Department of Hepatobiliary and Pancreatic Surgery, The Center for Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China; Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China.
Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China; Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China.
Eur J Surg Oncol. 2021 Oct;47(10):2533-2542. doi: 10.1016/j.ejso.2021.04.001. Epub 2021 Apr 19.
The use of the immunosuppressive agent sirolimus (SRL) following liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) is controversial. Sirolimus is a typical mammalian target of rapamycin (mTOR) inhibitor, and tuberous sclerosis 1-tuberous sclerosis 2 complex (TSC1/TSC2) is an important negative effector in the mTOR pathway. In this study, we investigated the effect of SRL-based immunosuppression on the prognosis of LT recipients with HCC beyond the Milan criteria based on TSC1/2 expression and explored the effect of TSC1 on HCC in vitro and in vivo.
We retrospectively analyzed 120 HCC patients who underwent LT in our hospital between January 1, 2015 and December 30, 2018. All patients had HCC beyond the Milan criteria and were divided into the SRL group (n = 50) and non-SRL group (n = 70). TSC1/2 expression levels in paraffin-embedded tissues were determined by immunohistochemistry (IHC) and then analyzed as subgroups. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method. TSC1 expression was silenced in Huh-7 and Bel-7402 cell lines for further cell function experiments.
88.3% of patients were HBV LT recipients. The SRL group exhibited better DFS and OS compared to the non-SRL group (P = 0.02, P = 0.003). Subgroup (TSC1-based or TSC2-based) analyses revealed that patients with low TSC1 or TSC2 expression benefited from sirolimus (DFS: P = 0.046, OS: P = 0.006 for TSC1; DFS: P = 0.05, OS: P = 0.003 for TSC2) compared with patients with high expression. TSC1 knockdown in Huh-7 and Bel-7402 HCC cell lines activated the mTORC1 pathway and enhanced cell proliferation, migration and sensitivity to SRL in vitro and in vivo.
TSC1/2 expression could be used to predict the prognosis of patients with HCC beyond the Milan criteria who underwent SRL-based immunosuppression following LT. TSC1 knockdown promoted HCC malignancy and enhanced sensitivity to SRL.
在肝癌（HCC）患者肝移植（LT）后使用免疫抑制剂西罗莫司（SRL）存在争议。西罗莫司是一种典型的哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，结节性硬化症 1-结节性硬化症 2 复合物（TSC1/TSC2）是 mTOR 通路中的重要负效因子。在这项研究中，我们根据 TSC1/2 表达研究了基于 SRL 的免疫抑制对米兰标准以外的 LT 受体中 HCC 患者预后的影响，并探讨了 TSC1 在 HCC 中的体外和体内作用。
我们回顾性分析了 2015 年 1 月 1 日至 2018 年 12 月 30 日期间在我院接受 LT 的 120 例 HCC 患者。所有患者均患有米兰标准以外的 HCC，并分为 SRL 组（n=50）和非 SRL 组（n=70）。通过免疫组织化学（IHC）检测石蜡包埋组织中 TSC1/2 的表达水平，并进行亚组分析。采用 Kaplan-Meier 法分析总生存期（OS）和无病生存期（DFS）。在 Huh-7 和 Bel-7402 细胞系中沉默 TSC1 表达，进行进一步的细胞功能实验。
88.3%的患者为 HBV LT 受体。与非 SRL 组相比，SRL 组的 DFS 和 OS 更好（P=0.02，P=0.003）。基于 TSC1 或 TSC2 的亚组分析显示，与高表达患者相比，低 TSC1 或 TSC2 表达的患者受益于西罗莫司（DFS：P=0.046，OS：P=0.006 用于 TSC1；DFS：P=0.05，OS：P=0.003 用于 TSC2）。在 Huh-7 和 Bel-7402 HCC 细胞系中敲低 TSC1 激活了 mTORC1 通路，并增强了细胞增殖、迁移和对 SRL 的敏感性，无论是在体内还是体外。
TSC1/2 表达可用于预测接受 LT 后基于 SRL 的免疫抑制治疗的米兰标准以外的 HCC 患者的预后。TSC1 敲低促进 HCC 恶性转化并增强对 SRL 的敏感性。
