LARP6 suppresses colorectal cancer progression through ZNF267/SGMS2-mediated imbalance of sphingomyelin synthesis.
LARP6 suppresses colorectal cancer progression through ZNF267/SGMS2-mediated imbalance of sphingomyelin synthesis.
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DOI：
10.1186/s13046-023-02605-4
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发表时间：
2023-01-24
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影响因子：
--
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中科院分区：
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结直肠癌（colorectal cancer，CRC）的发病率和死亡率不断上升，严重危害人类健康。LARP 6是La相关蛋白（LARP）家族的成员，是一种RNA结合蛋白，可能与结直肠癌的进展有关，但其在结直肠癌中的具体作用和机制尚不清楚。采用实时定量PCR（qPCR）、蛋白质印迹和免疫组织化学检测结直肠癌组织中LARP 6的表达。使用稳定的LARP 6过表达或干扰CRC细胞系，评价LARP 6对CRC进展的作用。高通量RNA免疫沉淀测序（RIP-seq）和一系列相关实验进行了解释LARP 6的功能。采用SPSS软件进行统计学分析。在这项研究中，我们发现LARP 6表达在CRC中下调，并与患者的总生存期和无复发生存期相关。此外，LARP 6表达的改变影响CRC细胞的侵袭和转移。在机制上，我们发现LARP 6结合ZNF 267 mRNA并调节其稳定性和翻译。LARP 6抑制ZNF 267下游靶点SGMS 2的表达，导致CRC细胞中神经酰胺和鞘磷脂失衡。有趣的是，LARP 6还增强CRC细胞的自噬活性，并且该作用至少部分地通过抑制SGMS 2介导的鞘磷脂合成来确定。我们的研究显示LARP 6/ZNF 267/SGMS 2轴如何影响CRC进展，这有助于进一步了解CRC发生的分子机制。在线版本包含补充材料，可通过10.1186/s13046-023-02605-4获得。
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. The online version contains supplementary material available at 10.1186/s13046-023-02605-4.
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影响因子：
11.8
作者：
Dermit M;Dodel M;Lee FCY;Azman MS;Schwenzer H;Jones JL;Blagden SP;Ule J;Mardakheh FK
通讯作者：
Mardakheh FK
影响因子：
14.9
作者：
Martino L;Pennell S;Kelly G;Busi B;Brown P;Atkinson RA;Salisbury NJ;Ooi ZH;See KW;Smerdon SJ;Alfano C;Bui TT;Conte MR
通讯作者：
Conte MR
DOI：
10.1038/nrm.2017.107
发表时间：
2018-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Hannun YA;Obeid LM
通讯作者：
Obeid LM
影响因子：
3.4
作者：
Adada, Mohamad;Luberto, Chiara;Canals, Daniel
通讯作者：
Canals, Daniel
影响因子：
9.2
作者：
Liu, Wenbo;Wang, Kang;Xiao, Ran
通讯作者：
Xiao, Ran