miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR-p-PI3K/AKT-c-JUN

Mengyang Zhao; Rongcheng Luo; Yiyi Liu; Linyuan Gao; Zhaojian Fu; Qiaofen Fu; Xiaojun Luo; Yiyu Chen; Xiaojie Deng; Zixi Liang; Xin Li; Chao Cheng; Zhen Liu; Weiyi Fang

doi:10.1038/ncomms11309

miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR-p-PI3K/AKT-c-JUN

Nat Commun. 2016 Apr 20:7:11309. doi: 10.1038/ncomms11309.

Authors

Mengyang Zhao^{1

2}, Rongcheng Luo¹, Yiyi Liu², Linyuan Gao², Zhaojian Fu², Qiaofen Fu², Xiaojun Luo¹, Yiyu Chen², Xiaojie Deng², Zixi Liang², Xin Li², Chao Cheng², Zhen Liu^{2

3}, Weiyi Fang^{1

2}

Affiliations

¹ Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou 510315, China.
² Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
³ Department of Pathology, Basic School of Guangzhou Medical University, Guangzhou 510182, China.

Abstract

The biological role of miR-3188 has not yet been reported in the context of cancer. In this study, we observe that miR-3188 not only reduces cell-cycle transition and proliferation, but also significantly prolongs the survival time of tumour-bearing mice as well as sensitizes cells to 5-FU. Mechanistic analyses indicate that miR-3188 directly targets mTOR to inactivate p-PI3K/p-AKT/c-JUN and induces its own expression. This feedback loop further suppresses cell-cycle signalling through the p-PI3K/p-AKT/p-mTOR pathway. Interestingly, we also observe that miR-3188 direct targeting of mTOR is mediated by FOXO1 suppression of p-PI3K/p-AKT/c-JUN signalling. In clinical samples, reduced miR-3188 is an unfavourable factor and negatively correlates with mTOR and c-JUN levels but positively correlates with FOXO1 expression. Our studies demonstrate that as a tumour suppressor, miR-3188 directly targets mTOR to stimulate its own expression and participates in FOXO1-mediated repression of cell growth, tumorigenesis and NPC chemotherapy resistance.

Publication types

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

MeSH terms

Adult
Aged
Aged, 80 and over
Animals
Carcinoma
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Drug Resistance, Neoplasm / genetics
Feedback, Physiological
Female
Forkhead Box Protein O1
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Neoplastic*
Humans
JNK Mitogen-Activated Protein Kinases / genetics*
JNK Mitogen-Activated Protein Kinases / metabolism
Male
Mice
MicroRNAs / genetics*
MicroRNAs / metabolism
Middle Aged
Nasopharyngeal Carcinoma
Nasopharyngeal Neoplasms / diagnosis
Nasopharyngeal Neoplasms / genetics*
Nasopharyngeal Neoplasms / metabolism
Nasopharyngeal Neoplasms / pathology
Neoplasm Staging
Neoplasm Transplantation
Phosphatidylinositol 3-Kinases / genetics*
Phosphatidylinositol 3-Kinases / metabolism
Prognosis
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Survival Analysis
TOR Serine-Threonine Kinases / genetics*
TOR Serine-Threonine Kinases / metabolism

Substances

FOXO1 protein, human
Forkhead Box Protein O1
Forkhead Transcription Factors
MIRN3189 microRNA, human
MicroRNAs
MTOR protein, human
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
JNK Mitogen-Activated Protein Kinases