title: Metastatic pathway-specific transcriptome analysis identifies MFSD4 as a putative tumor suppressor and biomarker for hepatic metastasis in patients with gastric cancer.
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.
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mitsuro
authors.initials: M
authors.lastname: Kanda
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Haruyoshi
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibata
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Goro
authors.initials: G
authors.lastname: Nakayama
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sugimoto
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Koike
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Michitaka
authors.initials: M
authors.lastname: Fujiwara
authors.affiliation: Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kodera
mesh_terms: D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008207:Lymphatic Metastasis; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059467:Transcriptome; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C000624601:MFSD4A protein, human; D026901:Membrane Transport Proteins
keywords: MFSD4; biomarker; gastric cancer; hepatic metastasis; tumor suppressor