한빛사논문
- 조회2,620
Abstract
Hyun Jin Bae1, 2, a, Kwang Hwa Jung1, 2, a, Jung Woo Eun1, 2, Qingyu Shen1, 2, Hyung Seok Kim1, 2, Se Jin Park1, 2, Woo Chan Shin1, 2, Hee Doo Yang1, 2, Won Sang Park1, 2, Jung Young Lee1, 2, Suk Woo Nam1, 2, 3,*
1 Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, 137-701, Republic of Korea
2 Functional RNomics Research Center, The Catholic University of Korea, Seoul, 137-701, Republic of Korea
3 Cancer Evolution Research Center, The Catholic University of Korea, Seoul, 137-701, Republic of Korea
*Corresponding author.
a H.J.Bae and K.H.Jung contributed equally to this work
Abstract
Background & Aims
Most common reason behind changes in histone deacetylase (HDAC) function is its overexpression in cancer. However, among HDACs in liver cancer, HDAC6 is uniquely endowed with a tumor suppressor, but the mechanism underlying HDAC6 inactivation has yet to be uncovered.
Methods
Microarray profiling and target prediction programs were used to identify miRNAs targeting HDAC6. A series of inhibitors, activators and siRNAs was introduced to validate regulatory mechanisms for microRNA-221-3p (miR-221) governing HDAC6 in hepatocarcinogenesis.
Results
Comprehensive miRNA profiling analysis identified seven putative endogenous miRNAs that are significantly upregulated in hepatocellular carcinoma (HCC). While miR-221 was identified as a suppressor of HDAC6 by ectopic expression of miRNA mimics in Dicer knockdown cells, targeted-disruption of miR-221 repressed cancer cell growth through derepressing HDAC6 expression. Suppression of HDAC6 via miR-221 was induced by JNK/c-Jun signaling in liver cancer cells but not in normal hepatic cells. Additionally, cytokine-induced NF-κBp65 independently regulated miR-221, thereby suppressing HDAC6 expression in HCC cells. HCC tissues derived from chemical-induced rat and H-ras12V transgenic mice liver cancer models validated that JNK/c-Jun activation and NF-kBp65 nuclear translocation are essential for the transcription of miR-221 leading to repression of HDAC6 in HCC.
Conclusions
Our findings suggest that the functional loss or suppression of the tumor suppressor HDAC6 is caused by induction of miR-221 through coordinated JNK/c-Jun- and NF-κB-signaling pathways during liver tumorigenesis, providing a novel target for the molecular treatment of liver malignancies.
Keywords : MicroRNA-221; Histone deacetylase 6; JNK/c-Jun; NF-κB; Liver Cancer
논문정보
- Research article
- 2015년 03월 (BRIC 등록일 2015-03-31)
- 국내 연구진
- 생명과학 > 세포생물학
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