Chen Libin, Shu Peng, Zhang Xuemei, Ye Shuyu, Tian Li, Shen Shourong, Ma Jian, Ai Feiyan, Li Xiayu
Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Central South University, Changsha, Hunan, China.
J Cancer. 2024 Apr 29;15(11):3452-3465. doi: 10.7150/jca.92588. eCollection 2024.
S100A8/S100A9 belong to the S100 calcium-binding protein family and play an essential role in the progression of chronic inflammation in diseases. It also regulates various biological processes such as tumor cell survival, apoptosis, and invasive metastasis. The extracellular form of S100A8/S100A9 functions by modulating cellular oxidative metabolism and facilitating inflammation-to-cancer progression. This modulation occurs through specific binding to receptors like RAGE and TLR4 and activation of signaling pathways including STAT3 and NF-κB. In tumor cells, S100A8 and S100A9 induce phenotypic changes by influencing calcium ion concentrations and other pathways. However, the precise function of high S100A8/S100A9 expression in colorectal cancer cells remains unclear. To explore the role of S100A8/S100A9 in colorectal cancer, we used immunohistochemistry and data from GEO and TCGA databases to analyze its expression in colorectal cancer cells, normal intestinal mucosa, and adjacent tissues. Functional models of high S100A8/S100A9 expression in colorectal cancer cells were established through transfection with overexpression plasmids. Protein microarrays, enzyme-linked immunosorbent assays (ELISAs), and real-time PCR were employed to assess the expression and secretion of 40 cytokines. MTT and Transwell invasion assays were conducted to evaluate changes in cell proliferation, invasion, and chemotaxis. Finally, tail vein and subcutaneous tumorigenesis assays assessed cell proliferation and migration in vivo. We observed significantly higher expression of S100A8/S100A9 in colorectal cancer epithelial cells compared to normal intestinal mucosa and adjacent tissues. Overexpression of S100A8/S100A9 in mouse colon cancer cells CT26.WT led to differential increases in the secretion levels of various cytokines (CXCL5, CXCL11, GM-CSF, G-CSF, IL1a, IL1b, sTNF RI, and CCL3). Additionally, this overexpression activated signaling pathways such as STAT3, NF-κB, and ERK-MAPK. The synthesis and secretion of inflammatory factors could be inhibited by using NF-κB and ERK-MAPK pathway inhibitors. Moreover, S100A8 promotes the proliferation and invasion of colon cancer cells. Notably, the CXCR2 inhibitor (SB265610) effectively reversed the phenotypic changes induced by the CXCL5/CXCR2 biological axis. Our findings indicate that increased expression of S100A8 and S100A9 in colon cancer epithelial cells enhances the secretion of inflammatory factors by activating NF-κB, ERK-MAPK, and other signaling pathways. S100A8 facilitates colon cancer cell proliferation, invasion, and metastasis through the CXCL5/CXCR2 biological axis.
S100A8/S100A9属于S100钙结合蛋白家族，在疾病慢性炎症进展中起重要作用。它还调节各种生物学过程，如肿瘤细胞存活、凋亡和侵袭转移。S100A8/S100A9的细胞外形式通过调节细胞氧化代谢和促进炎症向癌症进展发挥作用。这种调节通过与RAGE和TLR4等受体的特异性结合以及包括STAT3和NF-κB在内的信号通路的激活来实现。在肿瘤细胞中，S100A8和S100A9通过影响钙离子浓度和其他途径诱导表型变化。然而，S100A8/S100A9在结肠癌细胞中高表达的确切功能仍不清楚。为了探究S100A8/S100A9在结直肠癌中的作用，我们使用免疫组织化学以及来自GEO和TCGA数据库的数据来分析其在结肠癌细胞、正常肠黏膜和相邻组织中的表达。通过用过表达质粒转染建立结肠癌细胞中S100A8/S100A9高表达的功能模型。采用蛋白质微阵列、酶联免疫吸附测定（ELISA）和实时PCR来评估40种细胞因子的表达和分泌。进行MTT和Transwell侵袭试验以评估细胞增殖、侵袭和趋化性的变化。最后，通过尾静脉和皮下成瘤试验评估体内细胞增殖和迁移情况。我们观察到与正常肠黏膜和相邻组织相比，结肠癌细胞中S100A8/S100A9的表达显著更高。小鼠结肠癌细胞CT26.WT中S100A8/S100A9的过表达导致各种细胞因子（CXCL5、CXCL11、GM-CSF、G-CSF、IL1a、IL1b、sTNF RI和CCL3）的分泌水平有差异地增加。此外，这种过表达激活了STAT3、NF-κB和ERK-MAPK等信号通路。使用NF-κB和ERK-MAPK通路抑制剂可抑制炎症因子的合成和分泌。此外，S100A8促进结肠癌细胞的增殖和侵袭。值得注意的是，CXCR2抑制剂（SB265610）有效地逆转了由CXCL5/CXCR2生物学轴诱导的表型变化。我们的研究结果表明，结肠癌细胞中S100A8和S100A9表达的增加通过激活NF-κB、ERK-MAPK和其他信号通路增强了炎症因子的分泌。S100A8通过CXCL5/CXCR2生物学轴促进结肠癌细胞的增殖、侵袭和转移。
