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OBJECTIVE The present study aimed to explore the contribution of COPB2 (coatomer subunit beta) towards the tumorigenesis of cholangiocellular carcinomas and to elucidate the underlying mechanism(s). MATERIALS AND METHODS Expression of COPB2 mRNA by RBE and QBC939 cholangiocellular carcinoma cell lines was determined by qRT-PCR. We, then, silenced COPB2 expression in RBE cells by infection with a COPB2-siRNA lentivirus and measured the proliferation, cell-cycle distribution, and apoptosis of transduced cells. RESULTS COPB2 was highly expressed in RBE and QBC939 cholangiocellular carcinoma cell lines. Infection with COPB2-siRNA lentivirus in RBE cells significantly decreased COPB2 expression. More so, silencing of COPB2 by COPB2-siRNA significantly suppressed the proliferation and promoted the apoptosis of RBE cells by arresting transduced cells in the G1 phase. CONCLUSIONS Our results demonstrate that the COPB2 gene is highly expressed in cholangiocellular carcinoma cell lines, wherein knockdown inhibited the proliferation and promoted the arrest of cell-cycle progression and the apoptosis of cholangiocellular carcinomas. COPB2 may constitute an attractive target for therapeutic strategies against cholangiocellular cancers.