Cationic liposomes induce cytotoxicity in HepG2 via regulation of lipid metabolism based on whole-transcriptome sequencing analysis.

BACKGROUD: Cationic liposomes (CLs) can be used as non-viral vectors in gene transfer and drug delivery. However, the underlying molecular mechanism of its cytotoxicity has not been well elucidated yet. METHODS: We herein report a systems biology approach based on whole-transcriptome sequencing coupled with computational method to identify the predominant genes and pathways involved in the cytotoxicity of CLs in HepG2 cell line. RESULTS: Firstly, we validated the concentration-dependent cytotoxicity of CLs with an IC50 of 120 µg/ml in HepG2 exposed for 24 h. Subsequently, we used whole-transcriptome sequencing to identify 220 (77 up- and 143 down-regulated) differentially expressed genes (DEGs). Gene ontology (GO) and pathway analysis showed that these DEGs were mainly related to cholesterol, steroid, lipid biosynthetic and metabolic processes. Additionally, "key regulatory" genes were identified using gene act, pathway act and co-expression network analysis, and expression levels of 11 interested altered genes were confirmed by quantitative real time PCR. Interestingly, no cell cycle arrest was observed through flow cytometry. CONCLUSIONS: These data are expected to provide deep insights into the molecular mechanism of CLs cytotoxicity.

Cancer stem-like cell properties are regulated by EGFR/AKT/ß-catenin signaling and preferentially inhibited by gefitinib in nasopharyngeal carcinoma.

We report that the epidermal growth factor receptor (EGFR) pathway plays a critical role in regulating cancer stem-like cells (CSCs) in nasopharyngeal carcinoma (NPC), one of the most common malignant tumors in Southeast Asia. Effects of EGFR on maintaining CSCs are mainly mediated by AKT signaling, and ß-catenin is responsible for governing CSC properties in response to EGFR/AKT activation. Significantly, CSCs are enriched by cisplatin and decreased by gefitinib in NPC xenograft models. Upon reimplantation in secondary mice, tumor cells derived from cisplatin-treated mice grew rapidly, whereas regrowth of tumor cells from gefitinib-treated mice was severely diminished. We further demonstrate that expression of EGFR correlates with expression of ß-catenin and Nanog in primary tumor specimens from NPC patients. These findings provide mechanistic and preclinical evidence supporting the use of gefitinib alone or in combination with a chemotherapeutic agent in first-line therapy for patients with NPC. In addition, our results suggest that targeting ß-catenin represents a rational clinical modality for patients whose tumors harbor activated EGFR or AKT.