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Int J Clin Exp Pathol 2011;4(3):230-240

Original Article
Transcriptional factor typing with SOX2, HNF4aP1, and CDX2 closely relates to tumor
invasion and Epstein-Barr virus status in gastric cancer

Hiroshi Uozaki, Rita Rani Barua, Sun Minhua, Tetsuo Ushiku, Rumi Hino, Aya Shinozaki, Takashi Sakatani, Masashi Fukayama

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Received February 20, 2011; accepted February 28, 2011; Epub March 1, 2011; published March 31, 2011

Abstract: Background: Gastric cancer (GC) is a major cancer, sometimes associated with Epstein-Barr virus (EBV).  Some transcriptional
factors (TFs) are specific to the digestive tract and related to the character of the tumors. Methods: We studied three TFs, SOX2, CDX2, and
hepatocyte nuclear factor 4 alpha-promoter 1 (HNF4aP1) in GC. First, 255 tumors including 31 EBV-associated GC were
immunohistochemically examined using tissue arrays and compared TF type and mucin phenotype. We classified them into 4 TF types: N-TF
type as SOX2-/HNF4aP1- tumor, G: SOX2+/HNF4aP1-, GI: SOX2+/HNF4aP1+, and I: SOX2-/HNF4aP1+. Next, 915 GCs were intensely
investigated and compared with their clinicopathological factors.Results: In the first study, 255 GCs were classified into N-TF 44%, G-TF 31%,
GI-TF 3%, and I-TF 2%. The TF type did not strictly accord with the mucin phenotype, classified by MUC2/5AC/6/CD10 expression. EBV status
was the only factor related to both the TF and mucin phenotype classifications (P<0.0001, <0.0001). TF classification is related to more factors
including tumor stage, than mucin phenotype classification. The second study using 915 GCs revealed that N-TF gradually increased and I-TF
decreased as GC invaded deeper. TF classification was not related to nodal involvement in each tumor stage. HNF4aP1 and CDX2 were
independent factors for early stage tumor in logistic regression analysis. Conclusions: EBV-associated GC is a discriminating group in both TF
and mucin phenotype. TF classification, especially the absence of HNF4aP1 and CDX2, is related to tumor invasion. TF classification is a
useful marker to study the carcinogenesis of GC further. (IJCEP1102004).

Keywords: Gastric cancer, transcriptional factor, Epstein-Barr virus, SOX2, HNF4a

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Address all correspondence to:
Hiroshi Uozaki, MD, PhD
Department of Pathology
Graduate School of Medicine
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku
Tokyo, 113-0033 Japan
FAX: +81-3-3815-8379