한빛사
>
한빛사논문
한빛사논문
- 조회63
김진선Jin Sun Kim
울산대학교 의과대학, 서울아산병원
Clin. Cancer Res., Feb 24 2025, | https://doi.org/10.1158/1078-0432.CCR-24-1228
Synergistic Effects of Transarterial Chemoembolization and Lenvatinib on HIF-1α Ubiquitination and Prognosis Improvement in Hepatocellular Carcinoma
Sung Won Chung,1† Jin Sun Kim,1† Won-Mook Choi,1* Jonggi Choi,1 Danbi Lee,1 Ju Hyun Shim,1 Young-Suk Lim,1 Han Chu Lee,1 and Kang Mo Kim1*
1Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
†These authors equally contributed to this study as co-first authors.
*These authors equally contributed to this study as co-corresponding authors.
Address all correspondence and requests for reprints to: Kang Mo Kim, MD, PhD, Won-Mook Choi, MD, PhD
1Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
†These authors equally contributed to this study as co-first authors.
*These authors equally contributed to this study as co-corresponding authors.
Address all correspondence and requests for reprints to: Kang Mo Kim, MD, PhD, Won-Mook Choi, MD, PhD
Abstract
Purpose: A recent trial has shown that adding transarterial chemoembolization (TACE) to lenvatinib therapy results in enhanced therapeutic efficacy in hepatocellular carcinoma (HCC). We aimed to assess the effectiveness of the lenvatinib and TACE combination in a real-world clinical context for managing HCC and to elucidate the molecular pathways involved.
Experimental design: This retrospective analysis included 199 patients diagnosed with HCC and having intrahepatic lesions between 2018 and 2021. The cohort was divided into those who received lenvatinib plus TACE (n=62, combination group) and those who received lenvatinib monotherapy (n=137, monotherapy group). To further explore the underlying mechanisms, Huh-7 cells were exposed to lenvatinib or a vehicle for 48 hours under normoxic or hypoxic condition.
Results: Propensity score-matched analysis revealed a significant improvement in both overall survival (adjusted hazard ratio [aHR], 0.38; 95% CI, 0.24-0.59; P<0.001) and progression-free survival (aHR, 0.41; 95% CI, 0.26-0.64; P<0.001) in the combination group compared to the monotherapy group. In laboratory experiments, under hypoxic conditions, lenvatinib notably attenuated hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in Huh-7 cells without altering its mRNA levels. Intriguingly, lenvatinib facilitated the MDM2-mediated ubiquitination and subsequent degradation of HIF-1α. Additionally, cell viability assays confirmed a significant decrease in Huh-7 cell survival following lenvatinib treatment under hypoxic conditions.
Conclusions: The combination of lenvatinib and TACE significantly improved survival in HCC patients. The mechanistic foundation appears to be the lenvatinib-triggered degradation of HIF-1α via the MDM2-dependent ubiquitination pathway, highlighting a potential therapeutic target in HCC treatment.
Experimental design: This retrospective analysis included 199 patients diagnosed with HCC and having intrahepatic lesions between 2018 and 2021. The cohort was divided into those who received lenvatinib plus TACE (n=62, combination group) and those who received lenvatinib monotherapy (n=137, monotherapy group). To further explore the underlying mechanisms, Huh-7 cells were exposed to lenvatinib or a vehicle for 48 hours under normoxic or hypoxic condition.
Results: Propensity score-matched analysis revealed a significant improvement in both overall survival (adjusted hazard ratio [aHR], 0.38; 95% CI, 0.24-0.59; P<0.001) and progression-free survival (aHR, 0.41; 95% CI, 0.26-0.64; P<0.001) in the combination group compared to the monotherapy group. In laboratory experiments, under hypoxic conditions, lenvatinib notably attenuated hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in Huh-7 cells without altering its mRNA levels. Intriguingly, lenvatinib facilitated the MDM2-mediated ubiquitination and subsequent degradation of HIF-1α. Additionally, cell viability assays confirmed a significant decrease in Huh-7 cell survival following lenvatinib treatment under hypoxic conditions.
Conclusions: The combination of lenvatinib and TACE significantly improved survival in HCC patients. The mechanistic foundation appears to be the lenvatinib-triggered degradation of HIF-1α via the MDM2-dependent ubiquitination pathway, highlighting a potential therapeutic target in HCC treatment.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-25)
- 국내 연구진
- 의약학 > 응용의학
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
