Despite intensive efforts, a considerable proportion of colorectal cancer (CRC) patients develop local recurrence and distant metastasis. Stomatin-like protein 2 (SLP-2), a member of the highly conserved stomatin superfamily, is upregulated across cancer types. However, the biological and functional roles of SLP-2 remain elusive in CRC. Here, we report that high SLP-2 expression was found in CRC tissues and was linked to tumor progression and tumor cell differentiation. Additionally, high SLP-2 expression correlated with poor overall survival (OS) in CRC patients (p < 0.001). SLP-2 knockout (SLP-2KO), generated by CRISPR/Cas9, reduced cell growth, migration, and invasion; induced apoptosis in CRC cells; and reduced tumor xenograft growth in vivo. A 181-compound library screening showed that SLP-2KO produced resistance to JAK2 inhibitors (NVP-BSK805 and TG-101348) and a PIM1 inhibitor (SGI-1776), revealing that the JAK2-STAT3-PIM1 oncogenic pathway was potentially controlled by SLP-2 in CRC. In vitro and in vivo, TG-101348 combined with SGI-1776 was synergistic in CRC (combination index [CI] < 1). Overall, our findings suggest that SLP-2 controls the JAK2-STAT3-PIM1 oncogenic pathway, offering a rationale for a novel therapeutic strategy with combined SGI-1776 and TG-101348 in CRC. Additionally, SLP-2 may be a prognostic marker and biomarker for sensitivity to JAK2 and PIM1 inhibitors.

尽管付出了巨大的努力，但仍有相当一部分结直肠癌（CRC）患者出现局部复发和远处转移。Stomatin样蛋白2（SLP-2）是高度保守的Stomatin超家族的成员，在所有癌症类型中均上调。然而，SLP-2的生物学和功能作用在CRC中仍然难以捉摸。在这里，我们报道在CRC组织中发现高SLP-2表达，并与肿瘤进展和肿瘤细胞分化有关。此外，CRC患者的高SLP-2表达与较差的总生存期（OS）相关（p <0.001）。CRISPR / Cas9产生的SLP-2敲除（SLP-2KO）减少了细胞的生长，迁移和侵袭; 诱导CRC细胞凋亡；和减少体内肿瘤异种移植物的生长。181个化合物库筛选显示SLP-2KO产生了对JAK2抑制剂（NVP-BSK805和TG-101348）和PIM1抑制剂（SGI-1776）的抗性，表明JAK2-STAT3-PIM1致癌途径可能受SLP控制。 CRC中为-2。在体外和体内，TG-101348与SGI-1776联合在CRC中具有协同作用（组合指数[CI] <1）。总体而言，我们的发现表明SLP-2控制着JAK2-STAT3-PIM1致癌途径，为CRC中结合SGI-1776和TG-101348的新型治疗策略提供了理论依据。另外，SLP-2可能是对JAK2和PIM1抑制剂敏感的预后标志物和生物标志物。