RESUMO
Colorectal cancer (CRC) is a major health problem due to its high mortality rate. The incidence of CRC is increasing in young individuals. Oxaliplatin (OXA) is an approved third-generation drug and is used for first-line chemotherapy in CRC. Although current standard chemotherapy improves the overall survival of CRC patients, an increasing number of reports of OXA resistance in CRC therapy indicates that resistance has become an urgent problem in clinical applications. Dicer is a critical enzyme involved in miRNA maturation. The expression of Dicer has been reported to be involved in the resistance to various drugs in cancer. In the present study, we aimed to investigate the role of Dicer in OXA resistance in CRC. We found that OXA treatment inhibited Dicer expression through decreasing the protein stability. OXA-induced Dicer protein degradation occurred through both proteasomal and lysosomal proteolysis, while the CHIP E3 ligase was involved in OXA-mediated Dicer ubiquitination and degradation. We established stable OXA-resistant clones from CRC cells, and observed that the CHIP E3 ligase was decreased, along with the increased Dicer expression in OXA-resistant cells. Knockdown of Dicer resensitized CRC cells to OXA treatment. In this study, we have revealed the role of miRNA biogenesis factors in OXA resistance in CRC cells.
Assuntos
Antineoplásicos/farmacologia , RNA Helicases DEAD-box/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Oxaliplatina/farmacologia , Ribonuclease III/genética , Ubiquitina-Proteína Ligases/genética , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , RNA Helicases DEAD-box/antagonistas & inibidores , RNA Helicases DEAD-box/metabolismo , Células HCT116 , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , Proteólise , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ribonuclease III/antagonistas & inibidores , Ribonuclease III/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Heterogeneous nuclear ribonucleoprotein (hnRNP) Q1, an RNA-binding protein, has been implicated in many post-transcriptional processes, including RNA metabolism and mRNA splicing and translation. However, the role of hnRNP Q1 in tumorigenesis remains unclear. We previously performed RNA immunoprecipitation (RIP)-seq analysis to identify hnRNP Q1-interacting mRNAs and found that hnRNP Q1 targets a group of genes that are involved in mitotic regulation, including Aurora-A. Here, we demonstrate that altering the hnRNP Q1 level influences the expression of the Aurora-A protein, but not its mRNA. Stimulation with epidermal growth factor (EGF) enhances both binding between hnRNP Q1 and Aurora-A mRNA as well as the efficacy of the hnRNP Q1-induced translation of Aurora-A mRNA. The EGF/hnRNP Q1-induced translation of Aurora-A mRNA is mediated by the mTOR and ERK pathways. In addition, we show that hnRNP Q1 up-regulates the translation of a group of spindle assembly checkpoint (SAC) genes. hnRNP Q1 overexpression is positively correlated with the levels of Aurora-A and the SAC genes in human colorectal cancer tissues. In summary, our data suggest that hnRNP Q1 plays an important role in regulating the expression of a group of cell cycle-related genes. Therefore, it may contribute to tumorigenesis by up-regulating the translation of these genes in colorectal cancer.