Family with sequence similarity 189, member B (FAM189B), alias COTE1, a putative oncogene selectedby microarray, for the first time was here found to be significantly up-regulated in hepatocellular carcinoma(HCC) specimens and HCC cell lines. mRNA expression of COTE1 in HCC samples and cell lines was detectedby reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR, while protein expressionof COTE1 in HCC tissues was assessed by immunohistochemistry. In addition, invasion of HCC cells wasobserved after overexpressing or silencing COTE1. In the total of 48 paired HCC specimens, compared withthe adjacent non-cancer tissues, the expression of COTE1 was up-regulated in 31 (p<0.01). In HCC cell lines,COTE1 expression was significantly higher than in normal human adult liver (p<0.01). Overexpression ofCOTE1 enhanced HCC-derived LM6 and MHCC-L cellular invasion in vitro. In contrast, COTE1 knockdownvia RNAi markedly suppressed these phenotypes, as documented in LM3 and MHCC-H HCC cells. Mechanisticanalyses indicated that COTE1 could physically associate with WW domain oxidoreductase (WWOX), a tumorsuppressor. COTE1 may be closely correlated with invasion of hepatocellular carcinoma (HCC) cells and thusmay serve as an effective target for gene therapy.