IRCM, Univ Montpellier, Inserm, ICM, Montpellier, France.
Institut régional du Cancer de Montpellier (ICM), Montpellier, France.
PLoS One. 2022 Sep 14;17(9):e0274390. doi: 10.1371/journal.pone.0274390. eCollection 2022.
Spleen tyrosine kinase (Syk) expression have been both positively and negatively associated with tumorigenesis. Our goal was to evaluate the contribution of Syk and its two splice variants, full length Syk (L) and short isoform Syk (S), in the tumor biology of colorectal cancer cells (CRC). The analysis of Syk expression in primary human colorectal tumors, as well as the analysis of TCGA database, revealed a high Syk mRNA expression score in colorectal cancer tumors, suggesting a tumor promotor role of Syk in CRC. Our analysis showed that Syk (L) isoform is highly expressed in the majority of the tumor tissues and that it remains expressed in tumors in which global Syk expression is downregulated, suggesting the dependence of tumors to Syk (L) isoform. We also identified a small cluster of tumor tissues, which express a high proportion of Syk (S) isoform. This specific cluster is associated with overexpressed genes related to translation and mitochondria, and down regulated genes implicated in the progression of mitosis. For our functional studies, we used short hairpin RNA tools to target the expression of Syk in CRC cells bearing the activating K-Ras (G13D) mutation. Our results showed that while global Syk knock down increases cell proliferation and cell motility, Syk (L) expression silencing affects the viability and induces the apoptosis of the cells, confirming the dependence of cells on Syk (L) isoform for their survival. Finally, we report the promising potential of compound C-13, an original non-enzymatic inhibitor of Syk isolated in our group. In vitro studies showed that C-13 exerts cytotoxic effects on Syk-positive CRC cells by inhibiting their proliferation and their motility, and by inducing their apoptosis, while Syk-negative cell lines viability was not affected. Moreover, the oral and intraperitoneal administration of C-13 reduced the tumor growth of CRC DLD-1 cells xenografts in Nude mice in vivo.
脾酪氨酸激酶（Syk）的表达与肿瘤发生呈正相关和负相关。我们的目标是评估 Syk 及其两个剪接变体全长 Syk（L）和短同工型 Syk（S）在结直肠癌细胞（CRC）肿瘤生物学中的贡献。对原发性人结直肠肿瘤中 Syk 的表达分析以及 TCGA 数据库的分析表明，结直肠癌肿瘤中 Syk mRNA 表达评分较高，提示 Syk 在 CRC 中具有肿瘤促进作用。我们的分析表明，Syk（L）同工型在大多数肿瘤组织中高度表达，并且在全局 Syk 表达下调的肿瘤中仍然表达，表明肿瘤依赖于 Syk（L）同工型。我们还鉴定了一小部分肿瘤组织，其表达高比例的 Syk（S）同工型。这个特定的簇与翻译和线粒体相关的过表达基因以及与有丝分裂进展相关的下调基因有关。对于我们的功能研究，我们使用短发夹 RNA 工具来靶向 CRC 细胞中表达的 Syk，这些细胞携带激活的 K-Ras（G13D）突变。我们的结果表明，虽然全局 Syk 敲低增加了细胞增殖和细胞迁移，但 Syk（L）表达沉默会影响细胞活力并诱导细胞凋亡，这证实了细胞对 Syk（L）同工型的依赖性为了它们的生存。最后，我们报告了我们小组分离的原始非酶抑制剂 Syk 的化合物 C-13 的有希望的潜力。体外研究表明，C-13 通过抑制 Syk 阳性 CRC 细胞的增殖和迁移，并诱导其凋亡，对其发挥细胞毒性作用，而 Syk 阴性细胞系的活力不受影响。此外，C-13 的口服和腹腔内给药在体内减少了 Nude 小鼠中 CRC DLD-1 细胞异种移植物的肿瘤生长。
