• acetylation
• cancer
• deacetylation
• metabolic reprogramming

• Neoplasms/metabolism
• Humans
• Acetylation
• Protein Processing, Post-Translational
• Signal Transduction
• Energy Metabolism/physiology

• 82373339 National Natural Science Foundation of China
• National Natural Science Foundation of China

• Acute myeloblastic leukemia
• PDGFRB
• anoikis
• immunotherapy
• prognosis

• Astilbin
• epithelial-mesenchymal transition
• p53 acetylation
• radiation-induced lung injury
• radioprotective efficacy

• Animals
• Mice
• Humans
• Lung Injury/drug therapy
• Lung Injury/prevention & control
• Lung Injury/metabolism
• Acetylation
• Tumor Suppressor Protein p53/metabolism
• Mice, Inbred C57BL
• Lung/pathology
• Radiation Injuries/drug therapy
• Inflammation/metabolism

• 2023KY0120 The Basic Ability Enhancement Project of Young Teachers in Guangxi Zhuang Autonomous Region
• 82060019 National Natural Science Foundation of China

• DNA methylation
• ectopic endometrium
• endometriosis
• endometrium
• eutopic endometrium
• proliferative phase
• secretory phase

• FRGS/1/2020/SKK0/UKM/03/1 Fundamental Research Grant Scheme

• HOXA10
• Hepatitis B virus (HBV)
• hepatocellular carcinoma (HCC)
• miR-135a

• ERK signaling pathway
• HOXA10
• apoptosis
• esophageal cancer
• p38 signaling pathway
• proliferation

• Wnt/beta-catenin
• female cancer
• homeobox genes
• mouse model
• steroids

• Animals
• Embryo Implantation/physiology
• Endometrial Hyperplasia/genetics
• Endometrial Hyperplasia/metabolism
• Endometrial Neoplasms/pathology
• Endometrium/metabolism
• Female
• Homeobox A10 Proteins
• Homeodomain Proteins/genetics
• Homeodomain Proteins/metabolism
• Humans
• Mice

Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment.

To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets.

We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information’s Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis.

Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms.

This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.

• Hepatitis B virus
• Hepatocellular carcinoma
• Genomics
• Meta-analysis

Background: Non-apoptotic programmed cell death, including autophagy, ferroptosis, and pyroptosis, newly discovered in recent years, plays an important role in hepatocellular carcinoma (HCC). So, this study attempted to explore the relationship between non-apoptotic programmed cell death-related genes and the molecular characteristics, tumor microenvironment, and prognosis in HCC patients.

Methods: The transcriptomic and clinical data of HCC samples were downloaded from various public datasets, followed by acquiring non-apoptotic programmed cell death-related genes from the database. A gene signature model was then constructed using univariate and multivariate Cox regression analyses and validated in other cohorts as well as our institution sequencing data. Kaplan–Meier survival curves and time-dependent receiver operating characteristic curves were generated to evaluate the model’s predictive capability. Furthermore, the relationships among the gene signature, TP53 mutation, stemness, immune status, and responsiveness of transarterial chemoembolization (TACE) were analyzed.

Results: The gene signature model was constructed based on five autophagy-, three ferroptosis-, and two pyroptosis-related differentially expressed genes. The model accurately predicted that patients classified as low risk would have better overall survival than high-risk patients, which was robustly consistent with data from other cohorts as well as our institution sequencing data. The comprehensive results indicated that a high-risk index was correlated with a high TP53 mutation rate, high cancer cell stemness, high infiltration of immunosuppressive cells and low immunophenoscore, and low TACE responsiveness of HCC patients.

Conclusion: Collectively, the established non-apoptotic programmed cell death-related gene signature was shown to accurately predict prognosis, associated with the TP53 mutation and liver cancer cell stemness, reflect the tumor immune microenvironment, and predict TACE responsiveness in HCC patients.

• National Natural Science Foundation of China

Background: Low grade glioma is one of the most common lethal cancers in the human nervous system. Emerging evidence has demonstrated that homeobox A cluster (HOXA) gene family plays a critical role in the transcriptional regulation as well as cancer initiation and progression. However, the expression, biological functions and upstream regulatory mechanism of 11 HOXAs in low grade glioma are not yet clear.

Methods: In this study, we utilized various public databases and bioinformatics analyzed, including TCGA, CGGA, Rembrandt, HPA, LinkedOmics, cBioPortal, TISDIB, single-sample GSEA (ssGSEA), TIMER, LnCeVar, LASSO regression, Cox regression, Kaplan-Meier plot, and receiver operating, characteristic (ROC) analyses, GDSC and CTRP databases to analyzed the mRNA and protein expression profiles, gene mutation, clinical features, diagnosis, prognosis, signaling pathway, TMB, immune subtype, immune cell infiltration, immune modulator, ceRNA network and drug sensitivity of 11 HOXAs. Growth curve and transwell assays were utilized to study the biological characteristics of HOXA6 in LGG progression.

Results: In the present study, we found that 11 HOXAs (HOXA1, HOXA2, HOXA3, HOXA4, HOXA5, HOXA6, HOXA7, HOXA9, HOXA10, HOXA11 and HOXA3) were consistently up-regulated in LGG tissues and GBM tissues. Up-regulated of the HOXAs expression were significantly correlated with higher tumor stage, IDH mutation status, 1p/19q co-deletion, histological type and primary therapy outcome. Survival analyses showed that higher expression of HOXA1, HOXA2, HOXA3, HOXA4, HOXA5, HOXA7, HOXA9, HOXA10, HOXA11 and HOXA13 were correlated with shorter overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS) in LGG patients. Univariate and multivariate analyses revealed that HOXA1, HOXA6 expression and tumor grade, age, primary therapy outcome and age were independent factors affecting the prognosis of LGG patients. ROC curve analysis of HOXAs showed that HOXAs had a high accuracy (AUC > 0.80) in predicting LGG. Furthermore, gene functional enrichment analysis indicated that HOXAs mainly involved in the inflammatory response and immune regulation signaling pathway. CNV and DNA methylation significantly affect the expression of HOXAs. Finally, we uncover that HOXAs expression are highly correlated with immune cells infiltrate, immune modulator and drug sensitivity. We also uncover that the HOXAs related ceRNA network in LGG. More importantly, we found that HOXA6 was highly expressed in LGG cells lines and significantly affected their proliferation and migration abilities.

Conclusions: In conclusion, our data demonstrated that HOXA was correlated with progression and immune infiltration, and could serve as a prognostic biomarker for LGG.

• HOXA family
• cell migration
• low grade glioma
• next-generation sequencing
• prognostic biomarker

• Hepatocellular carcinoma (HCC)
• The Cancer Genome Atlas (TCGA)
• prognosis
• signature

Background: G-protein coupled receptor 34 (GPR34) is involved in cell motility, differentiation, and mitosis. GPR34 was reported to be highly expressed and play an oncogenic role in several solid tumors. Here, we investigated the mechanisms underlying how GPR34 promotes glioma progression. Methods: Bioinformatic analysis was performed on RNA-seq and clinical data from the gene expression omnibus (GEO), cancer genome atlas (TCGA), and Genotype-Tissue Expression (GTEx) databases. TIMER database and single-sample GSEA (ssGAEA) method were used to investigate the association between the GPR34 expression and immune infiltration level in glioma. Cox regression analysis was employed to ascertain whether the risk signature was an independent prognostic indicator for glioma. The viability and migratory/invasive potential of glioma cells were assessed using Cell Counting Kit-8, colony formation, wound healing, and Transwell assays. Results: We found that GPR34 expression was positively correlated with immune infiltration level and that high GPR34 level may be associated with poor prognosis in glioma. We further found that GPR34 may serve as an independent prognostic marker and prediction factor for the clinicopathological features of glioma. We showed that knocking down GPR34 attenuated the viability and migratory/invasive capacity of glioma cells (U251 and LN229), while GPR34 overexpression exerted the opposite effects. Additionally, core enrichment in the GSEA analysis indicated that GPR34-mediated gliomagenesis was associated with the cell cycle arrest, epithelial–mesenchymal transition (EMT), and activation of the TGF-β/Smad pathway; furthermore, inhibiting TGF-β/Smad signaling using LY2157299, a TGF-β inhibitor, reversed the oncogenic effects and malignant phenotype associated with GPR34 overexpression. Conclusion: GPR34 enhances the malignancy and carcinogenesis of glioma by promoting an EMT-like process, G1/S phase cell cycle transition, and TGF-β/Smad signaling. Accordingly, GPR34 likely functions as an oncogene in glioma and may represent a potential therapeutic target for this cancer.

• EMT
• GPR34
• TGF-beta/Smad signaling pathway
• bioinformatic analysis
• cell cycle
• glioma

• CAMKK2
• HOX genes
• HOXA10
• MMP1
• Nasopharyngeal carcinoma
• SKP2

• DNA damage
• Histone deacetylase1
• Innate immunity
• Pseudorabies virus

• DNA methylation
• GEO
• TCGA
• hepatocellular carcinoma
• prognosis

Previous research has highlighted the ability of Homeobox A10 (HOXA10) to the promote proliferation, migration, and epithelial-mesenchymal transformation of various cancers, including lung adenocarcinoma (LAD), which is characterized by an aggressive disease course that exhibits rapid proliferation and migration, with studies suggesting histone deacetylase 1 (HDAC1) to be a downstream mediator of HOXA10. The current study aimed to investigate the mechanism by which HOXA10-mediated HDAC1 influences the development of LAD.

The expression patterns of HOXA10, HDAC1, DNA methyltransferase 1 (DNMT1), and Kruppel-like factor 4 (KLF4) were determined. Additionally, the effect of HOXA10, HDAC1, or DNMT1 on invasive phenotypes of LAD was analyzed using depletion experiments. The interactions among HOXA10, HDAC1, DNMT1, and KLF4 were evaluated via chromatin immunoprecipitation, dual luciferase assay or co-immunoprecipitation. Furthermore, the tumorigenic ability of the LAD cells following HOXA10 silencing and/or HDAC1 overexpression in vivo was also investigated.

In the LAD tissues and cells, HOXA10, HDAC1, and DNMT1 all exhibited high levels of expression, while KLF4 was poorly expressed. HOXA10 silencing inhibited the expression of HDAC1, reduced LAD cell proliferation, migration, and invasion, and promoted the apoptosis. HDAC1 promoted DNMT1 expression through deacetylation, and DNMT1 inhibited the KLF4 expression through DNA methyltransferase. The in vitro findings were further attested through the use of in vivo assays.

Taken together, the key observations of the current study highlight the role of HOXA10 and HDAC1 in promoting the proliferation and migration of LAD cells. HOXA10-induced upregulation of HDAC1 interacts with DNMT1-KLF4 axis, while the inhibition of HOXA10 or HDAC1 represents a promising anti-tumor therapy target for LAD.

The online version contains supplementary material available at 10.1186/s13046-021-01867-0.

• DNMT1
• Deacetylation
• HDAC1
• HOXA10
• KLF4
• Lung adenocarcinoma
• Methylation

Homeobox A10 (HOXA10) belongs to the HOX gene family, which plays an essential role in embryonic development and tumor progression. We previously demonstrated that HOXA10 was significantly upregulated in gastric cancer (GC) and promoted GC cell proliferation. This study was designed to investigate the role of HOXA10 in GC metastasis and explore the underlying mechanism.

Immunohistochemistry (IHC) was used to evaluate the expression of HOXA10 in GC. In vitro cell migration and invasion assays as well as in vivo mice metastatic models were utilized to investigate the effects of HOXA10 on GC metastasis. GSEA, western blot, qRT-PCR and confocal immunofluorescence experiments preliminarily analyzed the relationship between HOXA10 and EMT. ChIP-qPCR, dual-luciferase reporter (DLR), co-immunoprecipitation (CoIP), colorimetric m⁶A assay and mice lung metastasis rescue models were performed to explore the mechanism by which HOXA10 accelerated the EMT process in GC.

In this study, we demonstrated HOXA10 was upregulated in GC patients and the difference was even more pronounced in patients with lymph node metastasis (LNM) than without. Functionally, HOXA10 promoted migration and invasion of GC cells in vitro and accelerated lung metastasis in vivo. EMT was an important mechanism responsible for HOXA10-involved metastasis. Mechanistically, we revealed HOXA10 enriched in the TGFB2 promoter region, promoted transcription, increased secretion, thus triggered the activation of TGFβ/Smad signaling with subsequent enhancement of Smad2/3 nuclear expression. Moreover, HOXA10 upregulation elevated m⁶A level and METTL3 expression in GC cells possible by regulating the TGFB2/Smad pathway. CoIP and ChIP-qPCR experiments demonstrated that Smad proteins played an important role in mediating METTL3 expression. Furthermore, we found HOXA10 and METTL3 were clinically relevant, and METTL3 was responsible for the HOXA10-mediated EMT process by performing rescue experiments with western blot and in vivo mice lung metastatic models.

Our findings indicated the essential role of the HOXA10/TGFB2/Smad/METTL3 signaling axis in GC progression and metastasis.

The online version contains supplementary material available at 10.1186/s13046-021-01859-0.

• EMT
• Gastric cancer
• HOXA10
• METTL3
• Smad2/3
• TGFB2

• CircHIPK3
• Circular RNA
• Diabetic nephropathy
• TGF-β1
• miR-185

Autophagy is a programmed cell degradation mechanism that has been associated with several physiological and pathophysiological processes, including malignancy. Improper induction of autophagy has been proposed to play a pivotal role in the progression of hepatocellular carcinoma (HCC).

Univariate Cox regression analysis of overall survival (OS) was performed to identify risk-associated autophagy-related genes (ARGs) in HCC data set from The Cancer Genome Atlas (TCGA). Multivariate cox regression was then performed to develop a risk prediction model for the prognosis of 370 HCC patients. The multi-target receiver operating characteristic (ROC) curve was used to determine the model’s accuracy. Besides, the relationship between drug sensitivity and ARGs expression was also examined.

A total of 62 differentially expressed ARGs were identified in HCC patients. Univariate and multivariate regression identified five risk-associated ARGs (HDAC1, RHEB, ATIC, SPNS1 and SQSTM1) that were correlated with OS in HCC patients. Of importance, the risk-associated ARGs were independent risk factors in the multivariate risk model including clinical parameters such as malignant stage (HR = 1.433, 95% CI = 1.293–1.589, P < 0.001). In addition, the area under curve for the prognostic risk model was 0.747, which indicates the high accuracy of the model in prediction of HCC outcomes. Interestingly, the risk-associated ARGs were also correlated with drug sensitivity in HCC cell lines.

We developed a novel prognostic risk model by integrating the molecular signature and clinical parameters of HCC, which can effectively predict the outcomes of HCC patients.

• Autophagy
• Autophagy-related genes
• Drug sensitivity
• HCC
• Molecular signature

The homeobox A cluster (HOXA) gene family, comprising 11 members, is involved in a wide spectrum of biological functions in human cancers. However, there is little research on the expression profile and prognostic values of HOXA genes in laryngeal squamous cell cancer (LSCC). Based on updated public resources and integrative bioinformatics analysis, we assessed the expression profile and prognostic values of the HOXA family members. Expression and methylation data on HOXA family members were obtained from The Cancer Genome Atlas (TCGA). The prognostic values of HOXA members and clinical features were identified. A gene set enrichment analysis (GSEA) was conducted to explore the mechanism underlying the involvement of HOXA members in LSCC. The associations between tumor immune infiltrating cells (TIICs) and the HOXA family members were evaluated using the Tumor Immune Estimation Resource (TIMER) database. HOXA2 and HOXA4 were downregulated and HOXA7 and HOXA9–13 were upregulated in LSCC. Upregulation of HOXA10, HOXA11, and HOXA13, along with two clinical characteristics (M stage and gender), were associated with a poor LSCC prognosis based on the results of univariate and multivariate Cox proportional hazards regression analyses. Although there were no significant correlations between TIICs and HOXA members, the GSEA results indicated that HOXA members participate in multiple biological processes underlying tumorigenesis. This study comprehensively analyzed the HOXA members, providing insights for further investigation of the HOXA family members as potential targets in LSCC.

• GSEA
• HOXA family
• LSCC
• TCGA
• prognosis