The drug resistance of cancer remains a major obstacle to successful chemotherapy. New strategies for improving chemotherapeutic efficacy are urgently required. Recent studies have indicated that LIPC plays a role in promoting the liver metastasis of colorectal cancer. In the present study, we aimed to investigate the effects of LIPC on theproliferation and clone formation of colorectal cancer-derived cells, and chemoresistance in hepatoblastoma-derived HepG2 cells. The activity and expression of LIPC were determined in the cell lines by RT-qPCR and western blot analysis. HepG2 cells in which LIPC was knocked down by LIPC short hairpin RNA (shRNA) and control cells [shRNA control (shCON)] were established and analyzed for cell proliferation and colony formation rates. FACS analysis was used to explore the association between LIPC and the tumor-derived cell biomarker, CD133, and the percentages of CD133-positive cells were assessed by FACS. Additionally, shLIPC- and shCON-transfected cells were treated with various concentrations of doxorubicin and 5-floxuridine (5-FU), and cell viability was determined by MTT assay. mRNA levels in the shLIPC- and shCON-transfected cells were compared by cDNA microarray and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The results revealed that the HepG2 cells exhibited a relatively higher LIPC activity and expression levels compared to the other colon cancer cell lines. The downregulation of LIPC in the HepG2 cells was associated with the decreased expression of CD133, decreased cell proliferation and colony formation, as well as increased resistance to chemotherapy. KEGG analysis of the cDNA microarray data revealed increased levels in the cell adhesion molecule (CAM) pathway, including CLDN10 and CLDN1, indicating that CAMs may play a role in LIPC-mediated tumor progression. The present findings indicate a potential role of LIPC as a promising therapeutic target in cancer.