Dong Xin, Zhang Xianbin, Liu Peng, Tian Yu, Li Li, Gong Peng
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of General Surgery & Institute of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Shenzhen University General Hospital & Shenzhen University Clinical Medical Academy, Shenzhen, China.
Front Oncol. 2022 May 2;12:896412. doi: 10.3389/fonc.2022.896412. eCollection 2022.
Lipolysis-stimulated lipoprotein receptor (LSR) is a type I single-pass transmembrane protein which is mainly expressed in the liver. In this study, we investigated if and how LSR is involved in the carcinogenesis of hepatocellular carcinoma (HCC).
To evaluate if LSR was abnormally expressed in human HCC tissues, and how its expression was associated with the survival probability of patients, we obtained data from Gene Expression Omnibus and The Cancer Genome Atlas Program. To investigate if and how LSR regulates tumor growth, we knocked down and overexpressed LSR in human HCC cell lines. In addition, to evaluate the interaction between LSR and yes-associated protein1 (YAP1), we mutated LSR at PPPY motif, a binding site of YAP1.
Totally, 454 patients were enrolled in the present study, and high expression of LSR significantly decreased the probability of death. Knockdown of LSR significantly increased the expansion of HCC cells and significantly promoted tumor growth. In addition, downregulation of LSR increased the nuclear accumulation and transcriptional function of YAP1. Conversely, overexpression of LSR impairs this function of YAP1 and phosphorylates YAP1 at serine 127. Of note, mutation of LSR at the PPPY motif could block the interaction between LSR and YAP1, and restore the transcriptional ability of YAP1.
The present study suggests that LSR binds to YAP1 the PPPY motif. Thus, LSR increases the phosphorylation of YAP1 and impairs the growth of HCC. This highlights that targeting LSR might be a promising therapeutic strategy for HCC.
脂肪分解刺激脂蛋白受体（LSR）是一种I型单次跨膜蛋白，主要在肝脏中表达。在本研究中，我们调查了LSR是否以及如何参与肝细胞癌（HCC）的致癌过程。
为了评估LSR在人HCC组织中是否异常表达，以及其表达如何与患者的生存概率相关，我们从基因表达综合数据库和癌症基因组图谱计划中获取数据。为了研究LSR是否以及如何调节肿瘤生长，我们在人HCC细胞系中敲低和过表达LSR。此外，为了评估LSR与Yes相关蛋白1（YAP1）之间的相互作用，我们在YAP1的结合位点PPPY基序处对LSR进行了突变。
本研究共纳入454例患者，LSR的高表达显著降低了死亡概率。敲低LSR显著增加了HCC细胞的增殖并显著促进了肿瘤生长。此外，LSR的下调增加了YAP1的核积累和转录功能。相反，LSR的过表达损害了YAP1的这种功能，并使YAP1在丝氨酸127处磷酸化。值得注意的是，LSR在PPPY基序处的突变可阻断LSR与YAP1之间的相互作用，并恢复YAP1 的转录能力。
本研究表明，LSR在PPPY基序处与YAP1结合。因此，LSR增加了YAP1的磷酸化并损害了HCC的生长。这突出表明靶向LSR可能是一种有前景的HCC治疗策略。
