Wu Ju, Song Jianhui, Ge Yuzhuang, Hou Shuangshuang, Chang Yaoyuan, Chen Xi, Nie Zhequn, Guo Lianyi, Yin Jiajun
Department of General Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, China; Key Laboratory of biomarker high throughput screening and target translation of breast and gastrointestinal tumor, Dalian University, Dalian, China.
Department of General Surgery, Affiliated Xinhua Hospital of Dalian University, Dalian 116021, China.
Cell Signal. 2025 Aug;132:111822. doi: 10.1016/j.cellsig.2025.111822. Epub 2025 Apr 16.
Despite advances in treatment, liver metastasis remains the predominant pattern of distant spread for colorectal cancer (CRC) and a major cause of cancer-related mortality. DNA Primase Subunit 1 (PRIM1) has been reported to play important roles in cancer progression. This study investigated the role of PRIM1 in CRC liver metastasis, focusing on its influence on neutrophil recruitment and the formation of neutrophil extracellular traps (NETs). In this study, PRIM1 was upregulated in liver metastasis tumor tissues. CCK-8 and Transwell assays showed that the proliferation, migration and invasion of CRC cells were promoted with the ablation of PRIM1 and inhibited with PRIM1 overexpression. For in vivo investigation, we observed that PRIM1 ablation reduced the number and size of metastasis nodules of MC38 cells. Importantly, PRIM1 depletion obviously reduced the percentage of Ly6G+ neutrophils in liver. In contrast, overexpression of PRIM1 reversed these effects. Besides, depletion of neutrophils by anti-Ly6G antibody in mice notably attenuated liver metastasis burden induced by the upregulation of PRIM1. Western blot and immunohistochemistry assays revealed that three chemokines CXCL8, C-GSF and CXCL2 were confirmed to be upregulated with PRIM1 overexpression. Furthermore, PRIM1 overexpression reduced the formation of NETs. These results suggested that PRIM1 could facilitate the liver metastasis of CRC via recruiting neutrophils and NET formation. In conclusion, our novel findings highlighted the important role of PRIM1 in neutrophil recruitment and CRC metastasis and provided new perspectives and potential targets for future research and treatment for CRC.
尽管在治疗方面取得了进展，但肝转移仍然是结直肠癌（CRC）远处转移的主要模式，也是癌症相关死亡的主要原因。据报道，DNA引发酶亚基1（PRIM1）在癌症进展中起重要作用。本研究调查了PRIM1在CRC肝转移中的作用，重点关注其对中性粒细胞募集和中性粒细胞胞外陷阱（NETs）形成的影响。在本研究中，PRIM1在肝转移肿瘤组织中上调。CCK-8和Transwell实验表明，PRIM1缺失促进了CRC细胞的增殖、迁移和侵袭，而PRIM1过表达则抑制了这些过程。在体内研究中，我们观察到PRIM1缺失减少了MC38细胞转移结节的数量和大小。重要的是，PRIM1缺失明显降低了肝脏中Ly6G+中性粒细胞的百分比。相反，PRIM1过表达逆转了这些效应。此外，用抗Ly6G抗体清除小鼠体内的中性粒细胞显著减轻了PRIM1上调诱导的肝转移负担。蛋白质免疫印迹和免疫组织化学分析表明，三种趋化因子CXCL8、C-GSF和CXCL2被证实随着PRIM1过表达而上调。此外，PRIM1过表达减少了NETs的形成。这些结果表明，PRIM1可通过募集中性粒细胞和形成NETs促进CRC的肝转移。总之，我们的新发现突出了PRIM1在中性粒细胞募集和CRC转移中的重要作用，并为CRC未来的研究和治疗提供了新的视角和潜在靶点。
