Upregulation of GOLPH3 mediated by Bisphenol a promotes colorectal cancer proliferation and migration: evidence based on integrated analysis.

Background: The interaction between environmental endocrine-disrupting chemicals, such as Bisphenol A (BPA), and their influence on cancer progression, particularly regarding the GOLPH3 gene in colorectal cancer, remains unclear. Methods: We performed an integrated analysis of transcriptional profiling, clinical data, and bioinformatics analyses utilizing data from the Comparative Toxicogenomics Database and The Cancer Genome Atlas. The study employed ClueGO, Gene Set Enrichment Analysis, and Gene Set Variation Analysis for functional enrichment analysis, alongside experimental assays to examine the effects of BPA exposure on colorectal cancer cell lines, focusing on GOLPH3 expression and its implications for cancer progression. Results: Our findings demonstrated that BPA exposure significantly promoted the progression of colorectal cancer by upregulating GOLPH3, which in turn enhanced the malignant phenotype of colorectal cancer cells. Comparative analysis revealed elevated GOLPH3 protein levels in cancerous tissues versus normal tissues, with single-cell analysis indicating widespread GOLPH3 presence across various cell types in the cancer microenvironment. GOLPH3 was also associated with multiple carcinogenic pathways, including the G2M checkpoint. Furthermore, our investigation into the colorectal cancer microenvironment and genomic mutation signature underscored the oncogenic potential of GOLPH3, exacerbated by BPA exposure. Conclusion: This study provides novel insights into the complex interactions between BPA exposure and GOLPH3 in the context of colorectal cancer, emphasizing the need for heightened awareness and measures to mitigate BPA exposure risks. Our findings advocate for further research to validate these observations in clinical and epidemiological settings and explore potential therapeutic targets within these pathways.

USP6 and circCYFIP2 target oncoprotein GOLPH3 for deubiquitination and induce platinum resistance in colon cancer.

GOLPH3 has been identified as an oncoprotein, playing a crucial role on progression and chemoresistancein of colon adenocarcinoma (COAD). However, it is still unclear the regulation of GOLPH3 expression at protein level. We discovered ubiquitin-specific proteases 6 (USP6) directly regulated the deubiquitination of the GOLPH3 protein and enhanced its stability in COAD. Overexpression of USP6 promoted COAD cell viability, inhibited apoptosis, and accelerated the growth of transplanted tumors growth in vitro and in vivo by deubiquitinating GOLPH3. Additionally, circCYFIP2 showed high expression levels in DDP-resistant colon cancer cells, promoting the cell proliferation. Mechanically, circCYFIP2 binds to both GOLPH3 protein and USP6, strengthening the interaction between GOLPH3 and USP6, and consequently induced DDP resistance in vitro and in vivo. In conclusion, USP6 operates as a deubiquitinase, targeting the GOLPH3 protein in COAD and enhancing its stability. Meanwhile, circCYFIP2 is crucial for the deubiquitination of GOLPH3 protein mediated by USP6 and acts as a scaffold to confer platinum resistance. The discovery of circCYFIP2/USP6/GOLPH3 pathway offers a potential target for overcoming chemoresistance in COAD.

CircMAPK9 promotes the progression of fibroblast-like synoviocytes in rheumatoid arthritis via the miR-140-3p/PPM1A axis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease, and fibroblast-like synoviocytes (FLSs) are key effector cells in RA development. Mounting evidence indicates that circular RNAs (circRNAs) participate in the occurrence and development of RA. However, the precise mechanism of circRNA mitogen-activated protein kinase (circMAPK9) in the cell processes of FLSs has not been reported. METHODS: The expression levels of circMAPK9, microRNA-140-3p (miR-140-3p), and protein phosphatase magnesium-dependent 1A (PPM1A) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assay. Cell proliferation was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell apoptosis and cycle distribution were assessed by flow cytometry. Cell migration and invasion were tested by transwell assay. All the proteins were inspected by western blot assay. Inflammatory response was evaluated by enzyme-linked immunosorbent assay (ELISA). The interaction between miR-140-3p and circMAPK9 or PPM1A was verified by dual-luciferase reporter assay. RESULTS: CircMAPK9 and PPM1A were upregulated and miR-140-3p was downregulated in RA patients and FLSs from RA patients (RA-FLSs). CircMAPK9 silence suppressed cell proliferation, migration, invasion, inflammatory response, and promoted apoptosis in RA-FLSs. MiR-140-3p was a target of circMAPK9, and miR-140-3p downregulation attenuated the effects of circMAPK9 knockdown on cell progression and inflammatory response in RA-FLSs. PPM1A was targeted by miR-140-3p, and circMAPK9 could regulate PPM1A expression by sponging miR-140-3p. Furthermore, miR-140-3p could impede cell biological behaviors in RA-FLSs via targeting PPM1A. CONCLUSION: CircMAPK9 knockdown might inhibit cell proliferation, migration, invasion, inflammatory response, and facilitate apoptosis in RA-FLSs via regulating miR-140-3p/PPM1A axis, offering a new mechanism for the comprehension of RA development and a new insight into the potential application of circMAPK9 in RA treatment.

[Predictive value of plasma cell-free DNA for prognosis of sepsis].

OBJECTIVE: To explore the predictive value of plasma cell-free DNA (cf-DNA) for prognosis in patients with sepsis. METHODS: 105 patients with sepsis admitted to department of emergency of the First Hospital of Quanzhou Affiliated to Fujian Medical University from June 2015 to June 2017 were enrolled. Patients were divided into sepsis group (n = 50) and severe sepsis group (n = 55). At the same time, 50 cases of physical examination center in our hospital were randomly selected as the healthy control group. The differences of cf-DNA, procalcitonin (PCT) and acute physiology and chronic health evaluation II (APACHE II) score among the three groups were compared. The correlation between cf-DNA and PCT or APACHE II were analyzed by Bivarite method. Logistic regression was used to analyze the independent predictors of sepsis. The receiver operating characteristic curve (ROC) was made to evaluate cf-DNA, PCT, APACHE II alone or combined ability to predict the prognosis of sepsis. RESULTS: The PCT, APACHE II and cf-DNA in the sepsis group and severe sepsis group were significantly higher than those in the healthy control group [PCT (µg/L): 5.80 (3.28, 8.85), 17.53 (8.40, 29.61) vs. 0.02 (0.01, 0.03); APACHE II: 13.04±3.03, 23.29±8.02 vs. 2.10±1.05; cf-DNA (µg/L): 1 438.0 (1 154.0, 1 576.0), 2 595.0 (2 162.0, 5 198.0) vs. 17.0 (13.0, 20.5); all P < 0.05], and the indicators in the severe sepsis group were further higher than the sepsis group (all P < 0.05). Correlation analysis showed that cf-DNA was significantly positive correlated with PCT [r = 0.675, 95% confidence interval (95%CI) = 0.575-0.766, P < 0.001] and APACHE II (r = 0.911, 95%CI = 0.874-0.939, P < 0.001). ROC curve analysis showed that the areas under ROC curve (AUC) of PCT, APACHE II, cf-DNA, PCT+APACHE II, cf-DNA+PCT, cf-DNA+APACHE II, cf-DNA+PCT+APACHE II to predict the prognosis of sepsis patients were 0.898, 0.905, 0.961, 0.941, 0.974, 0.976 and 0.982, respectively. It was shown that when predicted alone with PCT, APACHE II and cf-DNA, the AUC of cf-DNA was the largest (0.961), the sensitivity was 100%, and the specificity was 81.43%; the combined prediction of cf-DNA with PCT or APACHE II could further increase AUC, and the combined prediction of cf-DNA, PCT and APACHE II had the highest AUC (0.982), the sensitivity was 94.29%, the specificity was 98.57%. CONCLUSIONS: cf-DNA, PCT and APACHE II have certain predictive value for the prognosis of sepsis. The value of cf-DNA was the highest when predicted alone, but the predictive ability of cf-DNA combined with PCT and APACHE II was the best.