Oncotarget

Research Papers:

Metastatic pathway-specific transcriptome analysis identifies MFSD4 as a putative tumor suppressor and biomarker for hepatic metastasis in patients with gastric cancer

Mitsuro Kanda _, Dai Shimizu, Haruyoshi Tanaka, Masahiro Shibata, Naoki Iwata, Masamichi Hayashi, Daisuke Kobayashi, Chie Tanaka, Suguru Yamada, Tsutomu Fujii, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara and Yasuhiro Kodera

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Oncotarget. 2016; 7:13667-13679. https://doi.org/10.18632/oncotarget.7269

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Abstract

Mitsuro Kanda1,*, Dai Shimizu1,*, Haruyoshi Tanaka1, Masahiro Shibata1, Naoki Iwata1, Masamichi Hayashi1, Daisuke Kobayashi1, Chie Tanaka1, Suguru Yamada1, Tsutomu Fujii1, Goro Nakayama1, Hiroyuki Sugimoto1, Masahiko Koike1, Michitaka Fujiwara1 and Yasuhiro Kodera1

1 Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan

* These authors have contributed equally to this work

Correspondence to:

Mitsuro Kanda, email:

Keywords: gastric cancer, hepatic metastasis, MFSD4, biomarker, tumor suppressor

Received: November 04,2015 Accepted: January 29, 2016 Published: February 08, 2016

Abstract

Gastric cancer (GC) with hepatic metastasis remains a fatal disease. Global expression profiling was conducted using tissues from patients who had GC with synchronous hepatic metastasis, and major facilitator superfamily domain containing 4 (MFSD4) was identified as a candidate biomarker for hepatic metastasis in GC. Functional and expression analyses of this molecule in GC cell lines and clinical samples were conducted. We analyzed MFSD4 expression, DNA methylation, and copy number. RNA interference experiments evaluated the effects of MFSD4 expression on cell phenotype and apoptosis. We analyzed tissues of 200 patients with GC to assess the diagnostic performance of MFSD4 levels for predicting hepatic recurrence, metastasis, or both. Differential expression of MFSD4 mRNA by GC cell lines correlated positively with the levels of NUDT13 and OCLN mRNAs and inversely with those of BMP2. Hypermethylation of the MFSD4 promoter was detected in cells with lower levels of MFSD4 mRNA. Inhibition of MFSD4 expression significantly increased the invasiveness and motility of GC cells but did not influence cell proliferation or apoptosis. MFSD4 mRNA levels in primary GC tissues were reduced in patients with concomitant hepatic metastasis or recurrence compared with those without. Low levels of MFSD4 mRNA in primary GC tissues were an independent risk factor of hepatic recurrence and metastasis. MFSD4 expression in gastric tissues may represent a useful biomarker for identification of patients at high risk for hepatic recurrence, metastasis, or both.


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