Zinc finger protein X-linked (ZFX) is a zinc finger protein of Zfy family, which is highly conserved in vertebrates. This transcriptional regulator is not only highly expressed in embryonic stem cells (ESC) and hematopoietic stem cells, but is also upregulated in a number of human cancers where it is functional related to cell proliferation and survival. Hepatocellular carcinoma (HCC) is highly aggressive cancer that commonly resistant to most chemotherapies and displays stemness characteristics. In this study, we examined the expression of ZFX in HCC and its possible functional implications in liver tumorigenesis. Quantitative RT-PCR analysis showed common overexpressions of ZFX in 51.8% HCC tumors when compared with their adjacent nonmalignant liver (n 5 43/83; p 5 0.004). Inline with the pluripotency role of ZFX, we found silencing of ZFX readily inhibited self-renewal capability (p 5 0.0022), colony formation ability (p < 0.0001) and cell proliferation (p < 0.0001) through G0/G1 cell cycle arrest of HCC cells (p 5 0.0038). In addition, suppression of ZFX sensitized HCC cells to chemotherapeutic agent cisplatin (p < 0.0001). Further investigations suggested that ZFX bind on the promoter of two important mediators, namely Nanog and SOX-2, activating their expressions in HCC (p < 0.0001). Moreover, in vivo xenograft study demonstrated that overexpression of ZFX would promote the tumor growth (p 5 0.031). Taken together, our results show, for the first time, commonly overexpressions of ZFX in HCC, where it likely contributes to the stemness and pluripotent behavior of this highly malignant cancer.Hepatocellular carcinoma (HCC), which accounts for 80-90% of all liver cancers, is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. 1 HCC is an aggressive cancer with a high mortality rate; often due to being diagnosed at a late stage when curative therapies are least effective. 2 Moreover, most HCC patients show disease recurrence that rapidly progresses to advanced stages. It is general believed that the presence of cancer stem-like features is responsible for chemoresistance and recurrence of HCC. 3-7 ZFX is a zinc finger protein of the Zfy family that is highly conserved among vertebrates. It is a transcriptional factor encoded on the mammalian X chromosome and contains an acidic transcriptional activation domain, a nuclear localization sequence and a DNA binding domain. 8,9 Despite elevated levels are detected in pluripotent embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs) where it is required for maintenance of self-renewal ability, 8 ZFX is also found to be frequently overexpressed in a number of human cancers, including esophageal carcinoma, gastric cancer, prostate cancer, and glioma. 10-13 Common cancer stemness characteristics, including colony-forming ability, acquisition of drug resistance, cell survival, and cancer metastasis have been further proposed to be induced from ZFX in these cancers. In HCC, the role of ZFX however remains unexplored. The ...
The interstitial chromosome (chr.) 1q21-q22 region is frequently amplified in human cancers, where it has been reported to carry prognostic significance for patients. We attempted to delineate chr. 1q21-q22 for affected gene(s) in hepatocellular carcinoma (HCC) by array-CGH and detected copy number gains of ρ-guanine nucleotide exchange factor-H1 (GEF-H1) as most significant event. Gene expression evaluation in the HCC cohort indicated common up-regulations of GEF-H1 in 64% tumours compared to adjacent non-tumoural liver (64/100; paired t-test p < 0.0001). Moreover, GEF-H1 over-expressions correlated with microvascular invasion and advanced-stage tumours (p < 0.05). High GEF-H1 levels also predict shorter disease-free and overall survival of HCC patients (p < 0.03). Functional knock-down of GEF-H1 by RNAi indicated marked reduction in cell invasion through matrigel and an inhibition of cell migration (p < 0.035), but an effect on cell viability was not apparent. More interestingly, a mesenchymal-epithelial transition (MET) was readily observed in GEF-H1 knock-down cells, where a concomitant re-expression of epithelial markers (E-cadherin and cytokeratin 18) and cell adhesion proteins (α-catenin and γ-catenin) was found but down-regulation of mesenchymal features (N-cadherin, vimentin and fibronectin). This phenotype was accompanied by reduced filamentous actin polymerizations and diminution of the stress fibre formation. In addition, reduced active form of GTP-RhoA, together with its downstream effectors, including cleaved ROCK1 and phosphorylated MLC2, were also detected in GEF-H1-depleted cells. Taken together, our findings underscore a potent oncogenic role for GEF-H1 in promoting the metastatic potentials of HCC, possibly through activation of RhoA signalling and the EMT phenomenon.
Comparative transcriptome analysis was used to determine the differentially expressed genes in Escherichia coli during aerosolization from liquid suspension. Isogenic mutant studies were then used to examine the potential part played by some of these genes in bacterial survival in the air. Bioaerosols were sampled after 3 min of nebulization, which aerosolized the bacteria from the liquid suspension to an aerosol chamber (A0), and after further 30 min of airborne suspension in the chamber (A30). Bacteria at A0 showed 65 differentially expressed genes (30 downregulated and 35 upregulated) as compared to the original bacteria in the nebulizer. Droplet evaporation models predicted a drop in temperature in the bioaerosols, which coincides with the change in the expression of cold shock protein genes-cspB and cspG in the bacteria. The most notable group of differentially expressed genes was sorbitol transport and metabolism genes (srlABDEMR). Other genes associated with osmotic stress, nutrient limitation, DNA damage, and other stresses were differentially expressed in the bacteria at A0. After further airborne suspension, one gene (ypfM, which encodes a hypothetical protein with unknown function) was downregulated in the bacteria at A30 as compared to those at A0. Finally, isogenic mutants with either the dps or srlA gene deleted (both genes were upregulated at A0) had lower survival than the parental strain, which is a sign of their potential ability to protect the bacteria in the air.
The coronavirus disease 2019 (COVID-19) pandemic has led to 4,255,892 deaths worldwide. Although COVID-19 vaccines are available, mutant forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have reduced the effectiveness of vaccines. Patients with cancer are more vulnerable to COVID-19 than patients without cancer. Identification of new drugs to treat COVID-19 could reduce mortality rate, and traditional Chinese Medicine(TCM) has shown potential in COVID-19 treatment. In this study, we focused on lung adenocarcinoma (LUAD) patients with COVID-19. We aimed to investigate the use of curcumol, a TCM, to treat LUAD patients with COVID-19, using network pharmacology and systematic bioinformatics analysis. The results showed that LUAD and patients with COVID-19 share a cluster of common deregulated targets. The network pharmacology analysis identified seven core targets (namely, AURKA, CDK1, CCNB1, CCNB2, CCNE1, CCNE2, and TTK) of curcumol in patients with COVID-19 and LUAD. Clinicopathological analysis of these targets demonstrated that the expression of these targets is associated with poor patient survival rates. The bioinformatics analysis further highlighted the involvement of this target cluster in DNA damage response, chromosome stability, and pathogenesis of LUAD. More importantly, these targets influence cell-signaling associated with the Warburg effect, which supports SARS-CoV-2 replication and inflammatory response. Comparative transcriptomic analysis on in vitro LUAD cell further validated the effect of curcumol for treating LUAD through the control of cell cycle and DNA damage response. This study supports the earlier findings that curcumol is a potential treatment for patients with LUAD and COVID-19.
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