Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis

Zheng Chen, Zheng Li, Mohammed Soutto, Weizhi Wang, M. Blanca Piazuelo, Shoumin Zhu, Yan Guo, Maria J. Maturana, Alejandro H. Corvalan, Xi Chen, Zekuan Xu, Wael El-Rifai

Research output: Contribution to journalArticle

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Abstract

Background & Aims: microRNAs (miRNAs) are small noncoding RNAs that bind to the 3′ untranslated regions of mRNAs to promote their degradation or block their translation. Mice with disruption of the trefoil factor 1 gene (Tff1) develop gastric neoplasms. We studied these mice to identify conserved miRNA networks involved in gastric carcinogenesis. Methods: We performed next-generation miRNA sequencing analysis of normal gastric tissues (based on histology) from patients without evidence of gastric neoplasm (n = 64) and from TFF1-knockout mice (n = 22). We validated our findings using 270 normal gastric tissues (including 61 samples from patients without evidence of neoplastic lesions) and 234 gastric tumor tissues from 3 separate cohorts of patients and from mice. We performed molecular and functional assays using cell lines (MKN28, MKN45, STKM2, and AGS cells), gastric organoids, and mice with xenograft tumors. Results: We identified 117 miRNAs that were significantly deregulated in mouse and human gastric tumor tissues compared with nontumor tissues. We validated changes in levels of 6 miRNAs by quantitative real-time polymerase chain reaction analyses of neoplastic gastric tissues from mice (n = 39) and 3 independent patient cohorts (n = 332 patients total). We found levels of MIR135B-5p, MIR196B-5p, and MIR92A-5p to be increased in tumor tissues, whereas levels of MIR143-3p, MIR204-5p, and MIR133-3p were decreased in tumor tissues. Levels of MIR143-3p were reduced not only in gastric cancer tissues but also in normal tissues adjacent to tumors in humans and low-grade dysplasia in mice. Transgenic expression of MIR143-3p in gastric cancer cell lines reduced their proliferation and restored their sensitivity to cisplatin. AGS cells with stable transgenic expression of MIR143-3p grew more slowly as xenograft tumors in mice than control AGS cells; tumor growth from AGS cells that expressed MIR143-3p, but not control cells, was sensitive to cisplatin. We identified and validated bromodomain containing 2 (BRD2) as a direct target of MIR143-3p; increased levels of BRD2 in gastric tumors was associated with shorter survival times for patients. Conclusions: In an analysis of miRNA profiles of gastric tumors from mice and human patients, we identified a conserved signature associated with the early stages of gastric tumorigenesis. Strategies to restore MIR143-3p or inhibit BRD2 might be developed for treatment of gastric cancer.

Original languageEnglish (US)
Pages (from-to)1127-1139.e8
JournalGastroenterology
Volume156
Issue number4
DOIs
StatePublished - Mar 1 2019

Fingerprint

MicroRNAs
Stomach Neoplasms
Stomach
Carcinogenesis
Neoplasms
Heterografts
Cisplatin
Organoids
Cell Line
Small Untranslated RNA
3' Untranslated Regions
Knockout Mice
Real-Time Polymerase Chain Reaction
Histology
Messenger RNA
Survival
Growth

Keywords

  • Progression
  • Stomach
  • Transcription Factor
  • Tumor Suppressor

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis. / Chen, Zheng; Li, Zheng; Soutto, Mohammed; Wang, Weizhi; Piazuelo, M. Blanca; Zhu, Shoumin; Guo, Yan; Maturana, Maria J.; Corvalan, Alejandro H.; Chen, Xi; Xu, Zekuan; El-Rifai, Wael.

In: Gastroenterology, Vol. 156, No. 4, 01.03.2019, p. 1127-1139.e8.

Research output: Contribution to journalArticle

Chen, Z, Li, Z, Soutto, M, Wang, W, Piazuelo, MB, Zhu, S, Guo, Y, Maturana, MJ, Corvalan, AH, Chen, X, Xu, Z & El-Rifai, W 2019, 'Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis', Gastroenterology, vol. 156, no. 4, pp. 1127-1139.e8. https://doi.org/10.1053/j.gastro.2018.11.052
Chen, Zheng ; Li, Zheng ; Soutto, Mohammed ; Wang, Weizhi ; Piazuelo, M. Blanca ; Zhu, Shoumin ; Guo, Yan ; Maturana, Maria J. ; Corvalan, Alejandro H. ; Chen, Xi ; Xu, Zekuan ; El-Rifai, Wael. / Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis. In: Gastroenterology. 2019 ; Vol. 156, No. 4. pp. 1127-1139.e8.
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T1 - Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis

AU - Chen, Zheng

AU - Li, Zheng

AU - Soutto, Mohammed

AU - Wang, Weizhi

AU - Piazuelo, M. Blanca

AU - Zhu, Shoumin

AU - Guo, Yan

AU - Maturana, Maria J.

AU - Corvalan, Alejandro H.

AU - Chen, Xi

AU - Xu, Zekuan

AU - El-Rifai, Wael

PY - 2019/3/1

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N2 - Background & Aims: microRNAs (miRNAs) are small noncoding RNAs that bind to the 3′ untranslated regions of mRNAs to promote their degradation or block their translation. Mice with disruption of the trefoil factor 1 gene (Tff1) develop gastric neoplasms. We studied these mice to identify conserved miRNA networks involved in gastric carcinogenesis. Methods: We performed next-generation miRNA sequencing analysis of normal gastric tissues (based on histology) from patients without evidence of gastric neoplasm (n = 64) and from TFF1-knockout mice (n = 22). We validated our findings using 270 normal gastric tissues (including 61 samples from patients without evidence of neoplastic lesions) and 234 gastric tumor tissues from 3 separate cohorts of patients and from mice. We performed molecular and functional assays using cell lines (MKN28, MKN45, STKM2, and AGS cells), gastric organoids, and mice with xenograft tumors. Results: We identified 117 miRNAs that were significantly deregulated in mouse and human gastric tumor tissues compared with nontumor tissues. We validated changes in levels of 6 miRNAs by quantitative real-time polymerase chain reaction analyses of neoplastic gastric tissues from mice (n = 39) and 3 independent patient cohorts (n = 332 patients total). We found levels of MIR135B-5p, MIR196B-5p, and MIR92A-5p to be increased in tumor tissues, whereas levels of MIR143-3p, MIR204-5p, and MIR133-3p were decreased in tumor tissues. Levels of MIR143-3p were reduced not only in gastric cancer tissues but also in normal tissues adjacent to tumors in humans and low-grade dysplasia in mice. Transgenic expression of MIR143-3p in gastric cancer cell lines reduced their proliferation and restored their sensitivity to cisplatin. AGS cells with stable transgenic expression of MIR143-3p grew more slowly as xenograft tumors in mice than control AGS cells; tumor growth from AGS cells that expressed MIR143-3p, but not control cells, was sensitive to cisplatin. We identified and validated bromodomain containing 2 (BRD2) as a direct target of MIR143-3p; increased levels of BRD2 in gastric tumors was associated with shorter survival times for patients. Conclusions: In an analysis of miRNA profiles of gastric tumors from mice and human patients, we identified a conserved signature associated with the early stages of gastric tumorigenesis. Strategies to restore MIR143-3p or inhibit BRD2 might be developed for treatment of gastric cancer.

AB - Background & Aims: microRNAs (miRNAs) are small noncoding RNAs that bind to the 3′ untranslated regions of mRNAs to promote their degradation or block their translation. Mice with disruption of the trefoil factor 1 gene (Tff1) develop gastric neoplasms. We studied these mice to identify conserved miRNA networks involved in gastric carcinogenesis. Methods: We performed next-generation miRNA sequencing analysis of normal gastric tissues (based on histology) from patients without evidence of gastric neoplasm (n = 64) and from TFF1-knockout mice (n = 22). We validated our findings using 270 normal gastric tissues (including 61 samples from patients without evidence of neoplastic lesions) and 234 gastric tumor tissues from 3 separate cohorts of patients and from mice. We performed molecular and functional assays using cell lines (MKN28, MKN45, STKM2, and AGS cells), gastric organoids, and mice with xenograft tumors. Results: We identified 117 miRNAs that were significantly deregulated in mouse and human gastric tumor tissues compared with nontumor tissues. We validated changes in levels of 6 miRNAs by quantitative real-time polymerase chain reaction analyses of neoplastic gastric tissues from mice (n = 39) and 3 independent patient cohorts (n = 332 patients total). We found levels of MIR135B-5p, MIR196B-5p, and MIR92A-5p to be increased in tumor tissues, whereas levels of MIR143-3p, MIR204-5p, and MIR133-3p were decreased in tumor tissues. Levels of MIR143-3p were reduced not only in gastric cancer tissues but also in normal tissues adjacent to tumors in humans and low-grade dysplasia in mice. Transgenic expression of MIR143-3p in gastric cancer cell lines reduced their proliferation and restored their sensitivity to cisplatin. AGS cells with stable transgenic expression of MIR143-3p grew more slowly as xenograft tumors in mice than control AGS cells; tumor growth from AGS cells that expressed MIR143-3p, but not control cells, was sensitive to cisplatin. We identified and validated bromodomain containing 2 (BRD2) as a direct target of MIR143-3p; increased levels of BRD2 in gastric tumors was associated with shorter survival times for patients. Conclusions: In an analysis of miRNA profiles of gastric tumors from mice and human patients, we identified a conserved signature associated with the early stages of gastric tumorigenesis. Strategies to restore MIR143-3p or inhibit BRD2 might be developed for treatment of gastric cancer.

KW - Progression

KW - Stomach

KW - Transcription Factor

KW - Tumor Suppressor

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