南方医科大学学报

南方医科大学学报 ›› 2023, Vol. 43 ›› Issue (5): 733-740.doi: 10.12122/j.issn.1673-4254.2023.05.08

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S100A10可促进肺腺癌细胞的增殖和侵袭：基于激活Akt-mTOR信号通路

王会杰，孙珍贵，赵文英，耿 彪   

  1. 皖南医学院第一附属医院肿瘤内科，呼吸与危重症医学科，安徽 芜湖 241000
  • 出版日期:2023-05-20 发布日期:2023-06-12

S100A10 promotes proliferation and invasion of lung adenocarcinoma cells by activating the Akt-mTOR signaling pathway

WANG Huijie, SUN Zhengui, ZHAO Wenying, GENG Biao   

  1. Department of Oncology, Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Wannan Medical College, Wuhu 24100, China
  • Online:2023-05-20 Published:2023-06-12

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摘要： 目的 探讨S100钙结合蛋白A10（S100A10）在肺腺癌（LUAD）的表达水平及对患者预后的影响，以及S100A10对肺癌细胞增殖和转移的调控作用和作用机制。方法 采用免疫组化技术（IHC）检测S100A10在LUAD及癌旁组织中的表达水平。Western blot、CCK-8和EdU、Transwell实验分别测定S100A10蛋白的表达水平、细胞增殖和侵袭能力。通过基因集富集分析（GSEA）S100A10在肺腺癌中可能的调控通路。分别将A549-shS100A10和A549-shCtrl细胞，H1299-S100A10和H1299-GFP的细胞注射到裸鼠皮下，观察S100A10的表达水平对肿瘤增殖的影响。结果 与癌旁组织相比，肿瘤组织中S100A10的表达水平显著上调，并且S100A10表达水平升高与淋巴结转移、肿瘤分期、远处器官转移有关（P<0.05），而与分化程度、年龄、性别无关（P>0.05）。生存分析显示，肿瘤组织中S100A10表达水平越高，患者的预后越差（P<0.001）。体外实验显示，上调S100A10的表达，促进了肿瘤细胞的增殖和侵袭能力（P<0.001）。GSEA分析显示S100A10高表达显著富集至糖代谢、糖酵解、mTOR信号通路等基因集。葡萄糖消耗及乳酸生成实验表明，上调S100A10促进葡萄糖消耗和乳酸的生成，相反，下调S100A10抑制葡萄糖消耗和乳酸的生成。Western blot实验显示，S100A10能够促进Akt-mTOR信号通路激活。裸鼠移植瘤实验结果表明，上调S100A10的表达促进肿瘤增殖，而下调S100A10的表达则抑制肿瘤增殖（P<0.001）。结论 S100A10通过激活Akt-mTOR-糖酵解信号通路，进而促进肿瘤细胞的增殖和侵袭能力。

关键词: S100A10；肺腺癌；临床病理参数；Akt-mTOR；糖酵解；肿瘤细胞增殖和侵袭

Abstract: Objective To investigate the effects of expression levels of S100 calcium-binding protein A10 (S100A10) in lung adenocarcinoma (LUAD) on patient prognosis and the regulatory role of S100A10 in lung cancer cell proliferation and metastasis. Methods Immunohistochemistry was used to detect the expression levels of S100A10 in LUAD and adjacent tissues, and the relationship between S100A10 expression and clinicopathological parameters and prognosis of the patients was statistically analyzed. The lung adenocarcinoma expression dataset in TCGA database was analyzed using gene enrichment analysis (GSEA) to predict the possible regulatory pathways of S100A10 in the development of lung adenocarcinoma. Lactate production and glucose consumption of lung cancer cells with S100A10 knockdown or overexpression were analyzed to assess the level of glycolysis. Western blotting, CCK-8 assay, EdU-594 assay, and Transwell assays were performed to determine the expression level of S100A10 protein, proliferation and invasion ability of lung cancer cells. A549 cells with S100A10 knockdown and H1299 cells with S100A10 overexpression were injected subcutaneously in nude mice, and tumor growth was observed. Results The expression level of S100A10 was significantly upregulated in LUAD tissues as compared with the adjacent tissues, and an elevated S100A10 expression level was associated with lymph node metastasis, advanced tumor stage and distant organ metastasis (P<0.05), but not with tumor differentiation or the patients' age or gender (P>0.05). Survival analysis showed that elevated S100A10 expressions in the tumor tissue was associated with a poor outcome of the patients (P<0.001). In the lung cancer cells, S100A10 overexpression significantly promoted cell proliferation and invasion in vitro (P<0.001). GSEA showed that the gene sets of glucose metabolism, glycolysis and mTOR signaling pathway were significantly enriched in high expressions of S100A10. In the tumor-bearing nude mice, S100A10 overexpression significantly promoted tumor growth, while S100A10 knockdown obviously suppressed tumor cell proliferation (P<0.001). Conclusion S100A10 overexpression promotes glycolysis by activating the Akt-mTOR signaling pathway to promote proliferation and invasion of lung adenocarcinoma cells.

Key words: S100A10; lung adenocarcinoma; clinicopathological parameters; Akt-mTOR; glycolysis; tumor cell invasion and proliferation