Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression
<b>Background:</b> Aberrant expression of microRNAs in neoplastic lesions may serve as potential personalized therapeutic targets. To inhibit oncogenic microRNAs (oncomiRs) expression and restore tumor suppressor proteins, linear miRNA sponges have been developed, leading to several drug...
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2025-05-01
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| author | Qianyi Zhang Pengcheng Sun Guang Hu Xuanyao Yu Wen Zhang Xuan Feng Lan Yu Pengfei Zhang |
| author_facet | Qianyi Zhang Pengcheng Sun Guang Hu Xuanyao Yu Wen Zhang Xuan Feng Lan Yu Pengfei Zhang |
| author_sort | Qianyi Zhang |
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| description | <b>Background:</b> Aberrant expression of microRNAs in neoplastic lesions may serve as potential personalized therapeutic targets. To inhibit oncogenic microRNAs (oncomiRs) expression and restore tumor suppressor proteins, linear miRNA sponges have been developed, leading to several drugs in clinical trials. Despite their efficacy, chemically synthesized miRNA inhibitors face challenges with sustained inhibition and high production costs, hindering widespread clinical adoption. Additionally, single-stranded circular RNAs (circRNAs) act as miRNA sponges, enhancing protein expression and demonstrating stability and therapeutic potential in cancer treatment. Our approach involves the use of synthetic single-stranded circular nucleic acids, including circDNA and circRNA, to selectively target and inhibit a variety of aberrantly overexpressed oncomiRs in tumors. The objective of this strategy is to restore the expression levels of multiple tumor suppressor factors and to suppress the malignant progression of tumors. <b>Methods:</b> Our methodology comprises a two-step process. First, we identified tumor suppressor genes (TSGs) with abnormally low expression in hepatocellular carcinoma (HCC) tumor cells by transcriptomic analysis and targeted the upstream cancer miRNA clusters of these TSGs. Second, we designed and validated a fully complementary circDNA or circRNA construct, ligated by T4 DNA ligase or T4 RNA ligase, respectively, that specifically targets the sponge oncomiRs both in vitro and in vivo to inhibit the malignant progression of HCC. <b>Results:</b> CircNAs demonstrated superior, long-lasting therapeutic efficacy against HCC compared to inhibitors. Furthermore, we compared the immune effects in vivo of three different nucleic acid adsorption carriers, including commercial miRNA inhibitor, circDNA, and circRNA. We found that the miRNA inhibitor activates a more robust inflammatory response compared to circDNA and circRNA. <b>Conclusions:</b> These findings underscore the substantial therapeutic potential of circDNA in tumorigenesis and provide novel insights for the formulation of personalized treatment plans for malignant tumors, such as HCC. |
| format | Article |
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| language | English |
| publishDate | 2025-05-01 |
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| series | Biomedicines |
| spelling | doaj-art-6af16ef8582d4ce6a6629b0e43ea5a702025-08-20T02:33:40ZengMDPI AGBiomedicines2227-90592025-05-01135117110.3390/biomedicines13051171Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma ProgressionQianyi Zhang0Pengcheng Sun1Guang Hu2Xuanyao Yu3Wen Zhang4Xuan Feng5Lan Yu6Pengfei Zhang7School of Life Sciences, Tianjin University, Tianjin 300072, ChinaDepartment of Obstetrics and Gynecology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150001, ChinaHangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310018, ChinaInstitutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, ChinaInstitutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, ChinaInstitutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, ChinaInstitute of Basic Medicine, Inner Mongolia Academy of Medical Sciences, Hohhot 010010, ChinaInstitutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot 010070, China<b>Background:</b> Aberrant expression of microRNAs in neoplastic lesions may serve as potential personalized therapeutic targets. To inhibit oncogenic microRNAs (oncomiRs) expression and restore tumor suppressor proteins, linear miRNA sponges have been developed, leading to several drugs in clinical trials. Despite their efficacy, chemically synthesized miRNA inhibitors face challenges with sustained inhibition and high production costs, hindering widespread clinical adoption. Additionally, single-stranded circular RNAs (circRNAs) act as miRNA sponges, enhancing protein expression and demonstrating stability and therapeutic potential in cancer treatment. Our approach involves the use of synthetic single-stranded circular nucleic acids, including circDNA and circRNA, to selectively target and inhibit a variety of aberrantly overexpressed oncomiRs in tumors. The objective of this strategy is to restore the expression levels of multiple tumor suppressor factors and to suppress the malignant progression of tumors. <b>Methods:</b> Our methodology comprises a two-step process. First, we identified tumor suppressor genes (TSGs) with abnormally low expression in hepatocellular carcinoma (HCC) tumor cells by transcriptomic analysis and targeted the upstream cancer miRNA clusters of these TSGs. Second, we designed and validated a fully complementary circDNA or circRNA construct, ligated by T4 DNA ligase or T4 RNA ligase, respectively, that specifically targets the sponge oncomiRs both in vitro and in vivo to inhibit the malignant progression of HCC. <b>Results:</b> CircNAs demonstrated superior, long-lasting therapeutic efficacy against HCC compared to inhibitors. Furthermore, we compared the immune effects in vivo of three different nucleic acid adsorption carriers, including commercial miRNA inhibitor, circDNA, and circRNA. We found that the miRNA inhibitor activates a more robust inflammatory response compared to circDNA and circRNA. <b>Conclusions:</b> These findings underscore the substantial therapeutic potential of circDNA in tumorigenesis and provide novel insights for the formulation of personalized treatment plans for malignant tumors, such as HCC.https://www.mdpi.com/2227-9059/13/5/1171miRNA spongescircular single-stranded nucleic acidsHCCcancer therapy |
| spellingShingle | Qianyi Zhang Pengcheng Sun Guang Hu Xuanyao Yu Wen Zhang Xuan Feng Lan Yu Pengfei Zhang Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression Biomedicines miRNA sponges circular single-stranded nucleic acids HCC cancer therapy |
| title | Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression |
| title_full | Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression |
| title_fullStr | Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression |
| title_full_unstemmed | Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression |
| title_short | Circular Nucleic Acids Act as an Oncogenic MicroRNA Sponge to Inhibit Hepatocellular Carcinoma Progression |
| title_sort | circular nucleic acids act as an oncogenic microrna sponge to inhibit hepatocellular carcinoma progression |
| topic | miRNA sponges circular single-stranded nucleic acids HCC cancer therapy |
| url | https://www.mdpi.com/2227-9059/13/5/1171 |
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