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Homeobox-Only Protein Expression Is a Critical Prognostic Indicator of Pancreatic Neuroendocrine Tumor and Is Regulated by Promoter DNA Hypermethylation

2016; Lippincott Williams & Wilkins; Volume: 45; Issue: 9 Linguagem: Inglês

10.1097/mpa.0000000000000646

1536-4828

Hideki Ushiku, Keishi Yamashita, Hiroshi Kawamata, Mina Waraya, Hiroshi Katoh, Keigo Yokoi, Toshimichi Tanaka, Satoru Ishii, Nobuyuki Nishizawa, Mariko Kikuchi, Naoko Minatani, Ken Kojo, Hiroshi Tajima, Ryo Nishiyama, Takashi Kaizu, Yusuke Kumamoto, Masahiko Watanabe,

Pancreatic function and diabetes

Objectives We have identified homeobox-only protein (HOPX) as a tumor suppressor gene in various human cancer, and its expression was reduced by promoter DNA hypermethylation. Homeobox-only protein is strongly expressed on pancreatic islet cells; however, clinical relevance of HOPX expression has remained elusive in pancreatic neuroendocrine tumor (pNET). Methods We investigated 36 patients with pNET who undertook surgical resection between 1988 and 2012 for HOPX expression and DNA methylation to reveal its clinical significance. Results (1) Homeobox-only protein is strongly expressed on pancreatic islet cells by immunohistochemistry (IHC). Homeobox-only protein expression was recognized on pNET tumor cells for 1+ in 15, for 2+ in 16, and for 3+ in 5. (2) Homeobox-only protein IHC expression was significantly associated with prognosis (P = 0.03), and survival rate was 37.5%, 70.3%, and 100% in HOPX 1+, 2+, and 3+, respectively. (3) Promoter DNA methylation was quantitatively assessed, and HOPX hypermethylation is found in 6.3%, 11.8%, and 66.7% of G1/G2/G3 pNET, respectively (P = 0.02). (4) Multivariate Cox proportional hazards model identified HOPX IHC expression and HOPX promoter DNA hypermethylation as independent prognostic factors in pNET. Conclusions Homeobox-only protein expression is a critical prognostic indicator of pNET, and its regulation may be made through promoter DNA methylation.