Functional and clinical evidence for NDRG2 as a candidate suppressor of liver cancer metastasis.
We searched for potential suppressors of tumor metastasis by identifying the genes that are frequently down-regulated in hepatocellular carcinomas (HCC) while being negatively correlated with clinical parameters relevant to tumor metastasis, and we report here on the identification of N-myc downstream regulated gene 2 (NDRG2) as a promising candidate. NDRG2 expression was significantly reduced in HCC compared with nontumor or normal liver tissues [87.5% (35 of 40) and 62% (62 of 100) at RNA and protein levels, respectively]. Reduction of NDRG2 expression was intimately associated with promoter hypermethylation because its promoter region was found to carry extensively methylated CpG sites in HCC cell lines and primary tumors. Immunohistochemical analysis of NDRG2 protein in 100 HCC patient tissues indicated that NDRG2 expression loss is significantly correlated with aggressive tumor behaviors such as late tumor-node-metastasis (TNM) stage (P = 0.012), differentiation grade (P = 0.024), portal vein thrombi (P = 0.011), infiltrative growth pattern (P = 0.015), nodal/distant metastasis (P = 0.027), and recurrent tumor (P = 0.021), as well as shorter patient survival rates. Ectopically expressed NDRG2 suppressed invasion and migration of a highly invasive cell line, SK-Hep-1, and experimental tumor metastasis in vivo, whereas small interfering RNA-mediated knockdown resulted in increased invasion and migration of a weakly invasive cell line, PLC/PRF/5. In addition, NDRG2 could antagonize transforming growth factor beta1-mediated tumor cell invasion by specifically down-regulating the expression of matrix metalloproteinase 2 and laminin 332 pathway components, with concomitant suppression of Rho GTPase activity. These results suggest that NDRG2 can inhibit extracellular matrix-based, Rho-driven tumor cell invasion and migration and thereby play important roles in suppressing tumor metastasis in HCC.
Lee
Dong Chul
DC
Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon, Korea.
Kang
Yun Kyung
YK
Kim
Woo Ho
WH
Jang
Ye Jin
YJ
Kim
Dong Joon
DJ
Park
In Young
IY
Sohn
Bo Hwa
BH
Sohn
Hyun Ahm
HA
Lee
Hee Gu
HG
Lim
Jong Seok
JS
Kim
Jae Wha
JW
Song
Eun Young
EY
Kim
Dong Min
DM
Lee
Mi-Ni
MN
Oh
Goo Taeg
GT
Kim
Soo Jung
SJ
Park
Kyung Chan
KC
Yoo
Hyang Sook
HS
Choi
Jong Young
JY
Yeom
Young Il
YI
D001483:Base Sequence; D045744:Cell Line, Tumor; D018899:CpG Islands; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
C466228:NDRG2 protein, human; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins