Zhou Haiyang, Zhang Yinjie, Shen Yuhang, Chen Shuai, Yang Zhen, Wang Zhihuai, Qin Xihu, Zhu Chunfu
Department of General Surgery, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213000, China.
Nanjing Medical University, Nanjing, 210000, Jiangsu Province, China.
Comb Chem High Throughput Screen. 2025;28(8):1372-1383. doi: 10.2174/0113862073287250240424073108.
OBJECTIVES: This study aimed to explore the key oncogenic factor of metabolicassociated steatohepatitis (MASH) to hepatocellular carcinoma (HCC). METHODS: We utilized four differential GEO datasets (GSE164760, GSE139602, GSE197112, and GSE49541) to identify the key oncogenic factor for MASH-related HCC. The differential genes were analyzed using the GEO2R algorithm online. The GEPIA online website was used to explore the expression of selected four genes (SPP1, GNMT, CLDN11, and THBS2). The genetic alterations in genes were estimated by the cBioPortal website. The Kaplan-Meier Plotter online database was applied to explore the prognostic value of SPP1. Univariate and multivariate Cox analyses were carried out to further confirm the prognostic value of SPP1. The GO and KEGG enrichment analysis exported associated pathways with SPP1 expression. The positively or negatively related immune cells and immune checkpoint expressions were identified through Pearson correlation analysis. The lipogenesis-associated proteins were detected using western blotting and fluorescence. The high-fat diet (HFD) mouse model was constructed, and liver samples were collected. RESULTS: SPP1, GNMT, CLDN11, and THBS2 were determined in the transformation process of MASH to liver fibrosis. SPP1 and GNMT were upregulated in the HCC tumor tissue. SPP1, in particular, had the potential to be the prognostic factor through Cox analysis. Remarkably, SPP1 was highly expressed in HCC compared to normal tissues in three independent datasets (GSE121248, GSE14520, and GSE45267). SPP1 is mainly involved in the amplification and deep deletion mutations. SPP1 was found to be strongly correlated with ANXA2 expression, and ANXA2 was also highly expressed in HCC with significant prognostic performance. Moreover, SPP1 was found to participate in the carcinogenic mechanism and correlate with immune cells and immune checkpoint expression. SPP1 knockdown suppressed the SREBP1 and FASN expressions and increased the SIRT1 expression . Moreover, the HFD model validated the upregulation of SPP1 in the fatty liver . CONCLUSION: SPP1 may be the key oncogenic factor for the transformation of MASH to HCC, and it could be a potential immunotherapeutic target in HCC.
目的：本研究旨在探索代谢相关脂肪性肝炎（MASH）向肝细胞癌（HCC）转变的关键致癌因素。 方法：我们利用四个差异基因表达 omnibus 数据集（GSE164760、GSE139602、GSE197112 和 GSE49541）来确定 MASH 相关 HCC 的关键致癌因素。使用在线 GEO2R 算法分析差异基因。利用 GEPIA 在线网站探究选定的四个基因（SPP1、GNMT、CLDN11 和 THBS2）的表达情况。通过 cBioPortal 网站评估基因的基因改变情况。应用 Kaplan-Meier Plotter 在线数据库探究 SPP1 的预后价值。进行单因素和多因素 Cox 分析以进一步确认 SPP1 的预后价值。进行 GO 和 KEGG 富集分析导出与 SPP1 表达相关的通路。通过 Pearson 相关分析确定正相关或负相关的免疫细胞及免疫检查点表达。使用蛋白质免疫印迹法和荧光法检测脂肪生成相关蛋白。构建高脂饮食（HFD）小鼠模型并采集肝脏样本。 结果：在 MASH 向肝纤维化转变过程中确定了 SPP1、GNMT、CLDN11 和 THBS2。SPP1 和 GNMT 在 HCC 肿瘤组织中上调。特别是，通过 Cox 分析，SPP1 有可能成为预后因素。值得注意的是，在三个独立数据集（GSE121248、GSE14520 和 GSE45267）中，与正常组织相比，SPP1 在 HCC 中高表达。SPP1 主要参与扩增和深度缺失突变。发现 SPP1 与 ANXA2 表达密切相关，并且 ANXA2 在 HCC 中也高表达且具有显著的预后性能。此外，发现 SPP1 参与致癌机制并与免疫细胞及免疫检查点表达相关。敲低 SPP1 可抑制 SREBP1 和 FASN 表达并增加 SIRT1 表达。此外，HFD 模型验证了脂肪肝中 SPP1 的上调。 结论：SPP1 可能是 MASH 向 HCC 转变的关键致癌因素，并且它可能是 HCC 中一个潜在的免疫治疗靶点。
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