Most cancer causal variants are found in gene regulatory elements, e.g., enhancers. However, enhancer variants predisposing to hepatocellular carcinoma (HCC) remain unreported. Here we conduct a ...genome-wide survey of HCC-susceptible enhancer variants through a three-stage association study in 11,958 individuals and identify rs73613962 (T > G) within the intronic region of PRMT7 at 16q22.1 as a susceptibility locus of HCC (OR = 1.41, P = 6.02 × 10
). An enhancer dual-luciferase assay indicates that the rs73613962-harboring region has allele-specific enhancer activity. CRISPR-Cas9/dCas9 experiments further support the enhancer activity of this region to regulate PRMT7 expression. Mechanistically, transcription factor HNF4A binds to this enhancer region, with preference to the risk allele G, to promote PRMT7 expression. PRMT7 upregulation contributes to in vitro, in vivo, and clinical HCC-associated phenotypes, possibly by affecting the p53 signaling pathway. This concept of HCC pathogenesis may open a promising window for HCC prevention/treatment.
RNA-binding proteins play key roles in the posttranscriptional regulation of mRNA during cancer progression. Here, we show that RNA-binding motif protein 43 (RBM43) is significantly downregulated in ...human tumors, and its low expression is correlated with poor prognosis in patients with HCC. Overexpression of RBM43 suppressed cell proliferation in culture and resulted in the growth arrest of tumor xenografts, whereas downregulating RBM43 played an opposite role. We have also demonstrated that overexpression or knockdown of RBM43 affects the cell-cycle progression of liver cancer cells. Mechanistically, RBM43 directly associated with the 3'UTR of Cyclin B1 mRNA and regulated its expression. Moreover, loss of Rbm43 in mice promoted liver carcinogenesis and HCC development after diethylnitrosamine (DEN)-carbon tetrachloride (CCl
) treatment. Taken together, our data indicate that RBM43 is a tumor suppressor that controls the cell cycle through modulation of Cyclin B1 expression, providing evidence that RBM43 is particularly important in HCC.
Aurora-A is a serine/threonine kinase, which is overexpressed in multiple human cancers and plays a key role in tumorigenesis and tumor development. In this study, we found that the receptor of ...activated C-kinase1 (RACK1), an important regulator of biological functions, interacted with Aurora-A and co-localized with Aurora-A at centrosomes. Moreover, RACK1 induces the auto-phosphorylation of Aurora-A in vitro and in vivo. Depletion of RACK1 impaired the activation of Aurora-A in late G2 phase, then inhibited the mitotic entry and leaded to multi-polarity, severe chromosome alignment defects, or centrosome amplification. Taken together, these results suggest that RACK1 is a new partner of Aurora-A and play a critical role in the regulation of the Aurora-A activity during mitosis, which may provide a basis for future anticancer studies targeting Aurora-A.
PARP12 is a mono-ADP-ribosyltransferase, but its function remains largely unknown. Here, we identified four-and-a-half LIM-only protein 2 (FHL2) as a functional partner of PARP12 through protein ...affinity purification. Although PARP12 did not mono-ADP-ribosylate FHL2 in vitro and in vivo, PARP12 deficiency decreased the protein level of FHL2 by promoting its ubiquitination and increased the expression level of transforming growth factor beta1 (TGF-β1), which is independent of PARP12 enzymatic activity. We also provided evidence that PARP12 deficiency increased the migration and invasion of hepatocellular carcinoma (HCC) cells and promoted HCC metastasis in vivo by regulating the epithelial-mesenchymal transition process. These results indicated that PARP12 is a tumor suppressor that plays an important role in HCC metastasis through the regulation of FHL2 stability and TGF-β1 expression.
Alpha-fetoprotein (AFP) is one of the most commonly used and reliable biomarkers for Hepatocellular carcinoma（HCC). However, the underlying mechanism of AFP expression in HCC is poorly understood. In ...this study, we found that TCP10L, a gene specifically expressed in the liver, is down-regulated in HCC and that its expression inversely correlates with AFP expression. Moreover, overexpression of TCP10L suppresses AFP expression whereas knockdown of TCP10L increases AFP ex-pression, suggesting that TCP10L might be a negative regulator of AFP. We found that TCP10L is associated with the AFP promoter and inhibits AFP promoter-driven transcriptional acti-vity. Taken together, these results indicate that TCP10L nega-tively regulates AFP expression in HCC and that it could be a potential prognostic marker and therapeutic target for HCC.
Preeclampsia is a pregnancy disorder that seriously affects the outcome of mothers and infants and lacks effective prediction and diagnosis methods. ELABELA is the second endogenous ligand of the ...apelin receptor (APJ) and is associated with the pathogenesis of preeclampsia. In a previous study, the authors found that the downregulation of ELABELA expression is closely related to late-onset preeclampsia, which may be a marker for the clinical diagnosis of late-onset preeclampsia. In this study, the authors again collected 120 maternal blood samples, including 60 pregnant women with a medical diagnosis of late-onset preeclampsia. ELISA results showed that the serum ELABELA concentration in late-onset preeclampsia pregnant women (12.57 ± 7.77 ng/mL) was significantly lower than that in normal pregnant women (36.99 ± 23.58 ng/mL), which was consistent with previously reported results. Therefore, the authors used an ELABELA monoclonal antibody to label four colloidal gold nanoparticles with different diameters (15, 30, 55, and 150 nm) and developed a transverse-flow immunochromatographic band for the rapid and accurate detection of serum ELABELA levels. The strip test shows that colloidal gold with a diameter of 30 nm can be used as a good ELABELA detection marker and had more than 90% positive detection effect. Therefore, the authors hope that the colloidal gold strip with ELABELA as the diagnostic index developed by us will be popularized and applied in clinical diagnosis.
Alpha-fetoprotein (AFP) is one of the most commonly used and reliable biomarkers for Hepatocellular carcinoma（HCC). However, the underlying mechanism of AFP expression in HCC is poorly understood. In ...this study, we found that TCP10L, a gene specifically expressed in the liver, is down-regulated in HCC and that its expression inversely correlates with AFP expression. Moreover, overexpression of TCP10L suppresses AFP expression whereas knockdown of TCP10L increases AFP expression, suggesting that TCP10L might be a negative regulator of AFP. We found that TCP10L is associated with the AFP promoter and inhibits AFP promoter-driven transcriptional activity. Taken together, these results indicate that TCP10L negatively regulates AFP expression in HCC and that it could be a potential prognostic marker and therapeutic target for HCC. BMB Reports 2020; 53(8): 431-436
Activation of β‐catenin, the central effector of the canonical wingless‐type (Wnt) pathway, has been implicated in hepatocellular carcinoma (HCC). However, the transcription regulation mechanism of ...the β‐catenin gene in HCC remains unknown. Here we report that human zinc finger protein 191 (ZNF191) is a potential regulator of β‐catenin transcription. ZNF191, a Krüppel‐like protein, specifically interacts with the TCAT motif, which constitutes the HUMTH01 microsatellite in the tyrosine hydroxylase (TH) gene ex vivo. We demonstrate that ZNF191 is significantly overexpressed in human HCC specimens and is associated with growth of human HCC cells. Global profiling of gene expression in ZNF191 knockdown human hepatic L02 cells revealed that the important Wnt signal pathway genes β‐catenin and cyclin D1 messenger RNAs (mRNAs) are significantly down‐regulated. In agreement with transcription level, β‐catenin and cyclin D1 proteins are also down‐regulated in transient and stable ZNF191 knockdown L02 and hepatoma Hep3B cell lines. Moreover, significant correlation between ZNF191 and β‐catenin mRNA expression was detected in human HCCs. Promoter luciferase assay indicated that ZNF191 can increase transcription activity of the full‐length β‐catenin (CTNNB1) promoter, and nucleotide (nt)‐1407/‐907 of the CTNNB1 promoter exhibited the maximum transcriptional activity. Electrophoretic mobility shift assay showed that purified ZNF191 protein can directly bind to the CTNNB1 promoter, and the binding region is located at nt‐1254/‐1224. Finally, we demonstrate that the key binding sequence of ZNF191 in vivo is ATTAATT. Conclusion: ZNF191 can directly bind to the CTNNB1 promoter and activate the expression of β‐catenin and its downstream target genes such as cyclin D1 in hepatoma cell lines. This study uncovers a new molecular mechanism of transcription regulation of the β‐catenin gene in HCC. (HEPATOLOGY 2012;55:1830–1839)
The COVID-19 pandemic has led to public health problems, including depression. There has been a significant increase in research on depression during the COVID-19 pandemic. However, little attention ...has been paid to the overall trend in this field based on bibliometric analyses.
Co-Occurrence (COOC) and VOSviewer bibliometric methods were utilized to analyze depression in COVID-19 literature in the core collection of the Web of Science (WOS). The overall characteristics of depression during COVID-19 were summarized by analyzing the number of published studies, keywords, institutions, and countries.
A total of 9,694 English original research articles and reviews on depression during COVID-19 were included in this study. The United States, China, and the United Kingdom were the countries with the largest number of publications and had close cooperation with each other. Research institutions in each country were dominated by universities, with the University of Toronto being the most productive institution in the world. The most frequently published author was Ligang Zhang. Visualization analysis showed that influencing factors, adverse effects, and coping strategies were hotspots for research.
The results shed light on the burgeoning research on depression during COVID-19, particularly the relationship between depression and public health. In addition, future research on depression during COVID-19 should focus more on special groups and those at potential risk of depression in the general population, use more quantitative and qualitative studies combined with more attention to scale updates, and conduct longitudinal follow-ups of the outcomes of interventions. In conclusion, this study contributes to a more comprehensive view of the development of depression during COVID-19 and suggests a theoretical basis for future research on public health.
Objective: The murine double minute 2 gene encodes a negative regulator of the tumor protein p53. A single nucleotide polymorphism in murine double minute 2 promoter, SNP309 T>G, has been reported ...to alter murine double minute 2 protein expression and to accelerate tumor formation in humans. We carried out a meta‐analysis to explore the association between this polymorphism and prostate cancer risk.
Methods: All eligible studies were searched in PubMed. Crude odds ratios, with 95% confidence intervals, were assessed for the association using fixed‐ and random‐effects models.
Results: Overall, five case–control studies (872 cases, 1005 controls) were included in the meta‐analysis. A significant association between murine double minute 2 SNP309 and prostate cancer risk was observed for homozygote genetic model GG versus TT (odds ratio 0.72, 95% confidence interval 0.55–0.95, P < 0.05, P = 0.130 for heterogeneity), and for dominant model TG + GG versus TT (odds ratio 0.79, 95% confidence interval 0.65–0.96, P < 0.05, P = 0.119 for heterogeneity). The stratified analysis based on ethnicity showed a significant effect of the polymorphism on prostate cancer risk in Caucasians for GG versus TT.
Conclusions: Findings of the present meta‐analysis suggest that the murine double minute 2 309 G allele might be associated with a reduced risk of prostate cancer. The effect of murine double minute 2 309 G allele on tumorigenesis might be influenced by sex and hormonal status.
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