GCRIS

Circular RNAs (CircRNAs) are a novel class of single-stranded, covalently-closed RNA molecules. Functional investigations of the circRNAs provide insight into the mechanisms underlying gene regulation and cellular responses, which could ultimately lead to the development of new therapies for a wide range of diseases. In this thesis, four cisplatin (cis-diamminedichloroplatinum II, CP)-responsive circRNAs, circGALNT2, circBNC2, circBIRC6, and circCLASP1, were validated. The reverse genetics approaches, such as knockdown and overexpression strategies, showed that circCLASP1 is required for the proliferation of HeLa cells. The knockdown of circCLASP1 disrupts proliferation in HeLa, and its overexpression restores impaired proliferation. Further analyses revealed that circCLASP1 knockdown sensitizes HeLa cells against 20 μM and 40 μM cisplatin treatments. Interestingly, an IC50 dose of cisplatin causes Annexin V-/7AAD + cell death rather than apoptosis when combined with circCLASP1 knockdown. In light of these findings, five circRNA/miRNA/mRNA regulatory networks were constructed using computational approaches. Additionally, a transcriptomics analysis after circCLASP1 knockdown has supported all of these findings in that muscle cell proliferation genes were significantly altered upon circCLASP1 knockdown in HeLa cells. In conclusion, the findings suggest that the knockdown of circCLASP1 represses proliferation and sensitizes HeLa cells against cisplatin. CircCLASP1-knockdown mediated differential gene expression indicates proliferation, ROS response, iron metabolism, lipid peroxidation, and cell death. Further studies are needed to elucidate the precise mechanism of circCLASP1-mediated cell death and proliferation in muscle cells or liver cells and ROS-related diseases.

Phd Degree / Doktora

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