Sirolimus-based immunosuppression improves the prognosis of liver Transplantation Recipients with low TSC1/2 expression in hepatocellular carcinoma beyond the Milan Criteria

Qianwei Ye; Sunbin Ling; Guangjiang Jiang; Qiaonan Shan; Shengjun Xu; Qifan Zhan; Yifeng Wu; Yuchen Liu; Shusen Zheng; Xiao Xu

doi:10.1016/j.ejso.2021.04.001

Sirolimus-based immunosuppression improves the prognosis of liver Transplantation Recipients with low TSC1/2 expression in hepatocellular carcinoma beyond the Milan Criteria

Eur J Surg Oncol. 2021 Oct;47(10):2533-2542. doi: 10.1016/j.ejso.2021.04.001. Epub 2021 Apr 19.

Authors

Qianwei Ye¹, Sunbin Ling¹, Guangjiang Jiang¹, Qiaonan Shan², Shengjun Xu¹, Qifan Zhan¹, Yifeng Wu², Yuchen Liu³, Shusen Zheng⁴, Xiao Xu⁵

Affiliations

¹ 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.
² 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.
³ NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China; Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China.
⁴ 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, Shulan (Hangzhou) Hospital, Hangzhou, 310000, China. Electronic address: shusenzheng@zju.edu.cn.
⁵ 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; Zhejiang University Cancer Center, Hangzhou, 310058, China; NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, 310003, China; Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China. Electronic address: zjxu@zju.edu.cn.

PMID: 33902956
DOI: 10.1016/j.ejso.2021.04.001

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Hepatocellular carcinoma; Liver transplantation; Prognosis; Sirolimus; TSC1/2.

MeSH terms

Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / surgery*
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation / genetics
Disease-Free Survival
Female
Gene Silencing
Humans
Immunosuppressive Agents / therapeutic use*
Kaplan-Meier Estimate
Liver Neoplasms / metabolism
Liver Neoplasms / surgery*
Liver Transplantation
Male
Middle Aged
Retrospective Studies
Sirolimus / therapeutic use*
Survival Rate
Tuberous Sclerosis Complex 1 Protein / genetics
Tuberous Sclerosis Complex 1 Protein / metabolism*
Tuberous Sclerosis Complex 2 Protein / metabolism*

Substances

Immunosuppressive Agents
TSC1 protein, human
TSC2 protein, human
Tuberous Sclerosis Complex 1 Protein
Tuberous Sclerosis Complex 2 Protein
Sirolimus