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Research Papers:

A novel liver metastasis-correlated protein of pancreatic neuroendocrine neoplasm (PanNEN) discovered by proteomic analysis

Mitsuhiro Shimura, Masamichi Mizuma _, Tatsuyuki Takadate, Yasutake Katoh, Takashi Suzuki, Masahiro Iseki, Tatsuo Hata, Shuichi Aoki, Yukie Suzuki, Naoaki Sakata, Hideo Ohtsuka, Hiroki Hayashi, Takanori Morikawa, Kei Nakagawa, Fuyuhiko Motoi, Takeshi Naitoh, Kazuhiko Igarashi, Hironobu Sasano and Michiaki Unno

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Oncotarget. 2018; 9:24291-24303. https://doi.org/10.18632/oncotarget.25110

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Abstract

Mitsuhiro Shimura1, Masamichi Mizuma1, Tatsuyuki Takadate1, Yasutake Katoh2,3, Takashi Suzuki4, Masahiro Iseki1, Tatsuo Hata1, Shuichi Aoki1, Yukie Suzuki1, Naoaki Sakata1, Hideo Ohtsuka1, Hiroki Hayashi1, Takanori Morikawa1, Kei Nakagawa1, Fuyuhiko Motoi1, Takeshi Naitoh1, Kazuhiko Igarashi2,3, Hironobu Sasano5 and Michiaki Unno1

1Department of Surgery, Tohoku University Graduate School of Medicine, Aobaku, Sendai 980-8574, Japan

2Department of Biochemistry, Tohoku University Graduate School of Medicine, Aobaku, Sendai 980-8574, Japan

3Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Aobaku, Sendai 980-8574, Japan

4Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Aobaku, Sendai 980-8574, Japan

5Department of Pathology, Tohoku University Graduate School of Medicine, Aobaku, Sendai 980-8574, Japan

Correspondence to:

Masamichi Mizuma, email: masamichi@surg.med.tohoku.ac.jp

Keywords: PanNEN; liver metastasis; CNPY2; ANXA6; proteomics

Received: October 11, 2017    Accepted: March 17, 2018    Published: May 11, 2018

ABSTRACT

The aim of this study was to identify novel liver metastasis-correlated proteins of PanNEN by proteomics to compare pancreatic tumor (PT) with paired metastatic liver tumor (LT). Of 118 surgical cases with PanNEN, 7 cases with formalin-fixed paraffin-embedded (FFPE) tissues of both PT and paired LT were evaluated by proteomics. Tumor cells were selectively collected from FFPE tissues by laser capture microdissection. A total of 3,722 proteins were detected from extracted peptides by mass spectrometry-based shotgun analysis. Selection of the candidate proteins expressed differently between PT and LT were performed by semi-quantitative comparison in silico and confirmation with immunohistochemistry. We focused on ANXA6, CNPY2, RAB11B and TUBB3, all of which had higher expressions in LT. In all surgical cases with FFPE samples, liver recurrence-free survival (RFS) was evaluated in correlation to the expression of the candidate proteins in PT by immunohistochemistry. Liver RFS was significantly poorer in CNPY2 positive patients than in negative patients (10-year liver RFS; 39.8% vs. 92.3%, p = 0.012). Also, liver RFS tended to be poorer in ANXA6 positive patients than in those who were negative (10-year liver RFS; 51.4% vs. 95.0%, p = 0.099). In the multivariate analysis, the independent predictors of liver RFS were CNPY2 positivity (HR: 6.19, 95 % CI: 1.47–42.79, p = 0.011) and tumor size ≥ 42 mm (HR: 4.63, 95 % CI: 1.03–23.23, p = 0.045). In conclusion, CNPY2 is a novel liver metastasis-correlated protein of PanNEN.


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