A new study published in Cell Death and Disease has revealed the role of miR-93 in tumorigenesis and chemosensitivity.
Breast cancer and miRNAs
Breast cancer is the leading cause of morbidity and mortality among female malignancies worldwide. Chemotherapy is the mainstay treatment option. However, most patients face treatment failure and disease relapse due to chemoresistance. Acquired chemoresistance is common, meaning tumours are initially sensitive to the therapy but after several courses, they gradually become resistant to one or more drugs. Consequently, substantial research goes into understanding the molecular mechanism behind chemoresistance to develop novel strategies to improve therapeutic effect.
MicroRNAs (miRNAs) are a group of non-coding, single-stranded RNA that are 19-25 nucleotides in length. Mature miRNAs play an important role in gene regulation, by post-transcriptionally suppressing expression of target genes. They are involved in numerous biological processes, including cell proliferation, apoptosis, migration and invasion. In addition, miRNAs are frequently found to be dysregulated in various cancer types. In fact, recent evidence has emerged of its role in chemoresistance of different tumours.
MiR-93
In this study, conducted by researchers from Zhejiang University, China, miR-93 was investigated to determine its role in breast cancer tumorigenesis and chemosensitivity.
The team found that miR-93 is downregulated in chemoresistant breast cancers. To explore the correlation between miR-93 and chemoresistance, the team evaluated its role within cell function. They discovered that miR-93 inhibits cell proliferation, induces G1/S cell cycle arrest and enhances chemosensitivity to paclitaxel (PTX) in vitro and in vivo. Therefore, it plays a strong role in impairing chemoresistance of breast cancer cells.
Furthermore, two well-established oncogenes, E2F1 and CCND1, were found to act as dual targets of miR-93. These oncogenes are associated with chemoresistance of breast cancer. When these genes were knocked down, the researchers found reduced cell proliferation and PTX-sensitivity, whilst overexpression had the opposite effect. Most importantly, they discovered that overexpression of E2F1 and CCND1 abrogated miR-93 inhibitory effects on cell proliferation and cell cycle progress. Moreover, they revealed, through further mechanistic study, that miR-93 acts by directly targeting E2F1 and CCND1 to inactivate pRB/E2F1 pathway and AKT phosphorylation.
Chemoresistance mechanisms are heterogenous and very complex. Therefore, focusing on a single target or pathway will not produce a sustained response. These findings have shown that miR-93 downregulation is correlated with cell proliferation and chemoresistance. They have also shown dual targets, E2F1 and CCND1, are inhibited by miR-93 to suppress cell cycle progression and apoptosis. Therefore, this study provides a rationale for the treatment with miR-93 to overcome chemoresistance of breast cancer.
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