Critical Reviews in Eukaryotic Gene Expression最新文献

As an autophagy inhibitor, chloroquine (CQ) showed anti-tumor effect on several types of cancer and paclitaxel (PTX) is widely used in the treatment of esophageal carcinoma patients, but chemoresistance remains a major hurdle for PTX application due to the cytoprotective autophagy. Therefore, the aim of this study was to investigate whether CQ could elevate the anti-tumor effect of PTX on esophageal carcinoma cell line EC109 and explore the potential molecular mechanisms. We confirmed the suppressive effect of PTX on EC109 by MTT, scratch test, transwell and soft agar assay. And, we detected the key proteins in Akt/mTOR pathway, as well as the autophagy marker LC3 and p62 through Western Blot. In addition, GFP-LC3 plasmid was transfected into EC109 cells to monitor the autophagosome after CQ and PTX treatment. Ultimately, we observed the alterations in the proliferation and colony formation abilities of EC109 after knocking down mTOR by shRNA. We confirmed PTX could suppress the proliferation, migration and colony formation (all P < 0.05) abilities of EC109, and CQ could sensitize the inhibition effect of PTX by inhibiting autophagy through Akt/mTOR pathway. Furthermore, inhibiting Akt/mTOR pathway initiated autophagy and enhanced the sensitivity of EC109 to CQ and PTX. In summary, we suggest CQ could be used as a potential chemosensitizer for PTX in esophageal carcinoma treatment.

The objective of this study was to determine the regulatory mechanism of MAGI2-AS3 in clear cell renal cell carcinoma (ccRCC), thereby supplying a new insight for ccRCC treatment. Expression data in TCGA-KIRC were obtained. Target gene lncRNA for research was determined using expression analysis and clinical analysis. lncRNA's downstream regulatory miRNA and mRNA were predicted by bioinformatics databases. ccRCC cell malignant phenotypes were detected via CCK-8, colony formation, Transwell migration, and invasion assays. The targeting relationship between genes was assessed through dual-luciferase reporter gene analysis. Kaplan-Meier (K-M) analysis was carried out to verify the effect of MAGI2-AS3, miR-629-5p, and PRDM16 on the survival rate of ccRCC patients. MAGI2-AS3 expression in ccRCC tissue and cells was shown to be markedly decreased and its expression to continuously decline with tumor progression. MAGI2-AS3 suppresses ccRCC proliferation and migration. Dual-luciferase assay showed that MAGI2-AS3 binds miR-629-5p and that miR-629-5p binds PRDM16. In addition, functional experiments showed that MAGI2-AS3 facilitates PRDM16 expression by repressing miR-629-5p expression, thereby suppressing ccRCC cell aggression. K-M analysis showed that upregulation of either MAGI2-AS3 or PRDM16 significantly improves ccRCC patient survival, while upregulation of miR-629-5p has no significant impact. MAGI2-AS3 sponges miR-629-5p to modulate PRDM16 to mediate ccRCC development. Meanwhile, the MAGI2-AS3/miR-629-5p/PRDM16 axis, as a regulatory pathway of ccRCC progression, may be a possible therapeutic target and prognostic indicator of ccRCC.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult to treat of all malignancies. Multimodality regimens provide only short-term symptomatic improvement with minor impact on survival, underscoring the urgent need for novel therapeutics and treatment strategies for PDAC. We screened out the highly expressed gene LAMC2 in PDAC tissues through the GEO online database, and further demonstrated that it is related to the poor prognosis of PDAC patients. Next, we investigated the effect of LAMC2 in the development and metastasis of PDAC by silencing LAMC2 expression in PDAC cells. The results showed that silencing of LAMC2 inhibited the proliferation, invasion and metastasis, and promoted apoptosis of PDAC cells, silencing of LAMC2 also reversed the epithelial mesenchymal transition (EMT) and suppressed the activation of NF-κB signaling pathway. Our results identify LAMC2 as a pivotal regulator of PDAC malignant progression, and its overexpression is sufficient to confer the characteristically aggressive clinical features of this disease.

Higher-order genomic organization supports the activation of histone genes in response to cell cycle regulatory cues that epigenetically mediates stringent control of transcription at the G1/S-phase transition. Histone locus bodies (HLBs) are dynamic, non-membranous, phase-separated nuclear domains where the regulatory machinery for histone gene expression is organized and assembled to support spatiotemporal epigenetic control of histone genes. HLBs provide molecular hubs that support synthesis and processing of DNA replication-dependent histone mRNAs. These regulatory microenvironments support long-range genomic interactions among non-contiguous histone genes within a single topologically associating domain (TAD). HLBs respond to activation of the cyclin E/CDK2/NPAT/HINFP pathway at the G1/S transition. HINFP and its coactivator NPAT form a complex within HLBs that controls histone mRNA transcription to support histone protein synthesis and packaging of newly replicated DNA. Loss of HINFP compromises H4 gene expression and chromatin formation, which may result in DNA damage and impede cell cycle progression. HLBs provide a paradigm for higher-order genomic organization of a subnuclear domain that executes an obligatory cell cycle-controlled function in response to cyclin E/CDK2 signaling. Understanding the coordinately and spatiotemporally organized regulatory programs in focally defined nuclear domains provides insight into molecular infrastructure for responsiveness to cell signaling pathways that mediate biological control of growth, differentiation phenotype, and are compromised in cancer.

Recurrent miscarriage (RM) is a frustrating and complex pregnancy disorder and long noncoding RNAs (lncRNAs) modulate susceptibility to RM. This study expounded on the role of specificity protein 1 (SP1) in functions of chorionic trophoblast and decidual cells via regulating lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1). Chorionic villus tissues and decidual tissues of RM patients and normal pregnant women were collected. Real-time quantitative polymerase chain reaction and Western blotting revealed that SP1 and NEAT1 were downregulated in trophoblast and decidual tissues of RM patients, and the Pearson correlation analysis detected that they were positively correlated in expression level. Chorionic trophoblast and decidual cells of RM patients were isolated and intervened by vectors over-expressing SP1 or NEAT1 siRNAs. Thereafter, the cell counting kit-8, Transwell, flow cytometry assays detected that SP1 overexpression accelerated trophoblast cell proliferation, invasion, and migration, meanwhile, enhancing decidual cell proliferation while repressed apoptosis. Next, the dual-luciferase and Chromatin immunoprecipitation assays showed that SP1 bound to the NEAT1 promoter region and further activated NEAT1 transcription. Silencing NEAT1 reversed the efforts of SP1 overexpression on the functions of trophoblast and decidual cells. Overall, SP1 activated NEAT1 transcription, accelerating trophoblast cell proliferation, invasion, and migration and mitigating decidual cell apoptosis.

TPP1, as one of the telomere-protective protein complex, functions to maintain telomere stability. In this study, we found that TPP1 was significantly upregulated in esophageal cancer (EC). We found that the proliferation and migration ability were significantly inhibited, while the results of flow cytometry assay indicated that the growth was hindered in the G1 phase after TPP1 knockdown. However, the proliferative viability and migratory ability were reversed after TPP1 overexpression in EC cells. Then, we found a significant increase in β-galactosidase positivity following TPP1 knockdown and the opposite following TPP1 overexpression in EC cells. Furthermore, TPP1 knockdown increased DNA damage and upregulated expression of the γ-H2AXS139 in the cell nucleus. Correspondingly, DNA damage was reversed after TPP1 overexpression in EC cells. Similarly, we found that the expression of ATM/ATR pathway proteins were upregulated after TPP1 knockdown, while the expression of the above proteins was downregulated after TPP1 overexpression in EC cells. TPP1 knockdown significantly inhibited the growth of transplanted tumors and upregulated the expression of ATM/ATR pathway proteins in transplanted tissues, whereas TPP1 overexpression significantly promoted their proliferation and downregulated the expression of the above proteins in vivo. Strikingly, we found that TPP1 could reduce the chemosensitivity of EC cells to cisplatin, which may have a potential link to clinical chemoresistance. In conclusion, TPP1 regulates the DNA damage response through the ATM/ATR-p53 signaling pathway and chemoresistance and may be a new target for improving the efficacy of chemotherapy in the treatment of EC.

Objective: To identify and evaluate the bioinformatics of microRNA (miRNA) biomarkers in triple-negative breast cancer.

Methods: The MDA-MB-231 cell line with stable and low expression of c-Myc was created, and the expression patterns of messenger RNA (mRNA) and miRNA were investigated by cluster analysis. The genes regulated by c-Myc were then screened by transcriptome sequencing and miRNA sequencing. The negative binomial distribution of the DESeq software package was used to test for and determine the differential expression of genes.

Results: In the c-Myc deletion group, 276 differently expressed mRNAs were screened out by transcriptome sequencing, of which 152 mRNAs were considerably upregulated and 124 were significantly downregulated in comparison to the control group. One-hundred-seventeen (117) differentially expressed miRNAs were found using miRNA sequencing, of which 47 showed a substantial upregulation and 70 a significant downregulation. According to the Miranda algorithm, 1803 mRNAs could be targeted by 117 differently expressed miRNAs. Comparing the two sets of data, a total of 5 miRNAs were differentially expressed after targeted binding with 21 mRNAs, which were subjected to GO and KEGG enrichment analysis. The genes regulated by c-Myc were mainly enriched in signaling pathways such as extracellular matrix receptors and Hippo.

Conclusion: Twenty-one target genes and five differential miRNAs in the mRNA-c-Myc-miRNA regulatory network are potential therapeutic targets for triple-negative breast cancer.

Osteosarcoma (OS) is the most representative primary bone tumour in children and teenagers. This study explored the regulatory effects of long noncoding RNA MIR503HG (MIR503HG) on the biological functions of OS cells, and further investigated the potential mechanism of MIR503HG function exertion by analyzing the microRNA-103a-3p (miR-103a-3p) in OS cells and tissues. The expression of MIR503HG was examined using reverse transcription-quantitative PCR. OS cell proliferation was assessed by CCK-8 assay. Transwell assay was used to evaluate the migration and invasion of OS cells. The interaction between MIR503HG and miR-103a-3p was detected using the Dual-luciferase reporter assay. Forty-six paired OS tissues were collected, and the expression and correlation of MIR503HG and miR-103a-3p were evaluated. The expression of MIR503HG were significantly decreased in both OS cells and tissues. Over-expression of MIR503HG inhibited OS cell proliferation, migration and invasion. miR-103a-3p was directly targeted by MIR503HG in OS cells, and mediated the inhibitory effects of MIR503HG on OS cell malignant behaviors. miR-103a-3p expression was upregulated in OS tissues, which was negatively correlated with MIR503HG expression levels. The expression of MIR503HG was associated with OS patients' tumor size, differentiation, distant metastasis and clinical stage. Decreased MIR503HG in OS tissues and cell lines served as a tumor suppressor by inhibiting OS cell malignant behaviors through sponging miR-103a-3p. The findings of this study may provide evidence for the development of novel therapeutic targets of OS.

Runt-related transcription factor 3 (RUNX3) plays a pivotal role in tumor microenvironment and immune infiltration. However, the prognostic and immunological roles of RUNX3 in pancancer remain unclear. In the current study, we explored the expression profiles, prognostic landscape, and immune infiltration of RUNX3 in pancancer through a variety of online platforms, including HPA, ONCOMINE, UALCAN, GEPIA, PrognoScan, TCGA, TIMER, R2, and Reactome databases. In general, RUNX3 was widely expressed in tonsil, gallbladder, skin, spleen, lymph node, and bone marrow, and RUNX3 was frequently higher expression in tumor tissues compared to normal tissues. In prognostic analysis, the RUNX3 expression level was significantly correlated with the clinical outcomes of bladder cancer, blood cancer, brain cancer, breast cancer, colorectal cancer, lung cancer, and ovarian cancer. In mutation analysis, a total 72 mutation sites were located within amino acids 1 to 415 of RUNX3, including 65 missense sites and seven truncating sites, whereas the mutation frequency of skin cutaneous melanoma and uterine corpus endometrial carcinoma (UCEC) is relatively high (> 3%). In immune infiltration analysis, the RUNX3 expression level was significantly related to recognized markers and the immune infiltration levels of various types of immune cells in colon adenocarcinoma (COAD) and brain lower grade glioma (LGG). After that, 453 RUNX3 co-expressed genes were recognized in COAD, lymphoid neoplasm diffuse large B-cell lymphoma, LGG, and ovarian serous cystadenocarcinoma (OV). Pathway enrichment analysis revealed that RUNX3 co-expressed genes were remarkably enriched in immune system and tumor progression pathways. RUNX3 expression is associated with clinical prognosis, immune infiltration, and identified RUNX3 related pathways in a variety of tumors, which may serve as targets of promising prognostic markers and novel therapeutic targets for various human cancers.