The cancer-testis gene,MEIOB,sensitizes triple-negative breast cancer to PARP1 inhibitors by inducing homologous recombination deficiency

Objective:The newly defined cancer-testis(CT)gene,MEIOB,was previously found to play key roles in DNA double-strand break(DSB)repair.In this study,we aimed to investigate the effects and mechanisms of MEIOB in the carcinogenesis of triple-negative breast cancers(TNBCs).Methods:The Cancer Genome Atlas database was used to quantify the expression of MEIOB.Cox regression analysis was used to evaluate the association between MEIOB expression and the prognosis of human TNBC.The effects of MEIOB on cell proliferation and migration in TNBCs were also assessed in vitro.Patient-derived xenograft(PDX)models were used to assess the sensitivity of breast cancers with active MEIOB to PARP1 inhibitors.Results:We confirmed MEIOB as a CT gene whose expression was restricted to the testes and breast tumors,especially TNBCs.Its activation was significantly associated with poor survival in breast cancer patients[overall,hazard ratio(HR)=1.90(1.16–2.06);TNBCs:HR=7.05(1.16–41.80)].In addition,we found that MEIOB was oncogenic and significantly promoted the proliferation of TNBC cells.Further analysis showed that MEIOB participated in DSB repair in TNBCs.However,in contrast to its function in meiosis,it mediated homologous recombination deficiency(HRD)through the activation of poly ADP-ribose polymerase(PARP)1 by interacting with YBX1.Furthermore,activated MEIOB was shown to confer sensitivity to PARP inhibitors,which was confirmed in PDX models.Conclusions:MEIOB played an oncogenic role in TNBC through its involvement in HRD.In addition,dysregulation of MEIOB sensitized TNBC cells to PARP inhibitors,so MEIOB may be a therapeutic target of PARP1 inhibitors in TNBC.

A causal variant rs3769823 in 2q33.1 involved in apoptosis pathway leading to a decreased risk of non-small cell lung cancer

Objective:Although our previous genome-wide association study(GWAS)has identified chromosome 2q33.1 as a susceptibility locus for non-small cell lung cancer(NSCLC),the causal variants remain unclear.The aims of this study were to identify the causal variants in 2q33.1 and to explore their biological functions in NSCLC.Methods:CCK-8,colony formation,EdU incorporation,Transwell,and quantitative real-time polymerase chain reaction assays were applied to examine variant function.The tumor xenograft model was used to examine variant function in vivo.Caspase-8 activity assays,flow cytometry analysis,and co-immunoprecipitation assays were used to explore the molecular mechanism.Results:The missense variant rs3769823(A>G),which caused the substitution of lysine with arginine at amino acid 14 in caspase-8(caspase-8K14R),was identified as a potential causal candidate in 2q33.1.Compared with the wild type caspase-8(caspase8WT)group,the caspase-8K14R group had higher expression of caspase-8 and cleaved caspase-8.Caspase-8K14R inhibited the proliferation and metastasis of human lung cancer cell lines in vitro.Moreover,caspase-8K14R repressed lung cancer cell growth in vivo.Mechanistically,caspase-8K14R was more sensitive than caspase-8WT to tumor necrosis factor-related apoptosis-inducing ligand(TRAIL)-mediated apoptosis and showed higher binding of caspase-8 and FADD.Conclusions:These results suggested that rs3769823 is the causal variant in chromosome 2q33.1 and is involved in an apoptosis pathway,leading to a decreased risk of NSCLC.

Gene amplification-driven RNA methyltransferase KIAA1429 promotes tumorigenesis by regulating BTG2 via m6A-YTHDF2-dependent in lung adenocarcinoma

Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reasons for activation of KIAA1429(also known as VIRMA,an RNA methyltransferase)and its underlying mechanism in lung adenocarcinoma(LUAD)remain largely unexplored.In this study,we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.Methods:Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase.The in vitro and in vivo functions of KIAA1429 were investigated.Transcriptome sequencing,methylated RNA immunoprecipitation sequencing(MeRIP-seq),m6A dot blot assays and RNA immunoprecipitation(RIP)were performed to confirm the modified gene mediated by KIAA1429.RNA stability assays were used to detect the half-life of the target gene.Results:Copy number amplification drove higher expression of KIAA1429 in LUAD,whichwas correlatedwith poor overall survival.Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD.Mechanistically,the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays.We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner.Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA,leading to enhanced YTH m6A RNA binding protein 2(YTHDF2,the m6A“reader”)-dependent BTG2 mRNA stability and promoted the expression of BTG2;thus,participating in the tumorigenesis of LUAD.Conclusions:Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis,which may provide a novel view on the targeted molecular therapy of LUAD.

U-shaped association between telomere length and esophageal squamous cell carcinoma risk： a case-control study in Chinese population

Telomeres play a critical role in biological ageing by maintaining chromosomal integrity and preventing chromosome ends fusion. Epidemiological studies have suggested that inter-individual differences of telomere length could affect predisposition to multiple cancers, but evidence regarding esophageal squamous cell carcinoma （ESCC） was still uncertain. Several telomere length-related single nucleotide polymorphisms （TL- SNPs） in Caucasians have been reported in genome-wide association studies. However, the effects of telomere length and TL-SNPs on ESCC development are unclear. Therefore, we conducted a case-control study （1045 ESCC cases and 1433 controls） to evaluate the associations between telomere length, TL-SNPs, and ESCC risk in Chinese population. As a result, ESCC cases showed overall shorter relative telomere length （RTL） （median： 1.34） than controls （median： 1.50, P 〈 0.001）. More interestingly, an evident nonlinear U-shaped association was observed between RTL and ESCC risk （P 〈 0.001）, with odds ratios （95% confidence interval） equal to 2.40 （1.84- 3.14）, 1.36 （1.03-1.79）, 1.01 （0.76-1.35）, and 1.37 （1.03-1.82） for individuals in the 1st （the shortest）, 2nd, 3rd, and 5th （the longest） quintile, respectively, compared with those in the 4th quintile as reference group. No significant associations were observed between the eight reported TL-SNPs and ESCC susceptibility. These findings suggest that either short or extremely long telomeres may be risk factors for ESCC in the Chinese population.

The equivalent and aliovalent dopants boosting the thermoelectric properties of YbMg2Sb2

Antimony-based Zintl compounds AM2Sb2(A=Ca,Sr,Ba,Yb,Eu;M=Mg,Zn,Cd,Mn),which enable a broad range of manipulation on electrical and thermal transport properties,are considered as an important class of thermoelectric materials.Phonon and carrier transport engineering were realized in YbMg2Sb2 via equivalent and aliovalent substitution of Zn and Ag,respectively.The roomtemperature thermal conductivity reduces from 1.96 to 1.15 W m^-1 K^-1 for YbMg2-xZnxSb2 due to the mass and strain fluctuation through the formation of the absolute solid solution of YbMg2Sb2-YbZn2Sb2.Furthermore,the carrier concentration has been further optimized by Ag doping(from 0.42×10^19 to 7.72×10^19 cm^-3 at room temperature),and thus the electrical conductivity and the power factor are enhanced effectively.The integrated aspects make the dimensionless figure of merit(zT)reach 0.48 at 703 K,which is 60%higher than the pristine YbMgZnSb2 sample.