S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biomedical Sciences (대학원 의과학과) Theses (Ph.D. / Sc.D._의과학과)
The role of SIRT1 in avoiding AIM2-mediated antiviral defense in cervical cancer
자궁경부암에서 AIM2를 매개체로 하는 항바이러스 방어 기전 회피에 대한 SIRT1의 역할
- 의과대학 의과학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의과대학 의과학과, 2018. 8. 박종완.
- Mammalian cells are equipped with antiviral defense system. To survive and grow, human papillomavirus (HPV)-infected cervical cancer cells must overcome this host defense system. However, the precise mechanism whereby cervical cancer cells effective evade the defense system is not fully understood. I noted that Sirtuin 1 (SIRT1) is overexpressed in HPV-infected cervical cancer cells and hypothesized that SIRT1 plays a significant role in survival of cervical cancer. Here, I found that cervical cancer cells undergo massive death by SIRT1 knockdown, but this effect is reversed by SIRT1 restoration. SIRT1-knocked-down cells showed representative features of pyroptosis, as well as highly expressed absent in melanoma 2 (AIM2) and its downstream genes related to the inflammasome response. Mechanistically, SIRT1 repressed the NF-B-driven transcription of the AIM2 gene by destabilizing the RELB mRNA. Interestingly, pyroptotic death signaling in SIRT1-knocked-down cells was transmitted to naïve cervical cancer cells, which was mediated by extracellular vesicles carrying AIM2 inflammasome proteins. Furthermore, the growth of cervical cancer xenorgafts was noticeably inhibited by either SIRT1-targeting siRNAs or SIRT1 knockdown-derived extracellular vesicles. Immunohistochemical analyses showed that SIRT1 expression correlates with poor clinical outcome in cervical cancer. In conclusion, SIRT1 enables HPV-infected cervical cancer cells to continue growing by nullifying AIM2 inflammasome–mediated immunity. Without SIRT1, cervical cancer cells can no longer survive because of the derepression of the AIM2 inflammasome. SIRT1 could be a remarkable target for cervical cancer therapy.
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