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Clin Cancer Res. 2018 Mar 15;24(6):1459-1472. doi: 10.1158/1078-0432.CCR-17-2485. Epub 2018 Jan 12.

Clinical Utility of a STAT3-Regulated miRNA-200 Family Signature with Prognostic Potential in Early Gastric Cancer.

Yu L1,2, Wu D3, Gao H1,2, Balic JJ1,2, Tsykin A4,5,6, Han TS7, Liu YD1,2,8, Kennedy CL1,2, Li JK8, Mao JQ8, Tan P9,10,11, Oshima M7, Goodall GJ4,5,6, Jenkins BJ12,2.

Author information

1
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
2
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
3
Department of Periodontology, School of Dentistry, Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
4
Discipline of Medicine, University of Adelaide, Adelaide, South Australia.
5
School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia.
6
Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia.
7
Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
8
Department of General Surgery, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
9
Genome Institute of Singapore, Singapore.
10
Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore.
11
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
12
Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia. brendan.jenkins@hudson.org.au.

Abstract

Purpose: The majority of gastric cancer patients are diagnosed with late-stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early-stage gastric cancer (EGC) because the molecular events promoting gastric cancer initiation remain ill-defined.Experimental Design: miRNA microarrays were performed on gastric tissue from the gp130F/F preclinical EGC mouse model, prior to tumor initiation. Computation prediction algorithms were performed on multiple data sets and independent gastric cancer patient cohorts. Quantitative real-time PCR expression profiling was undertaken in gp130F/F-based mouse strains and human gastric cancer cells genetically engineered for suppressed activation of the oncogenic latent transcription factor STAT3. Human gastric cancer cells with modulated expression of the miR-200 family member miR-429 were also assessed for their proliferative response.Results: Increased expression of miR-200 family members is associated with both tumor initiation in a STAT3-dependent manner in gp130F/F mice and EGC (i.e., stage IA) in patient cohorts. Overexpression of miR-429 also elicited contrasting pro- and antiproliferative responses in human gastric cancer cells depending on their cellular histologic subtype. We also identified a miR-200 family-regulated 15-gene signature that integrates multiple key current indicators of EGC, namely tumor invasion depth, differentiation, histology, and stage, and provides superior predictive power for overall survival compared with each EGC indicator alone.Conclusions: Collectively, our discovery of a STAT3-regulated, miR-200 family-associated gene signature specific for EGC, with predictive power, provides a molecular rationale to classify and stratify EGC patients for endoscopic treatment. Clin Cancer Res; 24(6); 1459-72. ©2018 AACR.

PMID:
29330205
DOI:
10.1158/1078-0432.CCR-17-2485
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