The cell division cycle associated 8 (CDCA8) is a crucial component of the chromosome passenger complex (CPC). It has been implicated in the regulation of cell dynamic localization during mitosis. However, its role in hepatocellular carcinoma (HCC) is not clearly known. In this study, data of 374 patients with HCC were retrieved from the Cancer Genome Atlas (TCGA) database. Pan analysis of Gene Expression Profiling Interactive Analysis (GEPIA) database was performed to profile the mRNA expression of CDCA8 in HCC. Then, the Kaplan‐Meier plotter database was analysed to determine the prognostic value of CDCA8 in HCC. In addition, samples of tumour and adjacent normal tissues were collected from 88 HCC patients to perform immunohistochemistry (IHC), reverse transcription‐quantitative polymerase chain reaction (qRT‐PCR) and Western blotting. The results obtained from bioinformatic analyses were validated through CCK‐8 assay, EdU assay, colony formation assay, cell cycle assays and Western blotting experiments. Analysis of the Kaplan‐Meier plotter database showed that high expression of CDCA8 may lead to poor overall survival (OS, p = 4.06e‐05) in patients with HCC. For the 88 patients with HCC, we found that stages and grades appeared to be strongly linked with CDCA8 expression. Furthermore, the high expression of CDCA8 was found to be correlated with poor OS (p = 0.0054) and progression‐free survival (PFS, p = 0.0009). In vitro experiments revealed that inhibition of CDCA8 slowed cell proliferation and blocked the cell cycle at the G0/G1 phase. In vivo experiments demonstrated that inhibition of CDCA8 inhibited tumour growth. Finally, blockade of CDCA8 reduced the expression levels of cyclin A2, cyclin D1, CDK4, CDK6, Ki67 and PCNA. And, there is an interaction between CDCA8 and E2F1. In conclusion, this research demonstrates that CDCA8 may serve as a biomarker for early diagnosis and prognosis prediction of HCC patients. In addition, CDCA8 could be an effective therapeutic target in HCC.
Background Metabolic disorder is an essential characteristic of tumor development. Ketogenesis is a heterogeneous factor in multiple cancers, but the effect of ketogenesis on hepatocellular carcinoma (HCC) is elusive. Methods We aimed to explain the role of ketogenesis-related hydroxy-methyl-glutaryl-CoA lyase (HMGCL) on HCC suppression. Expression pattern of HMGCL in HCC specimens was evaluated by immunohistochemistry (IHC). HMGCL was depleted or overexpressed in HCC cells to investigate the functions of HMGCL in vitro and in vivo. The anti-tumor function of HMGCL was studied in subcutaneous xenograft and Trp53Δhep/Δhep; c-Myc-driven HCC mouse models. The mechanism of HMGCL-mediated tumor suppression was studied by IHC, western blot (WB) and Cut & Tag. Results HMGCL depletion promoted HCC proliferation and metastasis, whereas its overexpression reversed this trend. As HMGCL catalyzes β-hydroxy-butyric acid (β-OHB) production, we discovered that HMGCL increased acetylation at histone H3K9, which further promoted the transcription of dipeptidyl peptidase 4 (DPP4), a key protein maintains intracellular lipid peroxidation and iron accumulation, leading to HCC cells vulnerability to erastin- and sorafenib-induced ferroptosis. Conclusion Our study identified a critical role of HMGCL on HCC suppression, of which HMGCL regulated H3K9 acetylation through β-OHB and modulating the expression of DPP4 in a dose-dependent manner, which led to ferroptosis in HCC cells.
Background Tumor microenvironment (TME) refers to the cellular environment where tumors exist, including immune cells, fibroblasts, stromal cells, chemokines, etc. TME is closely related to the prognosis of various tumors; nevertheless, limited studies have established predictive prognosis models based on TME. This work aims to construct a survival prediction model for melanoma patients based on TME. Methods Data of 482 melanoma patients were extracted from The Cancer Genome Atlas (TCGA) database. Based on the infiltration of immune cells (Immune score), stromal cells (Stromal score), and tumor purity (Estimate score), the “Estimate” algorithm was used to construct 3 scores for each patient. To identify the differentially expressed genes (DEGs), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using DAVID database and visualized using the R software. The STRING database was used to construct the protein-protein interaction (PPI) network and functional modules. FGD2 expression was confirmed via Western Blotting and quantitative reverse transcription PCR (RT-qPCR) analyses. Results Patients with higher immune scores estimate scores showed better OS than those with lower scores. All three scores were related to age and primary tumor stage. Further, DEGs between patients with high immune/stromal scores and low immune/stromal scores were screened. Eventually, 10 down-regulated DEGs and 201 up-regulated DEGs were identified as TME associated genes. Out of these, the FGD2 gene demonstrated close association with survival and was confirmed in the included melanoma patients. Conclusion In summary, TME is closely associated with the prognosis of melanoma patients. Besides, genes including FGD2 promote the TME-mediated regulation of melanoma.
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