Targeted Disruption of Nemo-Like Kinase Inhibits Tumor Cell Growth by Simultaneous Suppression of Cyclin D1 and CDK2 in Human Hepatocellular Carcinoma

被引：74
作者：
Jung, Kwang Hwa [1 ]
Kim, Jeong Kyu [1 ]
Noh, Ji Heon [1 ]
Fun, Jung Woo [1 ]
Bae, Hyun Jin [1 ]
Xie, Hong Jian [1 ]
Ahn, Young Min [2 ]
Park, Won Sang [1 ]
Lee, Jung Young [1 ]
Nam, Suk Woo [1 ]
机构：
[1] Catholic Univ Korea, Coll Med, Microdissect Genom Res Ctr, Seoul 137701, South Korea
[2] Kyung Hee Univ, Coll Oriental Med, Dept Kidney Syst, Seoul, South Korea
来源：
JOURNAL OF CELLULAR BIOCHEMISTRY | 2010年 / 110卷 / 03期
关键词：
NLK; CELL CYCLE ARREST; CDK2; CYCLIN D1; HEPATOCELLULAR CARCINOMA; BETA-CATENIN DEGRADATION; COLORECTAL-CANCER; CAENORHABDITIS-ELEGANS; MAP KINASE; PATHWAY; PROTEIN; GENE; POLARITY; PHOSPHORYLATION;
D O I：
10.1002/jcb.22579
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
The Wnt/beta-catenin signaling pathway regulates various aspects of development and plays important role in human carcinogenesis. Nemo-like kinase (NLK), which is mediator of Wnt/beta-catenin signaling pathway, phosphorylates T-cell factor/lymphoid enhancer factor (TCF/LEF) factor and inhibits interaction of beta-catenin/TCF complex. Although, NLK is known to be a tumor suppressor in Wnt/beta-catenin signaling pathway of colon cancer, the other events occurring downstream of NLK pathways in other types of cancer remain unclear. In the present study, we identified that expression of NLK was significantly up-regulated in the HCCs compared to corresponding normal tissues in five selected tissue samples. Immunohistochemical analysis showed significant over-expression of NLK in the HCCs. Targeted-disruption of NLK suppressed cell growth and arrested cell cycle transition. Suppression of NLK elicited anti-mitogenic properties of the Hep3B cells by simultaneous inhibition of cyclinD1 and CDK2. The results of this study suggest that NLK is aberrantly regulated in HCC, which might contribute to the mitogenic potential of tumor cells during the initiation and progression of hepatocellular carcinoma; this process appears to involve the induction of CDK2 and cyclin D1 and might provide a novel target for therapeutic intervention in patients with liver cancer. J. Cell. Biochem. 110: 687-696, 2010. (C) 2010 Wiley-Liss. Inc.
引用
收藏
页码：687 / 696
页数：10
相关论文
共 30 条
[1]   Linking colorectal cancer to Wnt signaling [J].
Bienz, M ;
Clevers, H .
CELL, 2000, 103 (02) :311-320
[2]   Focus on hepatocellular carcinoma [J].
Bruix, J ;
Boix, L ;
Sala, M ;
Llovet, JM .
CANCER CELL, 2004, 5 (03) :215-219
[3]   ROTATION OF PHOTORECEPTOR CLUSTERS IN THE DEVELOPING DROSOPHILA EYE REQUIRES THE NEMO GENE [J].
CHOI, KW ;
BENZER, S .
CELL, 1994, 78 (01) :125-136
[4]   The ABC of APC [J].
Fearnhead, NS ;
Britton, MP ;
Bodmer, WF .
HUMAN MOLECULAR GENETICS, 2001, 10 (07) :721-733
[5]  
GRANA X, 1995, ONCOGENE, V11, P211
[6]   Regulation of lymphoid enhancer factor 1/T-Cell factor by mitogen-activated protein kinase-related nemo-like kinase-dependent phosphorylation in Wnt/β-catenin signaling [J].
Ishitani, T ;
Ninomiya-Tsuji, J ;
Matsumoto, K .
MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (04) :1379-1389
[7]   The TAK1-NLK-MAPK-related pathway antagonizes signalling between β-catenin and transcription factor TCF [J].
Ishitani, T ;
Ninomiya-Tsuji, J ;
Nagai, S ;
Nishita, M ;
Meneghini, M ;
Barker, N ;
Waterman, M ;
Bowerman, B ;
Clevers, H ;
Shibuya, H ;
Matsumoto, K .
NATURE, 1999, 399 (6738) :798-802
[8]   The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca2+ pathway to antagonize Wnt/β-catenin signaling [J].
Ishitani, T ;
Kishida, S ;
Hyodo-Miura, J ;
Ueno, N ;
Yasuda, J ;
Waterman, M ;
Shibuya, H ;
Moon, RT ;
Ninomiya-Tsuji, J ;
Matsumoto, K .
MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (01) :131-139
[9]   Binary specification of the embryonic lineage in Caenorhabditis elegans [J].
Kaletta, T ;
Schnabel, H ;
Schnabel, R .
NATURE, 1997, 390 (6657) :294-298
[10]   Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK [J].
Kanei-Ishii, C ;
Ninomiya-Tsuji, J ;
Tanikawa, J ;
Nomura, T ;
Ishitani, T ;
Kishida, S ;
Kokura, K ;
Kurahashi, T ;
Ichikawa-Iwata, E ;
Kim, Y ;
Matsumoto, K ;
Ishii, S .
GENES & DEVELOPMENT, 2004, 18 (07) :816-829
123