| 姜瑜珩,柳 叶,仲小敏,等.富含鸟嘌呤的RNA序列结合因子1通过AKT信号通路抑制结肠癌上皮间质转化及免疫逃逸的机制研究[J].肿瘤学杂志,2025,31(8):678-688. |
| 富含鸟嘌呤的RNA序列结合因子1通过AKT信号通路抑制结肠癌上皮间质转化及免疫逃逸的机制研究 |
| The Mechanism of Guanine-Rich RNA Sequence Binding Factor 1 Inhibits Epithelial-Mesenchymal Transition and Immune Evasion in Colon Cancer Through AKT Signaling Pathway |
| 投稿时间：2024-06-28 |
| DOI：10.11735/j.issn.1671-170X.2025.08.B005 |
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| 中文关键词: 富含鸟嘌呤的RNA序列结合因子1 AKT 结肠肿瘤 上皮细胞间质转化 免疫浸润 |
| 英文关键词:guanine-rich RNA sequence binding factor 1 AKT colon neoplasms epithelial-mesenchymal transition immune infiltration |
| 基金项目:淮安市科技项目（HAP202002） |
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| 摘要点击次数: 181 |
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| 中文摘要: |
| 摘 要： ［目的］ 探讨富含鸟嘌呤的RNA序列结合因子1（guanine -rich RNA sequence binding factor 1，GRSF1）抑制结肠癌上皮间质转化（epithelial-mesenchymal transition，EMT）的作用，并研究其潜在的分子机制。［方法］ 癌症基因组图谱（The Cancer Genome Atlas，TCGA）公共数据库分析GRSF1在结肠癌患者中表达及其与患者病理、预后、CD8+ T细胞浸润之间的关系。结肠癌组织芯片（n=90）组织化学染色验证GRSF1表达，并分析其表达与患者临床病理特征、预后及CD8+ T细胞浸润之间的关系。通过在人结肠癌细胞株中分别过表达和敲减GRSF1的表达后检测细胞的增殖、侵袭及迁移能力，Western blot检测细胞中EMT相关蛋白表达和AKT信号通路的激活。裸鼠皮下建立移植瘤模型，记录肿瘤生长和小鼠生存曲线及转移情况。小鼠结肠癌细胞系MC-38过表达GRSF1后建立小鼠结肠移植瘤模型，记录肿瘤生长和小鼠生存曲线及转移情况；流式细胞术检测小鼠肿瘤组织中CD8+ T细胞数量。［结果］ TCGA数据库分析显示，结肠癌组织中GRSF1表达较正常组织升高（P<0.05），且患者GRSF1表达越高，预后越好（HR=0.39，P<0.001），CD8+ T细胞浸润越多（Rho=0.38，P<0.001），淋巴结转移越少（χ2=3.353，P<0.001），病理分期越早（χ2=56.800，P<0.001）。临床样本验证结果显示，90例结肠癌患者中GRSF1表达较正常结肠组织升高（2.073±0.724 vs 1.127±0.499，t=10.26，P<0.001），高表达患者预后优于低表达患者（χ2=14.000，P=0.000 2）；且GRSF1表达与CD8+ T数量呈正相关（r=0.330 9，P<0.001）。人结肠癌细胞过表达GRSF1后细胞增殖（t=10.184，P=0.005）、侵袭（t=10.252，P<0.001）及迁移（t=11.621，P<0.001）能力均显著降低，而敲减GRSF1表达后则细胞增殖（t=4.874，P=0.008）、侵袭（t=13.530，P<0.001）及迁移能力（t=6.199，P<0.001）均显著增强。Western blot结果显示，GRSF1能够调控EMT相关蛋白E-cadherin、N-cadherin、Vimentin的表达，同时GRSF1的表达能够抑制AKT信号通路的激活。过表达GRSF1组小鼠的肿瘤生长曲线较对照组小鼠显著降低（t=3.469，P=0.008），生存较对照组小鼠显著升高（χ2=15.470，P<0.001），肿瘤组织中p-AKT表达被显著抑制。过表达GRSF1组MC-38移植瘤小鼠肿瘤组织浸润CD8+ T细胞数量较对照组小鼠显著增加（8.620%±1.936% vs 19.680%±4.201%，t=5.346，P=0.001）。［结论］ 结肠癌患者肿瘤组织中GRSF1的表达升高，GRSF1可能通过调控AKT信号通路抑制结肠癌EMT及免疫逃逸从而发挥抑制肿瘤的作用。 |
| 英文摘要: |
| Abstract： ［Objective］ To investigate the inhibitory effect of guanine-rich RNA sequence binding factor 1 (GRSF1) on epithelial-mesenchymal transition (EMT) in colon cancer and its molecular mechanism. ［Methods］ The data of expression of GRSF1 in colorectal cancer patients were obtained from The Cancer Genome Atlas (TCGA) public database， and its relationship with patient pathology， prognosis， and CD8+ T cell infiltration was analyzed. The expression of GRSF1 in colorectal cancer tissues (n=90) was examined by immunohistochemical staining in microarrays. The GRSF1 gene was transfected or knocked down in human colon cancer cell lines， the proliferation， invasion， and migration abilities of cells were detected. The expression of EMT-related proteins and the activation of the AKT signaling pathway were detected by Western blot. A subcutaneous xenograft tumor model in nude mice was established to record tumor growth， mouse survival curves and metastasis. An overexpressing GRSF1 mouse colorectal cancer cell line MC-38 was developed toestablish a xenograft mouse colorectal cancer model， the tumor growth， metastasis， and animal survival were observed. The number of CD8+ T cells in mouse tumor tissues was detected by flow cytometry. ［Results］ TCGA database showed that the expression of GRSF1 was higher in colon cancer tissues than that in normal tissues (P<0.05)； colorectal cancer patients with higher GRSF1 expression had more CD8+ T cell infiltration (Rho=0.38， P<0.001)， less lymph node metastasis (?字2=3.353， P<0.001)， earlier pathological stage (?字2=56.800， P<0.001)， and better prognosis (HR=0.39， P<0.001). The expression of GRSF1 was higher in 90 samples of colon cancer tissues compared to normal colon tissues (2.073 ± 0.724 vs 1.127 ± 0.499， t=10.26， P<0.001)， the prognosis of patients with high GRSF1 expression was better than that with low expression (?字2=14.000， P=0.000 2)， and the expression of GRSF1 was positively correlated with the number of CD8+ T cells (r=0.330 9， P<0.001). Overexpression of GRSF1 in human colon cancer cells significantly inhibited cell proliferation (t=10.184， P=0.005)， invasion (t=10.252， P<0.001) and migration abilities (t=11.621， P<0.001)； while knocking down GRSF1 expression significantly enhanced cell proliferation (t=4.874， P=0.008)， invasion (t=13.530， P<0.001) and migration ability (t=6.199， P<0.001). Western blot analysis showed that GRSF1 can regulate the expression of EMT-related proteins E-cadherin， N-cadherin， and Vimentin， and the expression of GRSF1 inhibited the activation of the AKT signaling pathway. The tumor growth curve of mice overexpressing GRSF1 was significantly reduced (t=3.469， P=0.008) and the survival was significantly increased (?字2=15.470， P<0.001) compared to the control group . The expression of p-AKT in tumor tissue was significantly lower than that in the control group. In addition， the number of CD8+ T cells in the tumor tissues of mice transplanted with overexpressing GRSF1 MC-38 cells was significantly increased compared to the control group (8.620% ± 1.936% vs 19.680% ± 4.201%， t=5.346， P=0.001). ［Conclusion］ The expression of GRSF1 in colon tumor tissues is upregulated. GRSF1 may inhibit colorectal cancer by regulating the AKT signaling pathway to suppress EMT and immune evasion. |
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