lenvatinib and Cell-Transformation--Neoplastic

MicroRNAs (miRNAs) play an important role in cancer proliferation, metastasis, drug resistance and apoptosis by targeting oncogenes or tumor suppressor genes. miR-3154 has been reported to be up-regulated in cervical cancer and leukemia, but its role in hepatocellular carcinoma (HCC) remains unclear. Here, we for the first time demonstrated that miR-3154 was elevated in HCC and liver cancer stem cells (CSCs). Up-regulated miR-3154 was associated with overall survival and disease-free survival of HCC patients. MiR-3154 knockdown inhibits HCC cells self-renewal, proliferation, metastasis, and tumorigenesis. Mechanistically, miR-3154 target directly to HNF4α. MiR-3154 knockdown upregulated HNF4α mRNA and protein expression. HNF4α interference abolish the differences of self-renewal, proliferation, metastasis, and tumorigenesis between miR-3154 knockdown cells and control hepatoma cells. Furthermore, miR-3154 expression was negatively correlated with HNF4α in HCC tissues. The combined HHC panels exhibited a better disease-free survival prognostic value for HCC patients than any of these components alone. More importantly, miR-3154 determines the responses of hepatoma cells to lenvatinib treatment. Analysis of patient cohort and patient-derived xenografts (PDXs) further suggest that miR-3154 might predict lenvatinib clinical benefit in HCC patients. In conclusion, we reveal the crucial role of miR-3514 in HCC progression and lenvatinib response, suggesting potential therapeutic targets for HCC.

Topics: Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Hepatocyte Nuclear Factor 4; Humans; Liver Neoplasms; MicroRNAs

RET gene fusions are recurrent oncogenes identified in thyroid and lung carcinomas. Lenvatinib is a multi-tyrosine kinase inhibitor currently under evaluation in several clinical trials. Here we evaluated lenvatinib in RET gene fusion-driven preclinical models. In cellular assays, lenvatinib inhibited auto-phosphorylation of KIF5B-RET, CCDC6-RET, and NcoA4-RET. Lenvatinib suppressed the growth of CCDC6-RET human thyroid and lung cancer cell lines, and as well, suppressed anchorage-independent growth and tumorigenicity of RET gene fusion-transformed NIH3T3 cells. These results demonstrate that lenvatinib can exert antitumor activity against RET gene fusion-driven tumor models by inhibiting oncogenic RET gene fusion signaling.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Transformation, Neoplastic; Cytoskeletal Proteins; Drug Screening Assays, Antitumor; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms; NIH 3T3 Cells; Oncogene Proteins, Fusion; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinolines; Signal Transduction