Colorectal cancer (CRC) is the third most common malignancy with high mortality around the world. However, the biological mechanism of CRC carcinogenesis is not completely known. In the present study, we determined the role of miR-92a in the regulation of CRC cell motility. Expression of miR-92a is aberrantly upregulated in human CRC tissues and cultured cells, as shown by RT-PCR analysis. The effects of miR-92a on the proliferation and migration of human CRC SW620 and LoVo cells were measured by CCK-8 and Transwell assay, respectively. Results showed that the proliferation and migration capacity of both SW620 and LoVo cells were significantly increased by miR-92a mimic transfection but reduced by miR-92a inhibition. Additionally, KLF4 was identified as a direct target of miR-92a in CRC cells through bioinformatics and luciferase reporter analysis. KLF4 overexpression attenuated the effects of miR-92a on the regulation of CRC cell motility. Further studies suggested that the cell cycle inhibitor p21 was aberrantly downregulated in CRC cells, whereas this inhibition was reversed by miR-92a inhibitor. In conclusion, our data demonstrated that miR-92a may play a positive role in the colorectal carcinogenesis by promoting the proliferation and migration of CRC cells through targeting KLF4 as well as downstream p21. This could be an alternative therapeutic target for CRC.

Hepatocellular carcinoma (HCC) remains a global health threat. The search for novel anti-HCC agents is urgent. In the current study, we synthesized a liposomal C8 ceramide, and analyzed its anti-tumor activity in pre-clinical HCC models. The liposomal C8 (ceramide) potently inhibited HCC cell (HepG2, SMMC-7721 and Huh-7 lines) survival and proliferation, more efficiently than free C8 ceramide. Yet, non-cancerous HL7702 human hepatocytes were resistant to the liposomal C8 treatment. Liposomal C8 activated caspase-dependent apoptosis in HCC cells, and HCC cytotoxicity by liposomal C8 was significantly attenuated with co-treatment of caspase inhibitors. At the molecular level, we showed that liposomal C8 activated ASK1 (apoptosis signal-regulating kinase 1)-JNK (Jun N-terminal protein kinase) signaling in HCC cells. On the other hand, JNK pharmacological inhibition or dominant negative mutation, as well as ASK1 shRNA-knockdown remarkably inhibited liposomal C8-induced apoptosis in HCC cells. Further studies showed that liposomal C8 inhibited AKT-mTOR (mammalian target of rapamycin) activation in HCC cells. Restoring AKT-mTOR activation by introducing a constitutively-active AKT alleviated HepG2 cytotoxicity by liposomal C8. In vivo, intravenous (i.v.) injection of liposomal C8 significantly inhibited HepG2 xenograft growth in severe combined immuno-deficient (SCID) mice, and mice survival was significantly improved. These preclinical results suggest that liposomal C8 could be further studied as a valuable anti-HCC agent.