Oncotarget

Research Papers:

Overexpression of denticleless E3 ubiquitin protein ligase homolog (DTL) is related to poor outcome in gastric carcinoma

Hiroki Kobayashi _, Shuhei Komatsu, Daisuke Ichikawa, Tsutomu Kawaguchi, Shoji Hirajima, Mahito Miyamae, Wataru Okajima, Takuma Ohashi, Toshiyuki Kosuga, Hirotaka Konishi, Atsushi Shiozaki, Hitoshi Fujiwara, Kazuma Okamoto, Hitoshi Tsuda and Eigo Otsuji

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Oncotarget. 2015; 6:36615-36624. https://doi.org/10.18632/oncotarget.5620

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Abstract

Hiroki Kobayashi1,*, Shuhei Komatsu1,*, Daisuke Ichikawa1, Tsutomu Kawaguchi1, Shoji Hirajima1, Mahito Miyamae1, Wataru Okajima1, Takuma Ohashi1, Toshiyuki Kosuga1, Hirotaka Konishi1, Atsushi Shiozaki1, Hitoshi Fujiwara1, Kazuma Okamoto1, Hitoshi Tsuda2,3, Eigo Otsuji1

1Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan

2Department of Pathology, National Cancer Center Hospital, Tokyo, Japan

3Department of Basic Pathology, National Defense Medical College, Saitama, Japan

*These authors have contributed equally to this work

Correspondence to:

Shuhei Komatsu, e-mail: skomatsu@koto.kpu-m.ac.jp

Keywords: gastric cancer, DTL, prognosis, oncogene, biomarker

Received: March 13, 2015     Accepted: October 02, 2015     Published: October 13, 2015

ABSTRACT

Background: Denticleless E3 ubiquitin protein ligase homolog (DTL) has been identified in amplified region (1q32) of several cancers and has an oncogenic function. In this study, we tested whether DTL acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC).

Methods: We analyzed 7 GC cell lines and 100 primary tumors that were curatively resected in our hospital between 2001 and 2003.

Results: Overexpression of the DTL protein was detected in GC cell lines (4/7 cell lines; 57%) and primary GC tumor samples (42/100 cases; 42%). Knockdown of DTL using several specific siRNAs inhibited the proliferation, migration and invasion in a TP53 mutation-independent manner. Overexpression of the DTL was significantly correlated with lymphatic invasion, deeper tumor depth and higher recurrence rate. Patients with DTL-overexpressing tumors had a worse survival rate than those with non-expressing tumors in overall survival (P = 0.0498, log-rank test) and disease-free survival (P = 0.0324, log-rank test). In a multivariate analysis, DTL positivity was independently associated with a worse overall survival (P = 0.0104, hazard ratio 3.7 [1.36–10.1]) and disease-free survival (P = 0.0070 (hazard ratio, 3.9 (1.45–10.46)) following radical gastrectomy.

Conclusions: These findings suggest that DTL overexpression plays a crucial role in tumor cell proliferation and highlights its usefulness as a prognosticator and potential therapeutic target in gastric cancer.


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