Identification of novel hub genes associated with liver metastasis of gastric cancer.
Understanding hub genes involved in gastric cancer (GC) metastasis could lead to effective approaches to diagnose and treat cancer metastasis. In this study, 272 differentially expressed genes between synchronous liver metastasis and the paired GC were selected from microarray assays. KEGG pathway analysis indicated that of 13 enriched pathways, 8 were involved in cancer metastasis. Literature-based annotations showed that the differentially expressed genes significantly enriched known metastasis-related genes. With the use of protein-protein interaction network, we found a subnetwork significantly enriching the metastasis-related genes and hubs. Unannotated hubs in this subnetwork were predicted to be novel metastasis-associated genes. Nine hubs in this subnetwork were validated by using quantitative RT-PCR, and 4 hubs were further validated by immunohistochemistry. NR4A2 was significantly down-regulated in synchronous liver metastasis compared with the paired GC at both transcriptional and translational levels. NR4A2 immunostaining was apparent in the mesenchymal cells of pathologically normal gastric mucosa and in the epithelial cells of primary GC. HSP90AA1 was not only up-regulated in the metastatic GC compared with primary GC at both transcriptional and translational levels, but also up-regulated in primary GC compared with the normal mucosa at the translational level. NR4A2, NR3C1, ARF3, XAB2, and alternatively spliced variants of NR4A2, SP8 and SP-novel, were significantly down-regulated, whereas CCNE1 significantly up-regulated, in primary GC compared with the normal gastric mucosa. Conclusively, NR4A2 and HSP90AA1 stand out as promising diagnostic markers and therapeutic targets for liver metastasis of GC. CCNE1 and NR3C1 indicate primary GC, rather than distant metastasis.
Chang
Wenjun
W
Department of Epidemiology, Second Military Medical University, and Department of General Surgery, the 1st Affiliated Hospital, Shanghai, China.
Ma
Liye
L
Lin
Liping
L
Gu
Liqiang
L
Liu
Xiaokang
X
Cai
Hui
H
Yu
Yongwei
Y
Tan
Xiaojie
X
Zhai
Yujia
Y
Xu
Xingxing
X
Zhang
Minfeng
M
Wu
Lingling
L
Zhang
Hongwei
H
Hou
Jianguo
J
Wang
Hongyang
H
Cao
Guangwen
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics*; D000067777:ELAV-Like Protein 2; D005260:Female; D020869:Gene Expression Profiling; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology
D014408:Biomarkers, Tumor; C475820:CCNE1 protein, human; D019927:Cyclin E; D051959:ELAV Proteins; D000067777:ELAV-Like Protein 2; C086811:ELAVL2 protein, human; D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; C497713:NR3C1 protein, human; C539882:NR4A2 protein, human; D009363:Neoplasm Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D015513:Oncogene Proteins; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid