环状RNA17调控雄激素受体变异体在去势抵抗型前列腺癌中的作用及其机制研究

The expression of AR-V7 is one of the critical mechanisms for the development of castration-resistant prostate cancer (CRPC). The regulating mechanism and the effect of AR-V7 to prostate cancer is still not clear. Research shows that circular RNA could affect the formation and development of tumor. In our preliminary study, we found that: 1) circular RNA 17 has higher expression in enzalutamide-sensitive PCa cell (C4-2 Parental cell) while its expression was lower in C4-2 enzalutamide-resistant cell. When circRNA 17 was knocked down in C4-2 Parental cell, AR-V7 expression was increased with concomitant increase of AR-V7 expression and enzalutamide-resistance and enhanced invasion; 2) circRNA 17 can bind miR-181a/c-5P and androgen receptor; 3) luciferase reporter assay confirmed that miR-181a/c-5P can also bind 3'-UTR of AR-V7. Therefore, we hypothesized that circRNA 17 can change AR-V7 expression by regulating miR-181a/c-5P, thus affecting the formation and development of castration-resistant prostate cancer. The project will examine the consequences of up- or down-regulation of circRNA 17 in three different prostate cancer cell lines in terms of miR-181a/c-5P and AR-V7 expression and interaction as well as sensitivity to enzalutamide and cellular invasion. We will also examine the mechanistic relationship among the circRNA 17, miR-181a/c-5p and AR-V7 in animal model in vivo. Success of this project will provide a scientific basis for identifying novel molecular diagnostic markers for and potential therapeutic approaches for castration-resistant prostate cancer.

AR-V7高表达是去势抵抗型前列腺癌(CRPC)形成的重要原因。前列腺癌中AR-V7的调节机制仍不明确。研究表明环状RNA能影响肿瘤的发生发展。我们研究发现：1)环状RNA17在恩杂鲁胺敏感前列腺癌细胞中高表达，其被敲除后AR-V7的表达上调，细胞对恩杂鲁胺的抗药性及侵袭性增强；2)环状RNA17有miR-181a/c-5P结合位点；3)miR-181a/c-5P可与AR-V7基因3'-UTR结合。故我们假设：环状RNA17通过miR-181a/c-5P调控AR-V7的表达而影响CRPC的发生发展。本项目拟通过上调或下调三种前列腺癌细胞株中环状RNA17表达后检测miR-181a/c-5P、AR-V7的表达、相互作用、细胞耐药性和侵袭性，以及这些细胞株在裸鼠中原位成瘤情况，探讨环状RNA17和AR-V7在CRPC发生发展中的作用。本项目的完成可为寻找CRPC新的分子标记和治疗靶标提供依据。

AR-V7高表达是去势抵抗型前列腺癌(CRPC)形成的重要原因。前列腺癌中AR-V7的调节机制仍不明确。研究表明环状RNA能影响肿瘤的发生发展。我们研究发现：1)环状RNA17在恩杂鲁胺敏感前列腺癌细胞中高表达，其被敲除后AR-V7的表达上调，细胞对恩杂鲁胺的抗药性及侵袭性增强；2)环状RNA17有miR-181a/c-5P结合位点；3)miR-181a/c-5P可与AR-V7基因3'-UTR结合。故我们假设：环状RNA17通过miR-181a/c-5P调控AR-V7的表达而影响CRPC的发生发展。本项目拟通过上调或下调三种前列腺癌细胞株中环状RNA17表达后检测miR-181a/c-5P、AR-V7的表达、相互作用、细胞耐药性和侵袭性，以及这些细胞株在裸鼠中原位成瘤情况，探讨环状RNA17和AR-V7在CRPC发生发展中的作用。本项目的完成可为寻找CRPC新的分子标记和治疗靶标提供依据。本研究还围绕恩杂鲁胺抵抗性前列腺癌，在前期研究基础上探讨环状RNA对其侵袭转移的影响，以及双极治疗中大剂量雄激素抑制恩杂鲁胺抵抗性前列腺癌细胞生长的机制。我们认为1. circUCK2得低表达可通过miR-767-5p抑制TET1的表达，从而促进EnzR细胞的增殖和侵袭；2. 大剂量雄激素可通过AR-BCL-2-Beclin1信号通路促进EnzR细胞的自噬性凋亡；3. 大剂量雄激素可通过AR-miR-493-3p-PARK2通路促进BCL-XL的表达；4. 抑制BCL-XL可增强大剂量雄激素对EnzR细胞的抑制作用；5. CircUCK2和BCL-XL均可作为前列腺癌治疗的新靶点。