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 Trp53^Δhep/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.

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: Despite advances in early diagnosis and treatment, cancer remains the leading cause of mortality worldwide. The insulin-like growth factor 2 mRNA binding protein (IGF2BP) family has been reported to be involved in a variety of human malignant tumours. However, little is known about their expression and prognostic value in human pancreatic cancer. Therefore, we performed a detailed cancer versus normal differential analysis. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to analyse the mRNA expression levels of the IGF2BP family in various cancers, including pancreatic cancer. Then, the LinkedOmics and GEPIA databases were used to assess the relation between the expression levels of IGF2BPs and overall survival (OS). Then, univariate and multivariate Cox regression analyses were performed, and subgroups based on grade and stage were analysed. The signalling pathways associated with IGF2BP2 and IGF2BP3 were then investigated via gene set enrichment analysis (GSEA). Results: IGF2BP2 and IGF2BP3 were associated with each subset of OS based on grade and stage. Further clinical correlation analysis of IGF2BP2 and IGF2BP3 confirmed that IGF2BP2 and IGF2BP3 are fundamental factors in promoting pancreatic cancer progression. Conclusion: IGF2BP2 and IGF2BP3 are key factors in promoting the progression of pancreatic cancer and are closely related to overall survival.

Background: Cancer is one of the most common causes of death, and the morbidity and mortality are gradually increasing in the world. KIF20A plays an important role in tumors, but its immune relevance in pan-cancer needs to be further studied.Methods: KIF20A-related information was download from The Cancer Genome Atlas (TCGA). Collecting RNA-seq data is fragments per kilobase million (FPKM) style data. The ESTIMATE algorithm was used for estimating the stromal and immune scores for 33 tumors. Then, we analyzed the correlation between KIF20A in pan-cancer and immune checkpoints and performed gene set enrichment analysis (GSEA) analysis on the co-expressed genes of KIF20A in pan-cancer.Results: We have confirmed that the expression of KIF20A has a intensive correlation with prognosis in 33 kinds of tumors. Its expression of KIF20A was related to a variety of immune cells and immune checkpoints. Based on the results of GSEA for further analysis, in multiple tumors, KIF20A is related to immune-related pathways.Conclusion: We have demonstrated that KIF20A played an important role in pan-cancer and could affect the occurrence or development of a variety of tumors. Moreover, KIF20A was related to immunity, and KIF20A- related immune research in pan-cancer also needs to be further demonstrate.

Background: Despite advances in early diagnosis and treatment, cancer remains the leading cause of mortality worldwide. The insulin-like growth factor 2 mRNA binding protein(IGF2BP) family has been reported to be involved in a variety of human malignant tumours. However, little is known about their expression and prognostic value in human pancreatic cancer. Therefore, we performed a detailed cancer versus normal differential analysis. Methods: The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were uesd to analyse the mRNA expression levels of the IGF2BP family in various cancers, including pancreatic cancer. Then, the LinkedOmics and GEPIA databases were used to assess the relation between the expression levels of IGF2BPs and overall survival (OS). Then, univariate and multivariate Cox regression analyses were performed , and subgroups based on grade and stage were analysed. The signalling pathways associated with IGF2BP2 and IGF2BP3 were then investigated via gene set enrichment nalysis(GSEA). Results: IGF2BP2 and IGF2BP3 were associated with each subset of OS based on grade and stage. Further clinical correlation analysis of IGF2BP2 and IGF2BP3 confirmed that IGF2BP2 and IGF2BP3 are fundamental factors in promoting pancreatic cancer progression. Conclusion: IGF2BP2 and IGF2BP3 are key factors in promoting the progression of pancreatic cancer and are closely related to overall survival.

Background:Metabolic disorder is an essential characteristic of tumor development. Ketogenesis as a heterogeneous factor in multiple cancer, but the effect of ketogenesis on hepatocellular carcinoma (HCC) is elusive.Methods:We aimed to explain a role of ketogenesis related hydroxymethylglutaryl-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 HMGCLin vitroandin vivo. The antitumor function of HMGCL was studied in subcutaneous xenograft andTrp53Δhep/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-hydroxybutyric 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.Conclusions: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.