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2022 ◽  
Vol 11 ◽  
Author(s):  
Xiaoxi Ouyang ◽  
Longxian Lv ◽  
Yalei Zhao ◽  
Fen Zhang ◽  
Qingqing Hu ◽  
...  

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high morbidity and mortality. Therefore, it is very important to find potential biomarkers that can effectively predict the prognosis and progression of HCC. Recent studies have shown that anti-silencing function 1B (ASF1B) may be a new proliferative marker for tumor diagnosis and prognosis. However, the expression and function of ASF1B in hepatocellular carcinoma remain to be determined. In this study, integrated analysis of the Cancer Genome Atlas (TCGA), genotypic tissue expression (GTEx), and Gene Expression Omnibus (GEO) databases revealed that ASF1B was highly expressed in HCC. Kaplan-Meier survival curve showed that elevated ASF1B expression was associated with poor survival in patients with liver cancer. Correlation analysis of immune infiltration suggested that ASF1B expression was significantly correlated with immune cell infiltration in HCC patients. Gene set enrichment analysis (GSEA) indicated that ASF1B regulated the cell cycle, DNA Replication and oocyte meiosis signaling. Our experiments confirmed that ASF1B was highly expressed in HCC tissues and HCC cell lines. Silence of ASF1B inhibited hepatocellular carcinoma cell growth in vitro. Furthermore, ASF1B deficiency induced apoptosis and cell cycle arrest. Mechanistically, ASF1B knockdown reduced the expression of proliferating cell nuclear antigen (PCNA), cyclinB1, cyclinE2 and CDK9.Moreover, ASF1B interacted with CDK9 in HCC cells. Taken together, these results suggest that the oncogenic gene ASF1B could be a target for inhibiting hepatocellular carcinoma cell growth.


2022 ◽  
Author(s):  
Singothu Siva Nagendra Babu ◽  
Shivani Singla ◽  
G. B. Jena

Abstract Colitis-associated colorectal cancer serves as a prototype of inflammation-associated cancers which is linked with repeated cycles of inflammation and DNA repair deficits. Several preclinical and clinical data reported that aspirin has chemo preventive effect in colorectal cancer and is associated with dose dependent side effects. Further, it has been reported that zinc supplementation improves the quality of life in patients undergoing chemotherapy by alteration of colonic cancer cell gene expression. However, explication of the detailed molecular mechanisms involved in combined administration of aspirin and zinc mediated protection against the colitis associated colorectal cancer deserves further investigation. For the induction of colitis associated colorectal cancer, male BALB/c mice were administered 1, 2-dimethylhydrazine dihydrochloride (DMH) 20 mg/kg/bw thrice, before the initiation of every DSS cycle (3%w/v in drinking water). One week after the initiation of DSS treatment, aspirin (40 mg/kg; p.o.) and zinc in the form of zinc sulphate (3 mg/kg; p.o.) was administered for 8 weeks. Combination of aspirin and zinc as intervention significantly ameliorated DAI score, myeloperoxidase activity, histological score, apoptotic cells and protein expression of various inflammatory markers including nuclear factor kappa light chain enhancer of activated B cells (NFκBp65), cycloxygenase -2 (COX-2), interleukin-6 (IL-6); proliferation markers such as proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription 3 (STAT3) expression significantly decreased and antioxidant enzymes nuclear factor erythroid 2–related factor 2 (Nrf-2), metallothionein, catalase and superoxide dismutase (SOD) significantly increased as evaluated by immunohistochemistry and western blot analysis.


Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 289
Author(s):  
Giovanni Luca Gravina ◽  
Alessandro Colapietro ◽  
Andrea Mancini ◽  
Alessandra Rossetti ◽  
Stefano Martellucci ◽  
...  

Cell proliferation requires the orchestrated actions of a myriad of proteins regulating DNA replication, DNA repair and damage tolerance, and cell cycle. Proliferating cell nuclear antigen (PCNA) is a master regulator which interacts with multiple proteins functioning in these processes, and this makes PCNA an attractive target in anticancer therapies. Here, we show that a cell-penetrating peptide containing the AlkB homolog 2 PCNA-interacting motif (APIM), ATX-101, has antitumor activity in a panel of human glioblastoma multiforme (GBM) cell lines and patient-derived glioma-initiating cells (GICs). Their sensitivity to ATX-101 was not related to cellular levels of PCNA, or p53, PTEN, or MGMT status. However, ATX-101 reduced Akt/mTOR and DNA-PKcs signaling, and a correlation between high Akt activation and sensitivity for ATX-101 was found. ATX-101 increased the levels of γH2AX, DNA fragmentation, and apoptosis when combined with radiotherapy (RT). In line with the in vitro results, ATX-101 strongly reduced tumor growth in two subcutaneous xenografts and two orthotopic GBM models, both as a single agent and in combination with RT. The ability of ATX-101 to sensitize cells to RT is promising for further development of this compound for use in GBM.


2022 ◽  
Vol 12 ◽  
Author(s):  
Chunhong Di ◽  
Guoxia Zheng ◽  
Yunheng Zhang ◽  
Enyu Tong ◽  
Yanli Ren ◽  
...  

The recombination signal binding protein for immunoglobulin kappa J region (RBPJ) has a dual effect on Kaposi’s sarcoma-associated herpesvirus (KSHV) replication. RBPJ interaction with replication and transcription activator (RTA) is essential for lytic replication, while the interaction with latency-associated nuclear antigen (LANA) facilitates latent infection. Furthermore, our previous study found that LANA decreased RBPJ through upregulating miRNA let-7a. However, it is unclear whether RTA regulates the expression of RBPJ. Here, we show RTA increases RBPJ by decreasing let-7a. During KSHV replication, the RBPJ expression level was positively correlated with the RTA expression level and negatively correlated with the LANA expression level. The let-7a expression level was inverse to RBPJ. Knockdown of RBPJ inhibited the self-activation of RTA promoter and LANA promoter and weakened LANA’s inhibition of RTA promoter. Collectively, these findings indicate that RTA and LANA compete for let-7a/RBPJ signal to control the KSHV replication. Regulating the RBPJ expression level by RTA and LANA plays an important role during KSHV replication.


2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Fei Ke ◽  
Xue-Dong Yu ◽  
Zi-Hao Wang ◽  
Jian-Fang Gui ◽  
Qi-Ya Zhang

Abstract Background Ranaviruses (family Iridoviridae) are promiscuous pathogens that can infect across species barriers in poikilotherms and can replicate in amphibian and fish cells and even in cultured mammalian cells. However, as nucleocytoplasmic large DNA viruses (NCLDVs), their replication and transcription mechanisms remain largely unknown. Here, we screened and uncovered the replication and transcription machinery of two ranaviruses, Andrias davidianus ranavirus (ADRV) and Rana grylio virus (RGV), by a combination of methods, including the isolation of proteins on nascent DNA, recombinant virus-based affinity, and NanoLuc complementation assay. Results The ranavirus replication and transcription machinery was deeply dissected and identified as a complicated apparatus containing at least 30 viral and 6 host proteins. The viral proteins ADRV-47L/RGV-63R (DNA polymerase, vDPOL), ADRV-23L/RGV-91R (proliferating cell nuclear antigen, vPCNA), ADRV-85L/RGV-27R (single-stranded DNA binding protein, vSSB), ADRV-88L/RGV-24R (vhelicase/primase), etc., constitute the core replisome. Specifically, the core of the transcription complex, the viral RNA polymerase, contain the host RNAPII subunits Rpb3, Rpb6, and Rpb11, which was a first report in NCLDVs. Furthermore, correlations and interactions among these factors in the machinery were described. Significantly, the replisome core protein vDPOL (ADRV-47L) can interact with numerous viral and host proteins and could act as a linker and regulation center in viral DNA replication and transcription. Thus, these results depicted an architecture for ranavirus replication and transcription. Conclusions Up to 36 components from ranavirus and their host were found to form viral replisomes and transcription complexes using a series of precise methods, which further constructed an architecture for ranavirus replication and transcription in which vDPOL was a key central factor and various components correlated and cooperated. Therefore, it provides a cornerstone for further understanding the mechanisms of the replication and transcription of ranaviruses which can ensure the efficient production of progeny virus and adaptation to cross-species infection.


2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Zhiliang Chen ◽  
Tony C. H. Chow ◽  
Shicong Wang ◽  
Gigi C. T. Leung ◽  
Sharon L. Y. Wu ◽  
...  

Background. Alcoholism is known to cause liver toxicity and is extensively researched. On the other hand, stress, depression, and obesity are interrelated conditions with alcoholism, and their medications would affect the liver itself. In this study, we investigated the effects of the drugs fluoxetine and atorvastatin on the liver and compared with those of alcohol in a mouse model. Methods. Comparisons of animals treated with the three drugs were carried out: serum aspartate transaminase (AST), alanine transaminase (ALT), and albumin were measured; liver tumor necrosis factor alpha (TNF alpha) and transforming growth factor beta (TGF beta-1) levels were evaluated; proliferative cells were detected via immunohistochemistry (IHC) targeting on proliferating cell nuclear antigen (PCNA) and minichromosome maintenance complex component 2 (MCM2); for apoptosis, IHC targeting on activated caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were employed; and histopathology was also documented in all groups. Results. For ALT, AST, albumin, and liver TNF alpha, only the ethanol group surged to significantly higher levels. For TGF beta-1, both ethanol and atorvastatin groups reached a significantly higher level. PCNA and MCM2 showed increased proliferation in the livers of all three groups, with the ethanol group having the highest number of positive cells followed by atorvastatin and then the fluoxetine group. As for cell death, both ethanol and fluoxetine groups showed significantly more apoptosis than control in TUNEL and activated caspase-3, while in the atorvastatin group, activated caspase-3 positive cells increased significantly, but the increase in TUNEL-positive cells did not reach statistical significance.


2021 ◽  
Vol 9 ◽  
Author(s):  
Haibao Zhang ◽  
Shan Xu ◽  
Dalin He ◽  
Xinyang Wang ◽  
Guodong Zhu

Objectives: Sonic hedgehog (SHH) signaling is important in bladder development. Mice with defective hedgehog signaling develop bladder anomalies. Clinically, urinary tract malformations are reported in human fetuses and infants with mutations of SHH and related signaling pathway genes. Information on the expression of SHH and associated signaling genes in normal human bladder development is fragmentary. This study determined the temporal and spatial expression patterns of SHH signaling pathway components in human fetal bladders by immunohistochemistry (IHC).Material and Methods: Twenty-four bladder specimens from 16 male and 8 female human fetuses aged 12- to 36-week (wk) were obtained from the First Affiliated Hospital of Xi'an Jiaotong University. The tissue slides were processed for IHC staining with SHH, Patched1 (PTC-1), Patched2 (PTC-2), Smoothened (SMO), GLI1 and proliferating cell nuclear antigen (PCNA). The expression levels of each gene were analyzed by semi-quantitative histological scoring system.Results: High intensity of SHH and SMO expression was detected in developing bladder urothelial cells, with no staining in lamina propria (LP), but with minimal expression of SMO in differentiating smooth muscle (SM) layers. The spatial distribution pattern of PTC1 and GLI1 was more complex with minimal expression in the LP layer, moderate expression in the SM layer, and high expression in the urothelium. PTC2 expression was mainly localized in the urothelium and LP, but no expression in the SM layer. All of the SHH signaling components were detected in fetal bladder tissues throughout the development, with expression peaks at 12- and 23-wk, coinciding with high cell proliferation as indicated by PCNA staining in the cell nuclei of urothelium and SM.Conclusions: The autocrine SHH signaling in the developing urothelium, and paracrine SHH signaling in the developing smooth muscle layer, mediated by SMO, PTC-1 and GLI1 were demonstrated during human bladder development. Expression of SHH signaling components peaked at 12-and 23-wk. The first expression peak at 12-wk may relate to urothelium growth, SM induction, and dilation of the bladder cavity. The second expression peaked at 23-wk may relate to urothelium and SM layer differentiation.


2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Zeng-Qiao Zhang ◽  
Xiao-Shen Hu ◽  
Ye-Chen Lu ◽  
Jun-Peng Zhang ◽  
Wen-Yao Li ◽  
...  

Objective. We evaluated the effects and mechanisms of GDC0623 on osteogenic differentiation of osteoblasts induced by IL-1β. Methodology. Osteoblasts were treated with 20 ng/ml IL-1β and 0.1 µM GDC0623. Cell proliferation levels were evaluated by the cell counting kit 8 (CCK8), EdU assay, and western blotting [proliferating cell nuclear antigen (PCNA) and Cyclin D1]. Osteoblasts were cultured in an osteogenic induction medium for 1–3 weeks after which their differentiations were assessed by alkaline phosphatase (ALP) staining, Alizarin Red staining, calcium concentration, immunocytochemistry staining, real-time quantitative PCR (RT-qPCR), and immunofluorescence staining. The osteogenesis-associated mechanisms were further evaluated by western blotting using appropriate antibodies. Results. Relative to the control group, IL-1β induced the rapid proliferation of osteoblasts and suppressed their osteogenic differentiations by upregulating the activities of MEK-Erk1/2 as well as Jak-Stat3 pathways and by elevating MMP13 and MMP9 levels. However, blocking of the MEK-Erk1/2 signaling pathway by GDC0623 treatment reversed these effects. Conclusion. Inhibition of Jak-Stat3 pathway by C188-9 downregulated the expression levels of MMP9 and MMP13, activated MEK-Erk1/2 pathway, and inhibited osteogenic differentiation.


Author(s):  
Alvaro Lucci ◽  
Marina C Vera ◽  
Carla G Comanzo ◽  
Florencia Lorenzetti ◽  
Anabela C Ferretti ◽  
...  

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared to single therapies. Combining δ-tocotrienol and IFN α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinases MMP-7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and ROS generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anticancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN α therapy showed promising results for HCC cells treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.


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