School of Second Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
Department of Endocrinology, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.
Hereditas. 2021 Apr 17;158(1):14. doi: 10.1186/s41065-021-00177-x.
Type 2 Diabetes Mellitus (T2DM) is an independent risk factor of hepatocellular carcinoma (HCC). However, the related genes and modules to hepatocarcinogenesis and progression in T2DM remain unclear.
The microarray data from Gene Expression Omnibus (GEO) were analyzed to screen differentially expressed genes (DEGs) of T2DM and HCC dataset. Then, weighted gene co-expression network analysis (WGCNA) was performed on these DEGs to detect the modules and genes, respectively. Common genes in modules with clinical interests of T2DM and HCC were obtained and annotated via GOSemSim package and Metascape. Genes related to late-stage HCC and high glycated haemoglobin (HbA1c) were also identified. These genes were validated by UALCAN analysis and univariate cox regression based on The Cancer Genome Atlas (TCGA). Finally, another two independent datasets were applied to confirm the results of our study.
A total of 1288 and 1559 DEGs of T2DM and HCC were screened, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment revealed several shared pathways in two diseases, such as pathways in cancer and metabolism. A total of 37 common genes correlated with T2DM and HCC were then identified with WGCNA. Furthermore, 12 genes from modules associated with late-stage HCC and high HbA1c were regarded as hub genes. Among these genes, 8 genes associated with tumor invasion and metastasis were validated by UALCAN analysis. Moreover, downregulations of ACAT1, SLC2A2, PCK1 and ABAT were significantly associated with poorer prognosis in HCC patients with elevated HbA1c. Additionally, the expressions of PCK1 and ABAT were raised in HepG2 cells pre-treated with metformin and phenformin.
The present study confirmed several metabolic genes related to hyperglycemia and malignant tumor, which may provide not only new insights into the pathogenesis of hepatocarcinogenesis and progression in T2DM, but also novel therapeutic targets for T2DM patients with HCC in the future.
2 型糖尿病（T2DM）是肝细胞癌（HCC）的独立危险因素。然而，T2DM 相关的肝癌发生和进展的相关基因和模块仍不清楚。
从基因表达综合数据库（GEO）中分析微阵列数据，筛选 T2DM 和 HCC 数据集的差异表达基因（DEGs）。然后，对这些 DEGs 进行加权基因共表达网络分析（WGCNA），分别检测模块和基因。通过 GOSemSim 包和 Metascape 获得与 T2DM 和 HCC 临床兴趣相关的模块中的常见基因，并进行注释。鉴定与晚期 HCC 和糖化血红蛋白（HbA1c）升高相关的基因。这些基因通过 UALCAN 分析和基于癌症基因组图谱（TCGA）的单变量 cox 回归进行验证。最后，应用另外两个独立数据集来验证我们的研究结果。
分别筛选出 T2DM 和 HCC 的 1288 个和 1559 个 DEGs。京都基因与基因组百科全书（KEGG）富集显示两种疾病存在一些共同途径，如癌症和代谢途径。然后通过 WGCNA 鉴定出与 T2DM 和 HCC 相关的 37 个共有基因。此外，还确定了与晚期 HCC 和高 HbA1c 相关的模块的 12 个基因作为枢纽基因。在这些基因中，通过 UALCAN 分析验证了 8 个与肿瘤侵袭和转移相关的基因。此外，在 HbA1c 升高的 HCC 患者中，ACAT1、SLC2A2、PCK1 和 ABAT 的下调与预后较差显著相关。此外，用二甲双胍和苯乙双胍预处理 HepG2 细胞后，PCK1 和 ABAT 的表达升高。
本研究证实了几种与高血糖和恶性肿瘤相关的代谢基因，这不仅为 T2DM 中肝癌发生和进展的发病机制提供了新的见解，而且为未来 T2DM 合并 HCC 患者提供了新的治疗靶点。
