcinoma. Pathobiology. 2011, 78: 302-310. 10.1159/000321703.CrossRefPubMed Jang BG, Kim WH: Molecular pathology of gastric carcinoma. Pathobiology. 2011, 78: 302-310. 10.1159/000321703.CrossRefPubMed
11.
go back to reference Goshima Y, Nakamura F, Strittmatter P, Strittmatter SM: Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature. 1995, 376: 509-514. 10.1038/376509a0.CrossRefPubMed Goshima Y, Nakamura F, Strittmatter P, Strittmatter SM: Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature. 1995, 376: 509-514. 10.1038/376509a0.CrossRefPubMed
12.
go back to reference Matsuo T, Stauffer JK, Walker RL, Meltzer P, Thiele CJ: Structure and promoter analysis of the human unc-33-like phosphoprotein gene. E-box required for maximal expression in neuroblastoma and myoblasts. J Biol Chem. 2000, 275: 16560-16568. 10.1074/jbc.M001312200.CrossRefPubMed Matsuo T, Stauffer JK, Walker RL, Meltzer P, Thiele CJ: Structure and promoter analysis of the human unc-33-like phosphoprotein gene. E-box required for maximal expression in neuroblastoma and myoblasts. J Biol Chem. 2000, 275: 16560-16568. 10.1074/jbc.M001312200.CrossRefPubMed
13.
go back to reference BioGPS..,http://biogps.org/ BioGPS..,http://​biogps.​org/​
14.
go back to reference Gao X, Pang J, Li LY, Liu WP, Di JM, Sun QP, Fang YQ, Liu XP, Pu XY, He D, Li MT, Su ZL, Li BY: Expression profiling identifies new function of collapsin response mediator protein 4 as a metastasis-suppressor in prostate cancer. Oncogene. 2010, 29: 4555-4566. 10.1038/onc.2010.213.CrossRefPubMed Gao X, Pang J, Li LY, Liu WP, Di JM, Sun QP, Fang YQ, Liu XP, Pu XY, He D, Li MT, Su ZL, Li BY: Expression profiling identifies new function of collapsin response mediator protein 4 as a metastasis-suppressor in prostate cancer. Oncogene. 2010, 29: 4555-4566. 10.1038/onc.2010.213.CrossRefPubMed
15.
go back to reference Kawahara T, Hotta N, Ozawa Y, Kato S, Kano K, Yokoyama Y, Nagino M, Takahashi T, Yanagisawa K: Quantitative proteomic profiling identifies DPYSL3 as pancreatic ductal adenocarcinoma-associated molecule that regulates cell adhesion and migration by stabilization of focal adhesion complex. PLoS One. 2013, 8: e79654-10.1371/journal.pone.0079654.PubMedCentralCrossRefPubMed Kawahara T, Hotta N, Ozawa Y, Kato S, Kano K, Yokoyama Y, Nagino M, Takahashi T, Yanagisawa K: Quantitative proteomic profiling identifies DPYSL3 as pancreatic ductal adenocarcinoma-associated molecule that regulates cell adhesion and migration by stabilization of focal adhesion complex. PLoS One. 2013, 8: e79654-10.1371/journal.pone.0079654.PubMedCentralCrossRefPubMed
16.
go back to reference Kanda M, Nomoto S, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S, Nakao A: Correlations of the expression of vascular endothelial growth factor B and its isoforms in hepatocellular carcinoma with clinico-pathological parameters. J Surg Oncol. 2008, 98: 190-196. 10.1002/jso.21095.CrossRefPubMed Kanda M, Nomoto S, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S, Nakao A: Correlations of the expression of vascular endothelial growth factor B and its isoforms in hepatocellular carcinoma with clinico-pathological parameters. J Surg Oncol. 2008, 98: 190-196. 10.1002/jso.21095.CrossRefPubMed
17.
go back to reference Sobin LH, Gospodarowicz MK, Wittekind C: International Union Against Cancer, TNM Classification of Malignant Tumors. 2009, Wiley-Blackwell, New York Sobin LH, Gospodarowicz MK, Wittekind C: International Union Against Cancer, TNM Classification of Malignant Tumors. 2009, Wiley-Blackwell, New York
18.
go back to reference Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007, 357: 1810-1820. 10.1056/NEJMoa072252.CrossRefPubMed Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, Furukawa H, Nakajima T, Ohashi Y, Imamura H, Higashino M, Yamamura Y, Kurita A, Arai K: Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007, 357: 1810-1820. 10.1056/NEJMoa072252.CrossRefPubMed
19.
go back to reference Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y: Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011, 29: 4387-4393. 10.1200/JCO.2011.36.5908.CrossRefPubMed Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T, Ohashi Y: Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 2011, 29: 4387-4393. 10.1200/JCO.2011.36.5908.CrossRefPubMed
20.
go back to reference Kanda M, Nomoto S, Okamura Y, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S, Nakao A: Detection of metallothionein 1G as a methylated tumor suppressor gene in human hepatocellular carcinoma using a novel method of double combination array analysis. Int J Oncol. 2009, 35: 477-483. 10.3892/ijo_00000448.CrossRefPubMed Kanda M, Nomoto S, Okamura Y, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S, Nakao A: Detection of metallothionein 1G as a methylated tumor suppressor gene in human hepatocellular carcinoma using a novel method of double combination array analysis. Int J Oncol. 2009, 35: 477-483. 10.3892/ijo_00000448.CrossRefPubMed
21.
go back to reference Inokawa Y, Nomoto S, Hishida M, Hayashi M, Kanda M, Nishikawa Y, Takeda S, Sugimoto H, Fujii T, Yamada S, Kodera Y: Detection of doublecortin domain-containing 2 (DCDC2), a new candidate tumor suppressor gene of hepatocellular carcinoma, by triple combination array analysis. J Exp Clin Cancer Res. 2013, 32: 65-PubMedCentralCrossRefPubMed Inokawa Y, Nomoto S, Hishida M, Hayashi M, Kanda M, Nishikawa Y, Takeda S, Sugimoto H, Fujii T, Yamada S, Kodera Y: Detection of doublecortin domain-containing 2 (DCDC2), a new candidate tumor suppressor gene of hepatocellular carcinoma, by triple combination array analysis. J Exp Clin Cancer Res. 2013, 32: 65-PubMedCentralCrossRefPubMed
22.
go back to reference Shimizu D, Kanda M, Nomoto S, Oya H, Takami H, Hibino S, Suenaga M, Inokawa Y, Hishida M, Takano N, Nishikawa Y, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Kodera Y: Identification of intragenic methylation in the TUSC1 gene as a novel prognostic marker of hepatocellular carcinoma. Oncol Rep. 2014, 31: 1305-1313.PubMed Shimizu D, Kanda M, Nomoto S, Oya H, Takami H, Hibino S, Suenaga M, Inokawa Y, Hishida M, Takano N, Nishikawa Y, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Kodera Y: Identification of intragenic methylation in the TUSC1 gene as a novel prognostic marker of hepatocellular carcinoma. Oncol Rep. 2014, 31: 1305-1313.PubMed
23.
go back to reference Kanda M, Nomoto S, Oya H, Takami H, Hibino S, Hishida M, Suenaga M, Yamada S, Inokawa Y, Nishikawa Y, Asai M, Fujii T, Sugimoto H, Kodera Y: Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma. Int J Oncol. 2014, 44: 44-52.PubMed Kanda M, Nomoto S, Oya H, Takami H, Hibino S, Hishida M, Suenaga M, Yamada S, Inokawa Y, Nishikawa Y, Asai M, Fujii T, Sugimoto H, Kodera Y: Downregulation of DENND2D by promoter hypermethylation is associated with early recurrence of hepatocellular carcinoma. Int J Oncol. 2014, 44: 44-52.PubMed
24.
go back to reference Loupy A, Hill GS, Suberbielle C, Charron D, Anglicheau D, Zuber J, Timsit MO, Duong JP, Bruneval P, Vernerey D, Empana JP, Jouven X, Nochy D, Legendre CH: Significance of C4d Banff scores in early protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA). Am J Transplant. 2011, 11: 56-65. 10.1111/j.1600-6143.2010.03364.x.CrossRefPubMed Loupy A, Hill GS, Suberbielle C, Charron D, Anglicheau D, Zuber J, Timsit MO, Duong JP, Bruneval P, Vernerey D, Empana JP, Jouven X, Nochy D, Legendre CH: Significance of C4d Banff scores in early protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA). Am J Transplant. 2011, 11: 56-65. 10.1111/j.1600-6143.2010.03364.x.CrossRefPubMed
25.
go back to reference Kanda M, Shimizu D, Nomoto S, Hibino S, Oya H, Takami H, Kobayashi D, Yamada S, Inokawa Y, Tanaka C, Fujii T, Sugimoto H, Koike M, Fujiwara M, Kodera Y: Clinical significance of expression and epigenetic profiling of TUSC1 in gastric cancer. J Surg Oncol. 2014, 110: 136-144.CrossRefPubMed Kanda M, Shimizu D, Nomoto S, Hibino S, Oya H, Takami H, Kobayashi D, Yamada S, Inokawa Y, Tanaka C, Fujii T, Sugimoto H, Koike M, Fujiwara M, Kodera Y: Clinical significance of expression and epigenetic profiling of TUSC1 in gastric cancer. J Surg Oncol. 2014, 110: 136-144.CrossRefPubMed
26.
go back to reference Hibino S, Kanda M, Oya H, Takami H, Shimizu D, Nomoto S, Hishida M, Niwa Y, Koike M, Yamada S, Nishikawa Y, Asai M, Nakayama G, Fujii T, Sugimoto H, Fujiwara M, Kodera Y: Reduced expression of DENND2D through promoter hypermethylation is an adverse prognostic factor in squamous cell carcinoma of the esophagus. Oncol Rep. 2014, 31: 693-700.PubMed Hibino S, Kanda M, Oya H, Takami H, Shimizu D, Nomoto S, Hishida M, Niwa Y, Koike M, Yamada S, Nishikawa Y, Asai M, Nakayama G, Fujii T, Sugimoto H, Fujiwara M, Kodera Y: Reduced expression of DENND2D through promoter hypermethylation is an adverse prognostic factor in squamous cell carcinoma of the esophagus. Oncol Rep. 2014, 31: 693-700.PubMed
27.
go back to reference Frame MC, Patel H, Serrels B, Lietha D, Eck MJ: The FERM domain: organizing the structure and function of FAK. Nat Rev Mol Cell Biol. 2010, 11: 802-814. 10.1038/nrm2996.CrossRefPubMed Frame MC, Patel H, Serrels B, Lietha D, Eck MJ: The FERM domain: organizing the structure and function of FAK. Nat Rev Mol Cell Biol. 2010, 11: 802-814. 10.1038/nrm2996.CrossRefPubMed
28.
29.
go back to reference Srivastava J, Elliott BE, Louvard D, Arpin M: Src-dependent ezrin phosphorylation in adhesion-mediated signaling. Mol Biol Cell. 2005, 16: 1481-1490. 10.1091/mbc.E04-08-0721.PubMedCentralCrossRefPubMed Srivastava J, Elliott BE, Louvard D, Arpin M: Src-dependent ezrin phosphorylation in adhesion-mediated signaling. Mol Biol Cell. 2005, 16: 1481-1490. 10.1091/mbc.E04-08-0721.PubMedCentralCrossRefPubMed
30.
go back to reference Sakaguchi T, Watanabe A, Sawada H, Yamada Y, Tatsumi M, Fujimoto H, Emoto K, Nakano H: Characteristics and clinical outcome of proximal-third gastric cancer. J Am Coll Surg. 1998, 187: 352-357. 10.1016/S1072-7515(98)00191-4.CrossRefPubMed Sakaguchi T, Watanabe A, Sawada H, Yamada Y, Tatsumi M, Fujimoto H, Emoto K, Nakano H: Characteristics and clinical outcome of proximal-third gastric cancer. J Am Coll Surg. 1998, 187: 352-357. 10.1016/S1072-7515(98)00191-4.CrossRefPubMed
31.
go back to reference Vogiatzi P, Vindigni C, Roviello F, Renieri A, Giordano A: Deciphering the underlying genetic and epigenetic events leading to gastric carcinogenesis. J Cell Physiol. 2007, 211: 287-295. 10.1002/jcp.20982.CrossRefPubMed Vogiatzi P, Vindigni C, Roviello F, Renieri A, Giordano A: Deciphering the underlying genetic and epigenetic events leading to gastric carcinogenesis. J Cell Physiol. 2007, 211: 287-295. 10.1002/jcp.20982.CrossRefPubMed
32.
go back to reference Kanda M, Shimizu D, Nomoto S, Takami H, Hibino S, Oya H, Hashimoto R, Suenaga M, Inokawa Y, Kobayashi D, Tanaka C, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Kodera Y: Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer. Gastric Cancer. 2014, Epub ahead of print, PubMed PMID: 24695972 Kanda M, Shimizu D, Nomoto S, Takami H, Hibino S, Oya H, Hashimoto R, Suenaga M, Inokawa Y, Kobayashi D, Tanaka C, Yamada S, Fujii T, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Kodera Y: Prognostic impact of expression and methylation status of DENN/MADD domain-containing protein 2D in gastric cancer. Gastric Cancer. 2014, Epub ahead of print, PubMed PMID: 24695972
33.
go back to reference Wang YY, Li L, Zhao ZS, Wang YX, Ye ZY, Tao HQ: L1 and epithelial cell adhesion molecules associated with gastric cancer progression and prognosis in examination of specimens from 601 patients. J Exp Clin Cancer Res. 2013, 32: 66-PubMedCentralCrossRefPubMed Wang YY, Li L, Zhao ZS, Wang YX, Ye ZY, Tao HQ: L1 and epithelial cell adhesion molecules associated with gastric cancer progression and prognosis in examination of specimens from 601 patients. J Exp Clin Cancer Res. 2013, 32: 66-PubMedCentralCrossRefPubMed
Metadata
Title
Dihydropyrimidinase-like 3 facilitates malignant behavior of gastric cancer
Authors
Mitsuro Kanda
Shuji Nomoto
Hisaharu Oya
Dai Shimizu
Hideki Takami
Soki Hibino
Ryoji Hashimoto
Daisuke Kobayashi
Chie Tanaka
Suguru Yamada
Tsutomu Fujii
Goro Nakayama
Hiroyuki Sugimoto
Masahiko Koike
Michitaka Fujiwara
Yasuhiro Kodera
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2014
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-014-0066-9

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