Cholesterol-conjugated let-7amimics: antitumor efficacy on hepatocellular carcinoma in vitro and in a preclinical orthotopic xenograft model of systemic therapy
| Autor: | Jiong Cai, Jie Chen, Yuan Zhi Li, Xuan Zeng, Yu Xia, Yang Ming Liu, Tao Yang, Jian Guan, Yu Xue Dong, Wei Dai, Hua Ye Han, Feng Yu Luo |
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| Jazyk: | angličtina |
| Předmět: |
Pathology
medicine.medical_specialty Cancer Research Carcinoma Hepatocellular Cell Survival Mice Nude Antineoplastic Agents Metastasis Mice In vivo Cell Line Tumor medicine Genetics Animals Humans Neoplasm Invasiveness Viability assay Cell Proliferation Cell growth business.industry Liver Neoplasms Hep G2 Cells Transfection medicine.disease Xenograft Model Antitumor Assays Up-Regulation Gene Expression Regulation Neoplastic MicroRNAs Cholesterol Oncology Cell culture Hepatocellular carcinoma Cancer research lipids (amino acids peptides and proteins) Stem cell business Research Article |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| DOI: | 10.1186/1471-2407-14-889 |
| Popis: | Background A major challenge to the clinical utility of let-7 for hepatocellular carcinoma (HCC) therapy is the lack of an effective carrier to target tumours. We confirmed the high transfection efficiency of cholesterol-conjugated let-7a miRNA mimics (Chol-let-7a) in human HCC cells, as well as their high affinity for liver tissue in nude mice. However, their antitumor efficacy via systemic delivery remains unknown. Methods We explored the effects of Chol-let-7a on HCC in vitro and in vivo. Cell viability and mobility, let-7a abundance and the target ras genes was measured. Live-cell image and cell ultrastructure was observed. Antitumor efficacy in vivo was analyzed by ultrasonography, hispatholgogy and transmission electronic microscopy in a preclinical model of HCC orthotopic xenografts with systemic therapy. Results Chol-let-7a inhibited the viability and mobility of HCC cells. Chol-let-7a was primarily observed in the cytoplasm and induced organelle changes, including autophagy. Mild changes were observed in the cells treated with negative control miRNA. Chol-let-7a reached HCC orthotopic tumours, significantly inhibited tumour growth, and prevented local invasion and metastasis. Compared to control tumours, Chol-let-7a-treated tumours showed more necrosis. Tumour cells showed no significant atypia, and mitoses were very rare after systemic Chol-let-7a therapy. Furthermore, let-7a abundance in orthotopic xenografts was coincident with a reduction in the expression of 3 human ras mRNAs and RAS proteins. Conclusions Chol-let-7a exerted significant antitumor effects by down-regulating all human ras genes at the transcriptional and translational levels. Chol-let-7a inhibited cell proliferation, growth, and metastasis, and mainly functioned in the cytoplasm. Chol-let-7a represents a potential useful modified molecule for systemic HCC therapy. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-889) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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