The GJB3 correlates with the prognosis, immune cell infiltration, and therapeutic responses in lung adenocarcinoma.
Gap junction protein beta 3 (GJB3) has been reported as a tumor suppressor in most tumors. However, its role in lung adenocarcinoma (LUAD) remains unknown. The purpose of this study is to explore the role of GJB3 in the prognosis and tumor microenvironment of LUAD patients. The data used in this study were acquired from The Cancer Genome Atlas, Gene Expression Omnibus, and imvigor210 cohorts. We found that GJB3 expression was increased in LUAD patients and correlated with LUAD stages. LUAD patients with high GJB3 expression exhibited a worse prognosis. A total of 164 pathways were significantly activated in the GJB3 high group. GJB3 expression was positively associated with nine transcription factors and might be negatively regulated by hsa-miR-6511b-5p. Finally, we found that immune cell infiltration and immune checkpoint expression were different between the GJB3 high and GJB3 low groups. In summary. GJB3 demonstrated high expression levels in LUAD patients, and those with elevated GJB3 expression displayed unfavorable prognoses. Additionally, there was a correlation between GJB3 and immune cell infiltration, as well as immune checkpoint expression in LUAD patients.
Dou R
，Liu R
，Su P
，Yu X
，Xu Y
... -
《Open Medicine》
Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma.
Lactate, previously considered a metabolic byproduct, is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment. Further investigations confirmed that lactate is a primary regulator, introducing recently described post-translational modifications of histone and non-histone proteins, termed lysine lactylation. Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation. However, our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited.
To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer.
RNA-seq and clinical data of pancreatic adenocarcinoma (PDAC) were obtained from the GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) databases via Xena Explorer, and GSE62452 datasets from GEO. Data on lactylation-related genes were obtained from publicly available sources. Differential expressed genes (DEGs) were acquired by using R package "DESeq2" in R. Univariate COX regression analysis, LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model. Further analyses, including functional enrichment, ESTIMATE, and CIBERSORT, were performed to analyze immune status and treatment responses in patients with pancreatic cancer. PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention; two PDAC cell lines with the most pronounced lactylation were selected. Subsequently, RT-PCR was employed to assess the expression of LRGs genes; SLC16A1, which showed the highest expression, was selected for further investigation. SLC16A1-mediated lactylation was analyzed by immunofluorescence, lactate production analysis, colony formation, transwell, and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells. In vivo validation was performed using an established tumor model.
In this study, we successfully identified 10 differentially expressed lactylation-related genes (LRGs) with prognostic value. Subsequently, a lactylation-related signature was developed based on five OS-related lactylation-related genes (SLC16A1, HLA-DRB1, KCNN4, KIF23, and HPDL) using Lasso Cox hazard regression analysis. Subsequently, we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma. A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups. Furthermore, we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport. Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression, indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma.
We constructed a novel lactylation-related prognostic signature to predict OS, immune status, and treatment response of patients with pancreatic adenocarcinoma, providing new strategic directions and antitumor immunotherapies.
Peng T
，Sun F
，Yang JC
，Cai MH
，Huai MX
，Pan JX
，Zhang FY
，Xu LM
... -
《-》
Impairment of α-tubulin and F-actin interactions of GJB3 induces aneuploidy in urothelial cells and promotes bladder cancer cell invasion.
We have previously identified an unsuspected role for GJB3 showing that the deficiency of this connexin protein induces aneuploidy in human and murine cells and accelerates cell transformation as well as tumor formation in xenograft models. The molecular mechanisms by which loss of GJB3 leads to aneuploidy and cancer initiation and progression remain unsolved.
GJB3 expression levels were determined by RT-qPCR and Western blot. The consequences of GJB3 knockdown on genome instability were assessed by metaphase chromosome counting, multinucleation of cells, by micronuclei formation and by the determination of spindle orientation. Interactions of GJB3 with α-tubulin and F-actin was analyzed by immunoprecipitation and immunocytochemistry. Consequences of GJB3 deficiency on microtubule and actin dynamics were measured by live cell imaging and fluorescence recovery after photobleaching experiments, respectively. Immunohistochemistry was used to determine GJB3 levels on human and murine bladder cancer tissue sections. Bladder cancer in mice was chemically induced by BBN-treatment.
We find that GJB3 is highly expressed in the ureter and bladder epithelium, but it is downregulated in invasive bladder cancer cell lines and during tumor progression in both human and mouse bladder cancer. Downregulation of GJB3 expression leads to aneuploidy and genomic instability in karyotypically stable urothelial cells and experimental modulation of GJB3 levels alters the migration and invasive capacity of bladder cancer cell lines. Importantly, GJB3 interacts both with α-tubulin and F-actin. The impairment of these interactions alters the dynamics of these cytoskeletal components and leads to defective spindle orientation.
We conclude that deregulated microtubule and actin dynamics have an impact on proper chromosome separation and tumor cell invasion and migration. Consequently, these observations indicate a possible role for GJB3 in the onset and spreading of bladder cancer and demonstrate a molecular link between enhanced aneuploidy and invasive capacity cancer cells during tumor cell dissemination.
Liu J
，Wang X
，Jiang W
，Azoitei A
，Eiseler T
，Eckstein M
，Hartmann A
，Stilgenbauer S
，Elati M
，Hohwieler M
，Kleger A
，John A
，Wezel F
，Zengerling F
，Bolenz C
，Günes C
... -
《-》
ResearchGate
(全网免费下载)
钛学术
(全网免费下载)
