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LZTFL1 通过 ZNRF1 介导的泛素蛋白酶体途径破坏 AKT 从而抑制肾肿瘤细胞生长。

LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway.

机构信息

Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.

Departments of Internal Medicine and Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA.

出版信息

Oncogene. 2023 May;42(19):1543-1557. doi: 10.1038/s41388-023-02666-x. Epub 2023 Mar 25.

DOI:10.1038/s41388-023-02666-x
PMID:36966254
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10039360/
Abstract

LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients' tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.

摘要

LZTFL1 是位于染色体 3p21.3 区域的肿瘤抑制因子，在包括肾癌在内的多种癌症类型中经常发生早期缺失。然而，其在肾癌发生中的作用尚不清楚。在这里，我们基于对患者肿瘤数据的广泛生物信息学分析，假设 LZTFL1 在透明细胞肾细胞癌（ccRCC）中具有肿瘤抑制功能，并基于在肾肿瘤细胞系和患者衍生异种移植（PDX）模型系统中的增益和功能丧失研究对其进行了验证。我们的研究表明，LZTFL1 通过 ZNRF1 介导的泛素蛋白酶体途径使 AKT 不稳定，从而抑制肾肿瘤细胞的增殖，并诱导细胞周期停滞在 G1 期。临床上，我们发现 LZTFL1 在 ccRCC 中经常缺失。LZTFL1 的下调与 ccRCC 的不良预后相关，可能可用作预后标志物。此外，我们通过慢病毒转导显示在 PDX 中过表达 LZTFL1 可抑制 PDX 的生长，这表明 LZTFL1 的重新表达可能是治疗 ccRCC 的一种策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10d3/10162943/bcd6cb606283/41388_2023_2666_Fig7_HTML.jpg
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