Clinical utility of a STAT3-regulated miRNA-200 family signature with prognostic potential in early gastric cancer

Liang Yu, Di Wu, Hugh Gao, Jesse J. Balic, Anna Tsykin, Tae Su Han, You Dong Liu, Catherine L. Kennedy, Ji Kun Li, Jie Qi Mao, Patrick Tan, Masanobu Oshima, Gregory J. Goodall, Brendan J. Jenkins

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1459-1472
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number6
DOIs
Publication statusPublished - 15 Mar 2018

Cite this

Yu, Liang ; Wu, Di ; Gao, Hugh ; Balic, Jesse J. ; Tsykin, Anna ; Han, Tae Su ; Liu, You Dong ; Kennedy, Catherine L. ; Li, Ji Kun ; Mao, Jie Qi ; Tan, Patrick ; Oshima, Masanobu ; Goodall, Gregory J. ; Jenkins, Brendan J. / Clinical utility of a STAT3-regulated miRNA-200 family signature with prognostic potential in early gastric cancer. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 6. pp. 1459-1472.
@article{29915323d74f47a0a85d5419220e3576,
title = "Clinical utility of a STAT3-regulated miRNA-200 family signature with prognostic potential in early gastric cancer",
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.",
author = "Liang Yu and Di Wu and Hugh Gao and Balic, {Jesse J.} and Anna Tsykin and Han, {Tae Su} and Liu, {You Dong} and Kennedy, {Catherine L.} and Li, {Ji Kun} and Mao, {Jie Qi} and Patrick Tan and Masanobu Oshima and Goodall, {Gregory J.} and Jenkins, {Brendan J.}",
year = "2018",
month = "3",
day = "15",
doi = "10.1158/1078-0432.CCR-17-2485",
language = "English",
volume = "24",
pages = "1459--1472",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research",
number = "6",

}

Yu, L, Wu, D, Gao, H, Balic, JJ, Tsykin, A, Han, TS, Liu, YD, Kennedy, CL, Li, JK, Mao, JQ, Tan, P, Oshima, M, Goodall, GJ & Jenkins, BJ 2018, 'Clinical utility of a STAT3-regulated miRNA-200 family signature with prognostic potential in early gastric cancer' Clinical Cancer Research, vol. 24, no. 6, pp. 1459-1472. https://doi.org/10.1158/1078-0432.CCR-17-2485

Clinical utility of a STAT3-regulated miRNA-200 family signature with prognostic potential in early gastric cancer. / Yu, Liang; Wu, Di; Gao, Hugh; Balic, Jesse J.; Tsykin, Anna; Han, Tae Su; Liu, You Dong; Kennedy, Catherine L.; Li, Ji Kun; Mao, Jie Qi; Tan, Patrick; Oshima, Masanobu; Goodall, Gregory J.; Jenkins, Brendan J.

In: Clinical Cancer Research, Vol. 24, No. 6, 15.03.2018, p. 1459-1472.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Clinical utility of a STAT3-regulated miRNA-200 family signature with prognostic potential in early gastric cancer

AU - Yu, Liang

AU - Wu, Di

AU - Gao, Hugh

AU - Balic, Jesse J.

AU - Tsykin, Anna

AU - Han, Tae Su

AU - Liu, You Dong

AU - Kennedy, Catherine L.

AU - Li, Ji Kun

AU - Mao, Jie Qi

AU - Tan, Patrick

AU - Oshima, Masanobu

AU - Goodall, Gregory J.

AU - Jenkins, Brendan J.

PY - 2018/3/15

Y1 - 2018/3/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85048078211&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-17-2485

DO - 10.1158/1078-0432.CCR-17-2485

M3 - Article

VL - 24

SP - 1459

EP - 1472

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 6

ER -