Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
J Exp Clin Cancer Res. 2023 Jan 24;42(1):33. doi: 10.1186/s13046-023-02605-4.
With increasing incidence and mortality, colorectal cancer (CRC) seriously endangers human health. LARP6, a member of La-related protein (LARP) family, is a RNA binding protein and probably associates with CRC progression, but its specific roles and mechanisms in CRC still remain unknown.
Quantitative real-time PCR (qPCR), western blot, and immunohistochemistry were employed to examine LARP6 expression in CRC tissues. Using the stable LARP6 overexpression or interference CRC cell lines, the effect of LARP6 on CRC progression were evaluated. High-throughput RNA immunoprecipitation sequencing (RIP-seq) and a series of relevant experiments were conducted to explain how LARP6 functions. SPSS software was used for statistical analysis.
In this study, we found that LARP6 expression is downregulated in CRC and correlates with patients' overall survival and relapse-free survival. Furthermore, altered LARP6 expression influences CRC cells invasion and metastasis. Mechanically, we discovered that LARP6 bind ZNF267 mRNA and regulated its stability and translation. LARP6 inhibited expression of SGMS2, a downstream target of ZNF267, resulting in ceramide and sphingomyelin imbalance in CRC cells. Interestingly, LARP6 also enhances autophagy activity of CRC cells, and the effect was at least partially determined by the inhibition of SGMS2-mediated sphingomyelin synthesis.
Our study showed how LARP6/ZNF267/SGMS2 axis influence CRC progression, which contributes to further understanding of the molecular mechanisms underlying CRC development.
随着发病率和死亡率的上升，结直肠癌（CRC）严重威胁着人类健康。LARP6 是 La 相关蛋白（LARP）家族的成员，是一种 RNA 结合蛋白，可能与 CRC 的进展有关，但它在 CRC 中的具体作用和机制尚不清楚。
采用定量实时 PCR（qPCR）、western blot 和免疫组织化学方法检测 CRC 组织中 LARP6 的表达。利用稳定过表达或干扰 LARP6 的 CRC 细胞系，评估 LARP6 对 CRC 进展的影响。通过高通量 RNA 免疫沉淀测序（RIP-seq）和一系列相关实验，解释 LARP6 的作用机制。采用 SPSS 软件进行统计学分析。
在本研究中，我们发现 LARP6 在 CRC 中的表达下调，并与患者的总生存和无复发生存相关。此外，改变 LARP6 的表达影响 CRC 细胞的侵袭和转移。从机制上讲，我们发现 LARP6 与 ZNF267 mRNA 结合，并调节其稳定性和翻译。LARP6 抑制 ZNF267 的下游靶标 SGMS2 的表达，导致 CRC 细胞中神经酰胺和鞘磷脂失衡。有趣的是，LARP6 还增强了 CRC 细胞的自噬活性，这种作用至少部分是由 SGMS2 介导的鞘磷脂合成抑制所决定的。
本研究表明 LARP6/ZNF267/SGMS2 轴如何影响 CRC 的进展，有助于进一步了解 CRC 发展的分子机制。
