ABSTRACT
Diabetes mellitus (DM) is recognized as a risk factor for hepatocellular carcinoma (HCC). High glucose levels have been implicated in inducing epithelial-mesenchymal transition (EMT), contributing to the progression of various cancers. However, the molecular crosstalk remains unclear. This study aimed to elucidate the molecular mechanisms linking DM to HCC. Initially, the expression of NCAPD2 in HCC cells and patients was measured. A series of functional in vitro assays to examine the effects of NCAPD2 on the malignant behaviors and EMT of HCC under high glucose conditions were then conducted. Furthermore, the impacts of NCAPD2 knockdown on HCC proliferation and the ß-catenin pathway were investigated in vivo. In addition, bioinformatics methods were performed to analyze the mechanisms and pathways involving NCAPD2, as well as its association with immune infiltration and drug sensitivity. The findings indicated that NCAPD2 was overexpressed in HCC, particularly in patients with DM, and its aberrant upregulation was linked to poor prognosis. In vitro experiments demonstrated that high glucose upregulated NCAPD2 expression, enhancing proliferation, invasion, and EMT, while knockdown of NCAPD2 reversed these effects. In vivo studies suggested that NCAPD2 knockdown might suppress HCC growth via the ß-catenin pathway. Functional enrichment analysis revealed that NCAPD2 was involved in cell cycle regulation and primarily interacted with NCAPG, SMC4, and NCAPH. Additionally, NCAPD2 was positively correlated with EMT and the Wnt/ß-catenin pathway, whereas knockdown of NCAPD2 inhibited the Wnt/ß-catenin pathway. Moreover, NCAPD2 expression was significantly associated with immune cell infiltration, immune checkpoints, and drugs sensitivity. In conclusion, our study identified NCAPD2 as a novel oncogene in HCC and as a potential therapeutic target for HCC patients with DM.
ABSTRACT
With changes in modern lifestyles, type 2 diabetes mellitus (T2DM) has become a global epidemic metabolic disease, and hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. T2DM is a complex metabolic disorder and has been considered an independent risk factor for HCC. Growing evidence supports that T2DM-related risk factors facilitate hepatocarcinogenesis via abundant mechanisms. With the wide implementation of microbiomics, transcriptomics, and immunotherapy, the understanding of the complex mechanisms of intestinal flora and immune cell subsets have advanced tremendously in T2DM-related HCC, uncovering new findings in T2DM-related HCC patients. In addition, reports have indicated the different effects of anti-DM drugs on the progression of HCC. In this review, we summarize the effects of major T2DM-related risk factors (including hyperglycemia, hyperinsulinemia, insulin, chronic inflammation, obesity, nonalcoholic fatty liver disease, gut microbiota and immunomodulation), and anti-DM drugs on the carcinogensis and progression of HCC, as well as their potential molecular mechanisms. In addition, other factors (miRNAs, genes, and lifestyle) related to T2DM-related HCC are discussed. We propose a refined concept by which T2DM-related risk factors and anti-DM drugs contribute to HCC and discuss research directions prompted by such evidence worth pursuing in the coming years. Finally, we put forward novel therapeutic approaches to improve the prognosis of T2DM-related HCC, including exploiting novel diagnostic biomarkers, combination therapy with immunocheckpoint inhibitors, and enhancement of the standardized management of T2DM patients.
