Sirolimus-based immunosuppression improves the prognosis of liver Transplantation Recipients with low TSC1/2 expression in hepatocellular carcinoma beyond the Milan Criteria期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

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

Institution:	1. Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People''s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China;2. Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;3. NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China;4. Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou 310000, China

Abstract:	BackgroundThe 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.MethodsWe 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.Results88.3% 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.ConclusionTSC1/2 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:	Sirolimus TSC1/2 Liver transplantation Hepatocellular carcinoma Prognosis CLTR"} {"#name":"keyword" "$":{"id":"kwrd0040"} "$$":[{"#name":"text" "_":"China Liver Transplant Registry CNIs"} {"#name":"keyword" "$":{"id":"kwrd0050"} "$$":[{"#name":"text" "_":"calcineurin inhibitors DFS"} {"#name":"keyword" "$":{"id":"kwrd0060"} "$$":[{"#name":"text" "_":"disease free survival EVR"} {"#name":"keyword" "$":{"id":"kwrd0070"} "$$":[{"#name":"text" "_":"everolimus FBS"} {"#name":"keyword" "$":{"id":"kwrd0090"} "$$":[{"#name":"text" "_":"fetal bovine serum HBV"} {"#name":"keyword" "$":{"id":"kwrd0100"} "$$":[{"#name":"text" "_":"hepatitis B virus HCC"} {"#name":"keyword" "$":{"id":"kwrd0110"} "$$":[{"#name":"text" "_":"hepatocellular carcinoma H-score"} {"#name":"keyword" "$":{"id":"kwrd0120"} "$$":[{"#name":"text" "_":"histochemistry score IHC"} {"#name":"keyword" "$":{"id":"kwrd0130"} "$$":[{"#name":"text" "_":"immunohistochemistry K–S"} {"#name":"keyword" "$":{"id":"kwrd0140"} "$$":[{"#name":"text" "_":"Kolmogorov-Smirnov LT"} {"#name":"keyword" "$":{"id":"kwrd0150"} "$$":[{"#name":"text" "_":"liver transplantation mTOR"} {"#name":"keyword" "$":{"id":"kwrd0160"} "$$":[{"#name":"text" "_":"mammalian target of rapamycin OS"} {"#name":"keyword" "$":{"id":"kwrd0170"} "$$":[{"#name":"text" "_":"overall survival p70S6K"} {"#name":"keyword" "$":{"id":"kwrd0180"} "$$":[{"#name":"text" "_":"p70S6 kinase SRL"} {"#name":"keyword" "$":{"id":"kwrd0190"} "$$":[{"#name":"text" "_":"sirolimus SRTR"} {"#name":"keyword" "$":{"id":"kwrd0200"} "$$":[{"#name":"text" "_":"Scientific Registry of Transplant Recipients STR"} {"#name":"keyword" "$":{"id":"kwrd0210"} "$$":[{"#name":"text" "_":"short-tandem repeat TSC1"} {"#name":"keyword" "$":{"id":"kwrd0220"} "$$":[{"#name":"text" "_":"tuberous sclerosis 1 TSC1"} {"#name":"keyword" "$":{"id":"kwrd0230"} "$$":[{"#name":"text" "_":"tuberous sclerosis 2 WB"} {"#name":"keyword" "$":{"id":"kwrd0240"} "$$":[{"#name":"text" "_":"western blotting YLLs"} {"#name":"keyword" "$":{"id":"kwrd0250"} "$$":[{"#name":"text" "_":"years of life lost 4EBP1"} {"#name":"keyword" "$":{"id":"kwrd0260"} "$$":[{"#name":"text" "_":"eIF4E-binding protein 1
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