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.

中文翻译：

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通过共表达网络分析鉴定与 2 型糖尿病肝癌发生和进展相关的代谢基因

2 型糖尿病 (T2DM) 是肝细胞癌 (HCC) 的独立危险因素。然而，与 T2DM 中肝癌发生和进展的相关基因和模块仍不清楚。分析来自基因表达综合 (GEO) 的微阵列数据以筛选 T2DM 和 HCC 数据集的差异表达基因 (DEG)。然后，对这些 DEG 进行加权基因共表达网络分析（WGCNA）以分别检测模块和基因。通过 GOSemSim 包和 Metascape 获得并注释了具有 T2DM 和 HCC 临床兴趣的模块中的常见基因。还鉴定了与晚期 HCC 和高糖化血红蛋白 (HbA1c) 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，应用另外两个独立的数据集来确认我们的研究结果。总共分别筛选了 1288 和 1559 DEGs 的 T2DM 和 HCC。京都基因和基因组百科全书 (KEGG) 的富集揭示了两种疾病的几种共享途径，例如癌症和代谢途径。然后用 WGCNA 鉴定了总共 37 个与 T2DM 和 HCC 相关的常见基因。此外，来自与晚期 HCC 和高 HbA1c 相关的模块的 12 个基因被视为枢纽基因。在这些基因中，8个与肿瘤侵袭和转移相关的基因通过UALCAN分析得到验证。此外，ACAT1、SLC2A2、PCK1 和 ABAT 的下调与 HbA1c 升高的 HCC 患者的较差预后显着相关。此外，PCK1和ABAT在二甲双胍和苯乙双胍预处理的HepG2细胞中表达上调。本研究证实了与高血糖和恶性肿瘤相关的几个代谢基因，这不仅可以为T2DM肝癌发生和进展的发病机制提供新的见解，而且为未来T2DM合并HCC的患者提供新的治疗靶点。