The role of proteasomes in tumorigenesis

Protein homeostasis is the basis of normal life activities,and the proteasomefamily plays an extremely important function in this process.The proteasome 2os is a concentric circle structure with twoαrings and twoβrings overlapped.The proteasome 2os can perform both ATP-dependent and non-ATP-dependent ubiquitination proteasome degradation by binding to various subunits(such as 19S,11S,and 200 PA),which is performed by its active subunitβ1,β2,andβ5.The proteasome can degrade misfolded,excess proteins tomaintain homeostasis.At the same time,it can be utilized by tumors to degrade over-proliferate and unwanted proteins to support their growth.Proteasomes can affect the development of tumors from several aspects including tumor signaling pathways such as NF-kB and p53,cell cycle,immune regulation,and drug resistance.Proteasome-encoding genes have been found to be overexpressed in a variety of tumors,providing a potential novel target for cancer therapy.In addition,proteasome inhibitors such as bortezomib,carfilzomib,and ixazomib have been put into clinical application as the first-line treatment of multiple myeloma.More and more studies have shown that it also has different therapeutic effects in other tumors such as hepatocellular carcinoma,non-small cell lung cancer,glioblastoma,and neuroblastoma.However,proteasome inhibitors are not much effective due to their tolerance and singleness in other tumors.Therefore,further studies on their mechanisms of action and drug interactions are needed to investigate their therapeutic potential.

Zinc-finger protein 382 antagonises CDC25A and ZEB1 signaling pathway in breast cancer

Our previous studies found that Zinc-finger protein 382(ZNF382)played as a tumor suppressor gene in esophageal and gastric cancers,and a positive correlation between the high expression of ZNF382 and better outcome in breast cancer patients.However,the biological roles and mechanisms of ZNF382 in breast cancer remains unclear.We detected ZNF382 expression by reverse-transcription PCR(RT-PCR)and real-time quantitative PCR(qRT-PCR)in breast cancer cells and tissues,and explored the impacts and mechanisms of ectopic ZNF382 expression in breast cancer cells in vitro and in vivo,respectively.Our results revealed that ZNF382 was significantly down-regulated in breast cancer tissues compared with adjacent non-cancer tissues.Restoration of ZNF382 expression in silenced breast cancer cells not only inhibited tumor cell colony formation,viability,migration and invasion,and epithelial-mesenchymal-transition(EMT),but also induced apoptosis and G0/G1 arrest.In conclusion,ZNF382 could induce G0/G1 cell cycle arrest through inhibiting CDC25A signaling,and,inhibit cell migration,invasion and EMT by antagonizing ZEB1 signaling in breast cancer cells.

Correspondence(reply):The application conditions of false discovery rate control

We have carefully read the correspondence“False Discov-ery Rate Control in Cancer Biomarker Selection”authored by Li.The author clarified the need of paying attention to the control of false discovery rate(FDR)when screening for cancer biomarkers.They expressed concerns about whether the 30 genes concluded in Figure 7 in our published paper“LPCAT1 functions as a novel prognostic molecular marker in hepatocellular carcinoma”call for FDR control.

Depression and stress levels increase risk of liver cancer through epigenetic downregulation of hypocretin

Recent studies suggest that Hypocretin (HCRT, Orexin) are involved in stress regulation of depression through the hypothalamic-pituitary-adrenal (HPA) axis. However, the molecular mechanism by which Hypocretin regulate neurobiological responses is unknown. Herein, the effects of chronic stress on the epigenetic modification of HCRT and its association with depression were explored with regard to a potential role in cancer progression. In the study, Sprague Dawley (SD) rats were used to establish an animal model of cancer with depression by administrating n-nitrosodiethylamine (DEN) and chronic unpredictable mild stress (CUMS). RNA-sequencing was used to detect differentially expressed genes in the hippocampus of rats and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the results of RNA-sequencing. The status of HCRT promoter methylation was assessed by methylation specific polymerase chain reaction. Behavioral tests showed that rats exposed to CUMS had significant depressive-like behaviors. The number of liver tumors and tumor load in depressed rats exposed to CUMS was higher than in SD rats without CUMS. RNA-sequencing revealed that HCRT was one of the most siginificantly downregulated gene in the hippocampus of SD rats with CUMS compared to non-stressed group, which was validated by qRT-PCR. HCRT mRNA expression was downregulated and the promoter for HCRT was hyper-methylated in those with depression. These results identified a critical role for chronic psychological stressors in tumorigenesis and cancer progression, via epigenetic HCRT downregulation. Such epigenetic downregulation may be the molecular basis for the association of cancer with depression.

LPCAT1 functions as a novel prognostic molecular marker in hepatocellular carcinoma

This study aimed to investigate the relationships between LPCAT1 expression and clinicopathologic parameters of hepatocellular carcinoma(HCC),further,to explore the effect of LPCAT1 on overall survival(OS)in patients with HCC,and its possible mechanism.Bioinformatics analysis using high throughput RNA-sequencing data from TCGA was utilized to explore the differential expression of LPCAT1 between normal and tumor tissues,and the associations between LPCAT1 expression and clinicopathological parameters.Survival analyses and subgroup survival analyses were utilized to elucidate the effect of LPCAT1 on OS in patients with HCC.Univariate analysis and multivariate analysis were used to investigate the prognostic factors.Potential LPCAT1 related tumor genes were identified by the methodology of differentially expressed genes(DEGs)screening.GO term enrichment analysis,KEGG pathway analysis and the PPI network were used to explore the potential mechanism.LPCAT1 was significantly overexpressed in HCC tumor tissues compared with normal tissues.The LPCAT1 expression was related to tumor grade,ECOG score,AFP and TNM stage,with P values of 0.000,0.000,0.007 and 0.000,respectively.Multivariate analysis demonstrated that LPCAT1 expression was independently associated with OS,with an HR of 1.04(CI:1.01–1.06,P=0.003).The KEGG pathway enrichment analyses showed that overlapped DEGs mainly participate in the cell cycle.Finally,we identified a hub gene,CDK1,which has been reported to act on the cell cycle,consistent with the result of KEGG enrichment analysis.Collectively,these data confirmed LPCAT1 was upregulated in HCC,and was an independent predictor of the prognosis.

PDCD2 as a prognostic biomarker in glioma correlates with malignant phenotype

Programmed cell death 2(PDCD2)is related to cancer progression and chemotherapy sensitivity.The role of PDCD2 in solid cancers(excluding hematopoietic malignancies)and their diagnosis and prognosis remains unclear.The TCGA,CGGA,GEPIA,cBioPortal,and GTEx databases were analyzed for expression,prognostic value,and genetic modifications of PDCD2 in cancer patients.Functional enrichment analysis,CCK8,colony formation assay,transwell assay,and xenograft tumor model were undertaken to study the PDCD2’s biological function in glioma(GBMLGG).The PDCD2 gene was associated with solid cancer progression.In the functional enrichment analysis results,PDCD2 was shown to participate in several important GBMLGG biological processes.GBMLGG cells may be inhibited in their proliferation,migration,invasion,and xenograft tumor growth by knocking down PDCD2.Our research can provide new insights into solid cancer prognostic biomarkers of PDCD2.