SPTLC1 表达降低预示 ccRCC 患者预后不良。

Decreased SPTLC1 expression predicts worse outcomes in ccRCC patients.

机构信息

Institutes of Biomedical Science, Fudan University, Shanghai, China.

Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

出版信息

J Cell Biochem. 2020 Feb;121(2):1552-1562. doi: 10.1002/jcb.29390. Epub 2019 Sep 12.

DOI:10.1002/jcb.29390

PMID:31512789

Abstract

OBJECTIVE

Serine palmitoyltransferase, long chain base subunit 1 (SPTLC1) catalyzes the first step in sphingolipid synthesis and has been implicated in the progression of various cancers. However, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. Here, we investigated the expression and prognostic value of SPTLC1 in ccRCC.

METHODS

Three ccRCC patient cohorts were studied. ccRCC and adjacent normal kidney tissue samples were obtained from 183 patients at the Fudan University Shanghai Cancer Center (FUSCC) and subjected to immunohistochemical staining and quantitative reverse-transcription polymerase chain reaction to evaluate SPTLC1 protein and messenger RNA (mRNA) expression. Two validation cohorts consisting of mRNA and clinicopathological data sets from patients with ccRCC were obtained from the Cancer Genome Atlas (TCGA, n = 429) and Oncomine (n = 178) databases. Associations between low and high SPTLC1 mRNA and protein expression and survival were evaluated using the Kaplan-Meier method and log-rank test. Independent prognostic factors were identified using univariate and multivariate Cox regression analysis.

RESULTS

SPTLC1 mRNA or protein were expressed at significantly lower levels in ccRCC tissues compared with normal kidney tissues in all three patient cohorts (P < .001). Low SPTLC1 expression was significantly associated with shorter overall survival in the FUSCC (P = .041) and Oncomine (P < .001) cohorts, and was significantly associated with shorter overall survival (P < .0001) and progression-free survival (P < .001) in the TCGA cohort. Bioinformatics analysis identified 10 genes significantly coregulated with SPTLC1 in ccRCC, most of which contributed to sphingomyelin metabolism (SPTLC2, SPTLC3, SPTSSA, SPTSSB, ORMDL1, ORMDL2, ORMDL3, ZDHHC9, GOLGA7B, and KDSR). Functional enrichment analysis predicted that SPTLC1 and its network play significant roles in inflammatory, hypoxia, and interferon gamma responses, and in allograft rejection pathways.

CONCLUSION

Low SPTLC1 expression is significantly associated with disease progression and poor survival in patients with ccRCC, suggesting that SPTLC1 may function as a tumor suppressor. Thus, SPTLC1 could be a potential new biomarker and/or therapeutic target for ccRCC.

摘要

目的

丝氨酸棕榈酰转移酶长链碱性亚基 1（SPTLC1）催化鞘脂合成的第一步，并且与各种癌症的进展有关。然而，其在透明细胞肾细胞癌（ccRCC）中的作用尚不清楚。在这里，我们研究了 SPTLC1 在 ccRCC 中的表达和预后价值。

方法

研究了三个 ccRCC 患者队列。来自复旦大学上海癌症中心（FUSCC）的 183 名患者获得了 ccRCC 和相邻正常肾组织样本，并进行了免疫组织化学染色和定量逆转录聚合酶链反应，以评估 SPTLC1 蛋白和信使 RNA（mRNA）的表达。来自癌症基因组图谱（TCGA，n=429）和 Oncomine（n=178）数据库的两个包含 ccRCC 患者 mRNA 和临床病理数据集的验证队列也被用于本研究。使用 Kaplan-Meier 方法和对数秩检验评估低和高 SPTLC1 mRNA 和蛋白表达与生存之间的关联。使用单变量和多变量 Cox 回归分析确定独立的预后因素。

结果

在所有三个患者队列中，与正常肾组织相比，ccRCC 组织中 SPTLC1 mRNA 或蛋白表达明显降低（P<0.001）。在 FUSCC（P=0.041）和 Oncomine（P<0.001）队列中，低 SPTLC1 表达与总生存期较短显著相关，在 TCGA 队列中，低 SPTLC1 表达与总生存期（P<0.0001）和无进展生存期（P<0.001）较短显著相关。生物信息学分析鉴定出 10 个在 ccRCC 中与 SPTLC1 显著相关的基因，其中大多数基因与鞘磷脂代谢有关（SPTLC2、SPTLC3、SPTSSA、SPTSSB、ORMDL1、ORMDL2、ORMDL3、ZDHHC9、GOLGA7B 和 KDSR）。功能富集分析预测 SPTLC1 及其网络在炎症、缺氧和干扰素 γ 反应以及同种异体移植排斥途径中发挥重要作用。