Radiotherapy is a common cancer therapeutic approach but radioresistance in tumors frequently prevents successful cancer control; therefore, overcoming radioresistance is essential for improving radiotherapy. MicroRNA-21 (miR-21) is an onco-miR that over- expresses in almost all types of human tumors. We and others have demonstrated that over- expression of miR-21 could result in tumorigenesis. Currently, there are only a few reports showed that miR-21 contributes to radioresistance of tumor cells, and the mechanism remains unclear. Recently, by using our miR-21 knock-in or miR-21 knockout mouse models, the embryo fibroblast cells derived from the mouse strains and knocking down miR-21 in several human tumor cell lines, we found that miR-21 plays an important role in radioresistance that is involved in promoting DNA double strand break (DSB) repair. Based on our previous publications and preliminary data, we will test the hypothesis that miR-21-mediated radioresistance occurs through its targets to promote DNA DSB repair. Since IR-induced cell killing occurs mainly by generating DSBs, and non-homologous end joining (NHEJ) and homologous recombination repair (HRR) are the two major pathways in mammalian cells to repair DNA DSB, it is important to elucidate if miR-21-mediated radioresistance occurs through stimulating NHEJ, HRR or both. It is also important to elucidate how miR-21 affects the DNA repair pathway(s) via its targets including Pten and Cdc25A (known targets of miR-21), as well as GSK3b (a novel target of miR- 21 identified by our group). For this purpose, two aims are designed: 1) Determine if miR-21- mediated radioresistance occurs through stimulating NHEJ, HRR or both. 2) Determine how miR-21 mediates radioresistance through its targets. Since miR-21 over-expressed in almost all types of human tumors, the results from this proposal are expected to not only enhance our knowledge of tumor cell radioresistance, but also provide novel targets and pathways for improving tumor radiotherapy.
In this proposal, we will elucidate how miR-21 mediates cell radioresistance through its targets to promote the repair of DNA DSBs. The results are expected to provide new factors and pathways for targeting to improve radiotherapy.
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| Liu, Min; Wang, Hongyan; Lee, Solah et al. (2016) DNA repair pathway choice at various conditions immediately post irradiation. Int J Radiat Biol 92:819-822 |
| Wang, Jian; Li, Zongcheng; Liu, Bailong et al. (2016) Systematic study of cis-antisense miRNAs in animal species reveals miR-3661 to target PPP2CA in human cells. RNA 22:87-95 |
| Wang, Jian; Farris, Alton B; Xu, Kaiming et al. (2016) GPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis. Nat Commun 7:11795 |
