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

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.

LZTFL1是一种位于染色体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早期缺失。然而，其在肾肿瘤发生中的作用仍然未知。在此，我们基于对患者肿瘤数据的大量生物信息学分析，假设LZTFL1在透明细胞肾细胞癌（ccRCC）中具有肿瘤抑制功能及其作用机制，并通过在肾肿瘤细胞系和患者来源的异种移植（PDX）模型系统中进行功能获得和功能缺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，并诱导细胞周期停滞在G1期，从而抑制肾肿瘤细胞增殖。在临床上，我们发现LZTFL1在ccRCC中经常缺失。LZTFL1的下调与ccRCC预后不良相关，可作为预后标志物。此外，我们通过慢病毒递送在PDX中过表达LZTFL1抑制了PDX的生长，这表明LZTFL1的重新表达可能是一种针对ccRCC的治疗策略。