Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer

Linlin Shao; Zheng Chen; Mohammed Soutto; Shoumin Zhu; Heng Lu; Judith Romero-Gallo; Richard Peek; Shutian Zhang; Wael El-Rifai

doi:10.1096/fj.201701456RR

Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer

Linlin Shao, Zheng Chen, Mohammed Soutto, Shoumin Zhu, Heng Lu, Judith Romero-Gallo, Richard Peek, Shutian Zhang, Wael El-Rifai

Surgery

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Helicobacter pylori infection is a major risk factor for the development of gastric cancer. Aberrant expression of microRNAs is strongly implicated in gastric tumorigenesis; however, their contribution in response to H. pylori infection has not been fully elucidated. In this study, we evaluated the expression ofmiR-135b-5p and its role in gastric cancer. We describe the overexpression of miR-135b-5p in human gastric cancer tissue samples compared with normal tissue samples. Furthermore, we found that miR-135b-5p is also up-regulated in gastric tumors from the trefoil factor 1-knockout mouse model. Infection with H. pylori induced the expression of miR-135b-5p in the in vitro and in vivo models. miR-135b-5p induction was mediated by NF-kB. Treatment of gastric cancer cellswith TNF-a inducedmiR-135b-5p in aNF-kB-dependentmanner.Mechanistically,we found thatmiR-135b-5p targets Kr üppel-like factor 4 (KLF4) and binds to its 39 UTR, leading to reduced KLF4 expression. Functionally, high levels of miR-135b-5p suppress apoptosis and induce cisplatin resistance. Our results uncovered a mechanistic link between H. pylori infection andmiR-135b-5p-KLF4, suggesting that targetingmiR-135b-5p could be a potential therapeutic approach to circumvent resistance to cisplatin.

Original language	English (US)
Pages (from-to)	264-274
Number of pages	11
Journal	FASEB Journal
Volume	33
Issue number	1
DOIs	https://doi.org/10.1096/fj.201701456RR
State	Published - Jan 2019

Keywords

H. pylori
Inflammation
KLF4
MicroRNA
Tff1 knockout

ASJC Scopus subject areas

Biotechnology
Biochemistry
Molecular Biology
Genetics

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@article{0401a58b52d74b2b934abb67c6b6146d,

title = "Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer",

abstract = "Helicobacter pylori infection is a major risk factor for the development of gastric cancer. Aberrant expression of microRNAs is strongly implicated in gastric tumorigenesis; however, their contribution in response to H. pylori infection has not been fully elucidated. In this study, we evaluated the expression ofmiR-135b-5p and its role in gastric cancer. We describe the overexpression of miR-135b-5p in human gastric cancer tissue samples compared with normal tissue samples. Furthermore, we found that miR-135b-5p is also up-regulated in gastric tumors from the trefoil factor 1-knockout mouse model. Infection with H. pylori induced the expression of miR-135b-5p in the in vitro and in vivo models. miR-135b-5p induction was mediated by NF-kB. Treatment of gastric cancer cellswith TNF-a inducedmiR-135b-5p in aNF-kB-dependentmanner.Mechanistically,we found thatmiR-135b-5p targets Kr {\"u}ppel-like factor 4 (KLF4) and binds to its 39 UTR, leading to reduced KLF4 expression. Functionally, high levels of miR-135b-5p suppress apoptosis and induce cisplatin resistance. Our results uncovered a mechanistic link between H. pylori infection andmiR-135b-5p-KLF4, suggesting that targetingmiR-135b-5p could be a potential therapeutic approach to circumvent resistance to cisplatin.",

keywords = "H. pylori, Inflammation, KLF4, MicroRNA, Tff1 knockout",

author = "Linlin Shao and Zheng Chen and Mohammed Soutto and Shoumin Zhu and Heng Lu and Judith Romero-Gallo and Richard Peek and Shutian Zhang and Wael El-Rifai",

note = "Funding Information: This study was supported by the U.S. National Institutes of Health, National Cancer Institute (R01CA93999 and R01CA177372), a Research Career Scientist Award (1IK6BX003787), and a merit award (I01BX001179) from the U.S. Department of Veterans Affairs (to W.E.-R.). The results were also supported by the Biostatistics and Bioinformatics Shared Resource at the Sylvester Comprehensive Cancer Center, University of Miami. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Veterans Affairs, the U.S. National Institutes of Health, or the University of Miami. The authors declare no conflicts of interest.",

year = "2019",

month = jan,

doi = "10.1096/fj.201701456RR",

language = "English (US)",

volume = "33",

pages = "264--274",

journal = "FASEB Journal",

issn = "0892-6638",

publisher = "FASEB",

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TY - JOUR

T1 - Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer

AU - Shao, Linlin

AU - Chen, Zheng

AU - Soutto, Mohammed

AU - Zhu, Shoumin

AU - Lu, Heng

AU - Romero-Gallo, Judith

AU - Peek, Richard

AU - Zhang, Shutian

AU - El-Rifai, Wael

N1 - Funding Information: This study was supported by the U.S. National Institutes of Health, National Cancer Institute (R01CA93999 and R01CA177372), a Research Career Scientist Award (1IK6BX003787), and a merit award (I01BX001179) from the U.S. Department of Veterans Affairs (to W.E.-R.). The results were also supported by the Biostatistics and Bioinformatics Shared Resource at the Sylvester Comprehensive Cancer Center, University of Miami. The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Veterans Affairs, the U.S. National Institutes of Health, or the University of Miami. The authors declare no conflicts of interest.

PY - 2019/1

Y1 - 2019/1

N2 - Helicobacter pylori infection is a major risk factor for the development of gastric cancer. Aberrant expression of microRNAs is strongly implicated in gastric tumorigenesis; however, their contribution in response to H. pylori infection has not been fully elucidated. In this study, we evaluated the expression ofmiR-135b-5p and its role in gastric cancer. We describe the overexpression of miR-135b-5p in human gastric cancer tissue samples compared with normal tissue samples. Furthermore, we found that miR-135b-5p is also up-regulated in gastric tumors from the trefoil factor 1-knockout mouse model. Infection with H. pylori induced the expression of miR-135b-5p in the in vitro and in vivo models. miR-135b-5p induction was mediated by NF-kB. Treatment of gastric cancer cellswith TNF-a inducedmiR-135b-5p in aNF-kB-dependentmanner.Mechanistically,we found thatmiR-135b-5p targets Kr üppel-like factor 4 (KLF4) and binds to its 39 UTR, leading to reduced KLF4 expression. Functionally, high levels of miR-135b-5p suppress apoptosis and induce cisplatin resistance. Our results uncovered a mechanistic link between H. pylori infection andmiR-135b-5p-KLF4, suggesting that targetingmiR-135b-5p could be a potential therapeutic approach to circumvent resistance to cisplatin.

AB - Helicobacter pylori infection is a major risk factor for the development of gastric cancer. Aberrant expression of microRNAs is strongly implicated in gastric tumorigenesis; however, their contribution in response to H. pylori infection has not been fully elucidated. In this study, we evaluated the expression ofmiR-135b-5p and its role in gastric cancer. We describe the overexpression of miR-135b-5p in human gastric cancer tissue samples compared with normal tissue samples. Furthermore, we found that miR-135b-5p is also up-regulated in gastric tumors from the trefoil factor 1-knockout mouse model. Infection with H. pylori induced the expression of miR-135b-5p in the in vitro and in vivo models. miR-135b-5p induction was mediated by NF-kB. Treatment of gastric cancer cellswith TNF-a inducedmiR-135b-5p in aNF-kB-dependentmanner.Mechanistically,we found thatmiR-135b-5p targets Kr üppel-like factor 4 (KLF4) and binds to its 39 UTR, leading to reduced KLF4 expression. Functionally, high levels of miR-135b-5p suppress apoptosis and induce cisplatin resistance. Our results uncovered a mechanistic link between H. pylori infection andmiR-135b-5p-KLF4, suggesting that targetingmiR-135b-5p could be a potential therapeutic approach to circumvent resistance to cisplatin.

KW - H. pylori

KW - Inflammation

KW - KLF4

KW - MicroRNA

KW - Tff1 knockout

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