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MiR-124 acts as a tumor suppressor by inhibiting the expression of sphingosine kinase 1 and its downstream signaling in head and neck squamous cell carcinoma

Oncotarget, 2017-04, Vol.8 (15), p.25005-25020

Copyright: © 2017 Zhao et al. 2017 ;ISSN: 1949-2553 ;EISSN: 1949-2553 ;DOI: 10.18632/oncotarget.15334 ;PMID: 28212569

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Title:
MiR-124 acts as a tumor suppressor by inhibiting the expression of sphingosine kinase 1 and its downstream signaling in head and neck squamous cell carcinoma
Author: Zhao, Yuan ; Ling, Zhiqiang ; Hao, Yubin ; Pang, Xiaowu ; Han, Xianlin ; Califano, Joseph A ; Shan, Liang ; Gu, Xinbin
Subjects: Animals ; Carcinoma, Squamous Cell - genetics ; Carcinoma, Squamous Cell - metabolism ; Carcinoma, Squamous Cell - pathology ; Cell Line, Tumor ; Genes, Tumor Suppressor ; Head and Neck Neoplasms - genetics ; Head and Neck Neoplasms - metabolism ; Head and Neck Neoplasms - pathology ; Heterografts ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; MicroRNAs - metabolism ; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors ; Phosphotransferases (Alcohol Group Acceptor) - biosynthesis ; Phosphotransferases (Alcohol Group Acceptor) - genetics ; Phosphotransferases (Alcohol Group Acceptor) - metabolism ; Research Paper ; Signal Transduction ; Squamous Cell Carcinoma of Head and Neck ; Transfection
Is Part Of: Oncotarget, 2017-04, Vol.8 (15), p.25005-25020
Description: By analyzing the expression profile of microRNAs in head and neck squamous cell carcinomas (HNSCC), we found that the expression level of miR-124 was 4.59-fold lower in tumors than in normal tissues. To understand its functions, we generated a miR-124-expressing subline (JHU-22miR124) and a mock vector-transfected subline (JHU-22vec) by transfecting the mimic of miR-124 into JHU-22 cancer cells. Restored expression of miR-124 in JHU-22miR124 cells led to reduced cell proliferation, delayed colony formation, and decreased tumor growth, indicating a tumor-suppressive effect of miR-124. Subsequent target search revealed that the 3'-UTR of SphK1 mRNA carries a complementary site for the seed region of miR-124. SphK1 was also detected to be overexpressed in HNSCC cell lines, but down-expressed in JHU-22miR124 cells and tumor xenografts. These results suggest that SphK1 is a target of miR-124. To confirm this finding, we constructed a 3'-UTR-Luc-SphK1 vector and a binding site-mutated luciferase reporter vector. Co-transfection of 3'-UTR-Luc-SphK1 with miR-124 expression vector exhibited a 9-fold decrease in luciferase activity compared with mutated vector, suggesting that miR-124 inhibits SphK1 activity directly. Further studies on downstream signaling demonstrated accumulation of ceramide, increased expression of the pro-apoptotic Bax, BAD and PARP, decreased expression of the anti-apoptotic Bcl-2 and Bcl-xL, and enhanced expression of cytochrome c and caspase proteins in JHU-22miR124 compared with JHU-22vec cells and tumor xenografts. We conclude that miR-124 acts as a tumor suppressor in HNSCC by directly inhibiting SphK1 activity and its downstream signals.
Publisher: United States: Impact Journals LLC
Language: English
Identifier: ISSN: 1949-2553
EISSN: 1949-2553
DOI: 10.18632/oncotarget.15334
PMID: 28212569
Source: GFMER Free Medical Journals
MEDLINE
PubMed Central
Alma/SFX Local Collection

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MiR-124 acts as a tumor suppressor by inhibiting the expression of sphingosine kinase 1 and its downstream signaling in head and neck squamous cell carcinoma

Copyright: © 2017 Zhao et al. 2017 ;ISSN: 1949-2553 ;EISSN: 1949-2553 ;DOI: 10.18632/oncotarget.15334 ;PMID: 28212569

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