Loss of RACK1 Promotes Metastasis of Gastric Cancer by Inducing a miR-302c/IL8 Signaling Loop

Ling Chen; Lingqiang Min; Xuefei Wang; Junjie Zhao; Hua Chen; Jing Qin; Weidong Chen; Zhenbin Shen; Zhaoqing Tang; Qiangjun Gan; Yuanyuan Ruan; Yihong Sun; Xinyu Qin; Jianxin Gu

doi:10.1158/0008-5472.CAN-14-3690

Loss of RACK1 Promotes Metastasis of Gastric Cancer by Inducing a miR-302c/IL8 Signaling Loop

Cancer Res. 2015 Sep 15;75(18):3832-41. doi: 10.1158/0008-5472.CAN-14-3690. Epub 2015 Jul 21.

Authors

Ling Chen¹, Lingqiang Min¹, Xuefei Wang¹, Junjie Zhao¹, Hua Chen², Jing Qin¹, Weidong Chen¹, Zhenbin Shen¹, Zhaoqing Tang¹, Qiangjun Gan¹, Yuanyuan Ruan³, Yihong Sun⁴, Xinyu Qin⁴, Jianxin Gu⁵

Affiliations

¹ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
² Department of Statistics, Oklahoma State University, Stillwater, Oklahoma.
³ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. sun.yihong@zs-hospital.sh.cn qin.xinyu@zs-hospital.sh.cn yuanyuanruan@fudan.edu.cn.
⁴ Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. sun.yihong@zs-hospital.sh.cn qin.xinyu@zs-hospital.sh.cn yuanyuanruan@fudan.edu.cn.
⁵ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.

PMID: 26199092
DOI: 10.1158/0008-5472.CAN-14-3690

Abstract

Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and invasion and metastasis of gastric cancer represent the major reason for its poor prognosis. In this study, we found that loss of the receptor for activated C-kinase 1 (RACK1) promoted the metastasis of gastric cancer by enhancing the autocrine expression of IL8 in vitro and in vivo. microRNA (miRNA; miR) array identified that RACK1 modulated the expression of a series of miRNAs, including the miR-302 cluster, and RACK1 modulated the IL8 expression and tumor invasion through miRNA-302c. Moreover, upregulation of IL8 in turn decreased the level of miRNA-302c and induced IL8 expression in a feedback manner. Tissue microarray also indicated that RACK1 was correlated with invasion/metastasis phenotype, IL8 expression, as well as 5-year survival in clinical cases of gastric cancer. Together, our results imply that loss of RACK1 in gastric cancer links epigenetics to inflammatory cytokines to promote tumor metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Autocrine Communication
Female
GTP-Binding Proteins / deficiency
GTP-Binding Proteins / genetics
GTP-Binding Proteins / physiology*
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Interleukin-8 / biosynthesis
Interleukin-8 / genetics
Interleukin-8 / physiology*
Male
Mice
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / genetics*
Middle Aged
Neoplasm Invasiveness
Neoplasm Metastasis / genetics*
Neoplasm Proteins / deficiency
Neoplasm Proteins / genetics
Neoplasm Proteins / physiology*
Peritoneal Neoplasms / secondary
RNA, Small Interfering / pharmacology
Receptors for Activated C Kinase
Receptors, Cell Surface / deficiency
Receptors, Cell Surface / genetics
Receptors, Cell Surface / physiology*
Receptors, Interleukin-8 / biosynthesis
Receptors, Interleukin-8 / genetics
Signal Transduction
Stomach Neoplasms / genetics
Stomach Neoplasms / mortality
Stomach Neoplasms / pathology*

Substances

Interleukin-8
MIRN302 microRNA, mouse
MicroRNAs
Neoplasm Proteins
RACK1 protein, human
RNA, Small Interfering
Receptors for Activated C Kinase
Receptors, Cell Surface
Receptors, Interleukin-8
GTP-Binding Proteins