Upregulation of hsa-miR-141-3p promotes uterine cervical carcinoma progression via targeting dual-specificity protein phosphatase 1.

We aimed to explore the aberrant expression status of hsa-miR-141-3p and dual-specificity protein phosphatase 1 (DUSP1) and their relative mechanisms in uterine cervical carcinoma (UCC).Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was conducted to detect the expression of hsa-miR-141-3p. Immunohistochemical (IHC) staining was performed to examine the expression of DUSP1 in UCC. Gene chips and RNA-seq datasets were also obtained to assess the expression level. Integrated standardized mean difference (SMD) was calculated to evaluate the expression status of hsa-miR-141-3p in UCC tissues comprehensively. DUSP1-overexpression and hsa-miR-141-3p-inhibition HeLa cells were established, and CCK-8, transwell, wound healing, cell cycle, and apoptosis assays were implemented. The targets of hsa-miR-141-3p were obtained with online tools, and the combination of hsa-miR-141-3p and DUSP1 was validated via dual-luciferase reporter assay. Single-cell RNA-seq data were analyzed to explore hsa-miR-141-3p and DUSP1 in different cells. An integrated SMD of 1.41 (95% CI[0.45, 2.38], p = 0.0041) with 558 samples revealed the overexpression of hsa-miR-141-3p in UCC tissues. And the pooled SMD of -1.06 (95% CI[-1.45, -0.66], p < 0.0001) with 1,268 samples indicated the downregulation of DUSP1. Inhibition of hsa-miR-141-3p could upregulate DUSP1 expression and suppress invasiveness and metastasis of HeLa cells. Overexpression of DUSP1 could hamper proliferation, invasion, and migration and boost apoptosis and distribution of G1 phase. The dual-luciferase reporter assay validated the combination of hsa-miR-141-3p and DUSP1. Moreover, the targets of hsa-miR-141-3p were mainly enriched in the MAPK signaling pathway and activated in fibroblasts and endothelial cells. The current study illustrated the upregulation of hsa-miR-141-3p and the downregulation of DUSP1 in UCC tissues. Hsa-miR-141-3p could promote UCC progression by targeting DUSP1.

Increased LACTB2 Expression Regulates Oxidative Phosphorylation and mTORC1 Signaling of Colorectal Cancer.

This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired from UCSC Xena, GTEx, Gene Expression Omnibus, and TCGA. Pooled analysis of the mRNA expression of LACTB2 in CRC was performed using Stata software. The protein expression of LACTB2 in CRC tissues was evaluated by immunohistochemistry. The relationship between immune cell infiltration and LACTB2 expression was investigated using CIBERSORT. The potential signaling pathways and biological mechanisms of LACTB2 were explored using GSEA, KEGG, and GO. Subsequently, further screening of small molecular compounds with potential therapeutic effects on CRC was conducted through the HERB database, followed by molecular docking studies of these compounds with the LACTB2 protein. The integration and analysis of expression data obtained from 2294 CRC samples and 1286 noncancerous colorectal samples showed that LACTB2 was highly expressed in CRC. Immunohistochemistry performed on in-house tissue samples confirmed that LACTB2 protein expression was upregulated in CRC. CIBERSORT revealed lower B cell infiltration levels in the high LACTB2 expression group than in the low expression group. GO, KEGG, and GSEA analyses showed that LACTB2 expression and genes positively correlating with it were mainly related to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tumor progression.

AZGP1 Up-Regulation is a Potential Target for Andrographolide Reversing Radioresistance of Colorectal Cancer.

Background: Radiation resistance is a challenge that limits the therapeutic benefit of colorectal cancer (CRC) treatment, but the mechanism underlying CRC radiation resistance remains unclear. Andrographolide shows a broad-spectrum anti-tumor effect in various malignancies, including CRC, its effect and how it functions in CRC initiation, and radiation have not been established. This study aimed to explore the mechanism of CRC radiation resistance and the potential mechanisms of andrographolide on CRC radiation. Methods: Two acquired radioresistant cell lines were established and high throughput sequencing was employed to screen out the differentially expressed genes. The expression of AZGP1, which was upregulated in the acquired radioresistant tissues, was verified by microarray data recomputing. The common targets of andrographolide, CRC initiation, and radiation resistance were obtained, and the corresponding functional enrichment and pathway analysis were performed. The interaction between AZGP1 and andrographolide was investigated using molecular docking. Results: AZGP1 was upregulated in both the radioresistant cell model and microarray data. Moreover, AZGP1 was upregulated in cancerous colorectal tissue and displayed a tendency toward elevated expression in patients with an unfavorable prognosis. AZGP1 was identified as the common target of andrographolide, colorectal cancer initiation, and radiotherapy resistance. Ultimately, the protein structure of AZGP1 proved to be closely intertwined with the crystal texture of andrographolide. Conclusion: AZGP1 is recognized as a crucial factor for both CRC initiation and radioresistance. Andrographolide may affect the radioresistance of CRC via the targeting of AZGP1. Thus, the combination of andrographolide and AZGP1 intervention might be a promising strategy for improving the treatment benefit of CRC radiotherapy.

Upregulation of the transmembrane protease serine 3 mRNA level in radioresistant colorectal cancer tissues.

Aim: To investigate the clinical role of transmembrane protease serine 3 (TMPRSS3) in radioresistance and prognosis of colorectal cancer (CRC). Methods: Standardized mean difference (SMD) and summary area under the curve (AUC) of TMPRSS3 were calculated by combining all available high-throughput data globally. The prognostic significance of TMPRSS3 was determined by Kaplan-Meier and Cox regression analyses. Results:TMPRSS3 was remarkably upregulated in 198 CRC radioresistant cases compared with nonradioresistance (SMD = 0.38, AUC = 0.71). Overexpression of TMPRSS3 was observed in 1601 CRC patients compared with control subjects without CRC. TMPRSS3 was a risk factor for disease-free survival of CRC with the summarized hazard ratio 1.28. Conclusion: TMPRSS3 contributes to the radioresistance and unfavorable prognosis of CRC.

Clinical significance and molecular mechanism of angiotensin-converting enzyme 2 in hepatocellular carcinoma tissues.

During the pandemic of the coronavirus disease 2019, there exist quite a few studies on angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 infection, while little is known about ACE2 in hepatocellular carcinoma (HCC). The detailed mechanism among ACE2 and HCC still remains unclear, which needs to be further investigated. In the current study with a total of 6,926 samples, ACE2 expression was downregulated in HCC compared with non-HCC samples (standardized mean difference = -0.41). With the area under the curve of summary receiver operating characteristic = 0.82, ACE2 expression showed a better ability to differentiate HCC from non-HCC. The mRNA expression of ACE2 was related to the age, alpha-fetoprotein levels and cirrhosis of HCC patients, and it was identified as a protected factor for HCC patients via Kaplan-Meier survival, Cox regression analyses. The potential molecular mechanism of ACE2 may be relevant to catabolic and cell division. In all, decreasing ACE2 expression can be seen in HCC, and its protective role for HCC patients and underlying mechanisms were explored in the study.

Active Enhancer Assessment by H3K27ac ChIP-seq Reveals Claudin-1 as a Biomarker for Radiation Resistance in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) represents the third most common malignant tumor in the worldwide. Radiotherapy is the common therapeutic treatment for CRC, but radiation resistance is often encountered. ChIP-seq of Histone H3K27 acetylation (H3K27ac) has revealed enhancers that play an important role in CRC. This study examined the relationship between an active CRC enhancer and claudin-1 (CLDN1), and its effect on CRC radiation resistance. METHODS: The target CRC genes of active enhancers were obtained from public H3K27ac ChIP-seq, and the genes highly expressed in radio-resistant CRC were screened and intersected with enhancer-driven genes. The clinical roles of CLDN1 in radiation resistance were examined using the t-test, standard mean deviation (SMD), summary receiver operating characteristic curve and Kaplan-Meier curves. The co-expressed genes of CLDN1 were calculated using Pearson Correlation analysis, and Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes and Gene Set Variation Analysis (GSVA) analyses were used to examine the molecular mechanisms of CLDN1. RESULTS: Total 13 703 CRC genes were regulated by enhancers using 58 H3K27ac ChIP-seq. Claudin-1 (CLDN1) was enhancer-driven and notably up-regulated in CRC tissues compared to non-CRC controls, with a SMD of 3.45 (95 CI % = .56-4.35). CLDN1 expression was increased in radiation-resistant CRC with a SMD of .42 (95% CI = .16-.68) and an area under the curve of .74 (95% CI = .70-.77). The cell cycle and immune macrophage levels were the most significant pathways associated with CLDN1. CONCLUSION: CLDN1 as an enhancer-regulated gene that can boost radiation resistance in patients with CRC.