miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR-p-PI3K/AKT-c-JUN.
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.
Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou 510315, China.|Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Mengyang
M
Zhao
Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou 510315, China.
Rongcheng
R
Luo
Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Yiyi
Y
Liu
Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Linyuan
L
Gao
Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Zhaojian
Z
Fu
Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Qiaofen
Q
Fu
Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou 510315, China.
Xiaojun
X
Luo
Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Yiyu
Y
Chen
Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Xiaojie
X
Deng
Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Zixi
Z
Liang
Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Xin
X
Li
Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Chao
C
Cheng
Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.|Department of Pathology, Basic School of Guangzhou Medical University, Guangzhou 510182, China.
Zhen
Z
Liu
Cancer Center, Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou 510315, China.|Cancer Research Institute, Southern Medical University, Guangzhou 510515, China.
Weiyi
W
Fang
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002277:Carcinoma; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D025461:Feedback, Physiological; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C085126:FOXO1 protein, human; C000598218:MIRN3189 microRNA, human; C546842:MTOR protein, human