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

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

doi:10.18632/oncotarget.7269

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.

Highlights

Gastric cancer (GC) is one of the most common malignancies and the third leading cause of cancerrelated deaths worldwide [1, 2]
After literature review regarding current knowledge on functional aspect of each gene, we decided to focus on major facilitator superfamily domain containing 4 (MFSD4) because 1) MFSD4 exhibited the second strongest suppression in primary GC tissues among 21 candidates, 2) MFSD4 expression levels were comparable between primary GC tissues and liver tissues with metastases, 3) MFSD4 encodes a membrane trafficking protein that may be involved in cellular functions and transportation of growth factors, and 4) we sought novel molecules as potential biomarkers for GC there have been no reports on oncological roles of MFSD4
The levels of MFSD4 mRNAs differed among GC cell lines

Summary

Introduction

Gastric cancer (GC) is one of the most common malignancies and the third leading cause of cancerrelated deaths worldwide [1, 2]. Hepatic metastasis and relapse contribute to the high incidence of GC-related fatalities, and represent a frequent and crucial problem for oncologists [3, 4]. GC metastasizes through three distinct metastatic pathways; lymphatic, hematogeneous and direct dissemination from the serosal surface [7,8,9]. Each metastatic pathway is considered to require survival of select clones that accumulate specific mutations or epigenetic abnormalities. Knowledge of the unique molecular attributes of each metastatic pathway will improve our understanding of the biology of metastatic GC and facilitate development of specific biomarkers and appropriate targeted therapies, leading to efficacious personalized treatment [10]. Studies to identify and explore diagnostic biomarkers and molecular targets to predict and treat hepatic metastases among others are warranted

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