Overexpression of Dehydrogenase/Reductase 9 Predicts Poor Response to Concurrent Chemoradiotherapy and Poor Prognosis in Rectal Cancer Patients.

Objective: To reduce the risk of locoregional recurrence, the addition of neoadjuvant concurrent chemoradiotherapy (CCRT) is recommended before surgical management for rectal cancer patients. However, despite identical tumor histology, individual patient response to neoadjuvant CCRT varies greatly. Accordingly, a comprehensive molecular characterization that is used to predict CCRT efficacy is instantly needed. Methods: Pearson's chi-squared test was utilized to correlate dehydrogenase/reductase 9 (DHRS9) expression with clinicopathological features. Survival curves were created applying the Kaplan-Meier method, and the log-rank test was conducted to compare prognostic utility between high and low DHRS9 expression groups. Multivariate Cox proportional hazards regression analysis was applied to identify independent prognostic biomarkers based on variables with prognostic utility at the univariate level. Results: Utilizing a public transcriptome dataset, we identified that the DHRS9 gene is the most considerably upregulated gene related to epithelial cell differentiation (GO: 0030855) among rectal cancer patients with CCRT resistance. Employing immunohistochemical staining, we also demonstrated that high DHRS9 immunoexpression is considerably associated with an aggressive clinical course and CCRT resistance in our rectal cancer cohort. Among all variables with prognostic utility at the univariate level, only high DHRS9 immunoexpression was independently unfavorably prognostic of all three endpoints (all p ≤ 0.048) in the multivariate analysis. In addition, applying bioinformatic analysis, we also linked DHRS9 with unrevealed functions, such as keratan sulfate and mucin synthesis which may be implicated in CCRT resistance. Conclusion: Altogether, DHRS9 expression may serve as a helpful predictive and prognostic biomarker and assist decision-making for rectal cancer patients who underwent neoadjuvant CCRT.

Identifying potential signatures for atherosclerosis in the context of predictive, preventive, and personalized medicine using integrative bioinformatics approaches and machine-learning strategies.

Background: Atherosclerosis is a major contributor to morbidity and mortality worldwide. Although several molecular markers associated with atherosclerosis have been developed in recent years, the lack of robust evidence hinders their clinical applications. For these reasons, identification of novel and robust biomarkers will directly contribute to atherosclerosis management in the context of predictive, preventive, and personalized medicine (PPPM). This integrative analysis aimed to identify critical genetic markers of atherosclerosis and further explore the underlying molecular immune mechanism attributing to the altered biomarkers. Methods: Gene Expression Omnibus (GEO) series datasets were downloaded from GEO. Firstly, differential expression analysis and functional analysis were conducted. Multiple machine-learning strategies were then employed to screen and determine key genetic markers, and receiver operating characteristic (ROC) analysis was used to assess diagnostic value. Subsequently, cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) and a single-cell RNA sequencing (scRNA-seq) data were performed to explore relationships between signatures and immune cells. Lastly, we validated the biomarkers' expression in human and mice experiments. Results: A total of 611 overlapping differentially expressed genes (DEGs) included 361 upregulated and 250 downregulated genes. Based on the enrichment analysis, DEGs were mapped in terms related to immune cell involvements, immune activating process, and inflaming signals. After using multiple machine-learning strategies, dehydrogenase/reductase 9 (DHRS9) and protein tyrosine phosphatase receptor type J (PTPRJ) were identified as critical biomarkers and presented their high diagnostic accuracy for atherosclerosis. From CIBERSORT analysis, both DHRS9 and PTPRJ were significantly related to diverse immune cells, such as macrophages and mast cells. Further scRNA-seq analysis indicated DHRS9 was specifically upregulated in macrophages of atherosclerotic lesions, which was confirmed in atherosclerotic patients and mice. Conclusions: Our findings are the first to report the involvement of DHRS9 in the atherogenesis, and the proatherogenic effect of DHRS9 is mediated by immune mechanism. In addition, we confirm that DHRS9 is localized in macrophages within atherosclerotic plaques. Therefore, upregulated DHRS9 could be a novel potential target for the future predictive diagnostics, targeted prevention, patient stratification, and personalization of medical services in atherosclerosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00289-y.

Identification of Proteomic Signatures in Chronic Obstructive Pulmonary Disease Emphysematous Phenotype.

Chronic obstructive pulmonary disease (COPD) is a highly heterogeneous disease. Emphysematous phenotype is the most common and critical phenotype, which is characterized by progressive lung destruction and poor prognosis. However, the underlying mechanism of this structural damage has not been completely elucidated. A total of 12 patients with COPD emphysematous phenotype (COPD-E) and nine patients with COPD non-emphysematous phenotype (COPD-NE) were enrolled to determine differences in differential abundant protein (DAP) expression between both groups. Quantitative tandem mass tag-based proteomics was performed on lung tissue samples of all patients. A total of 29 and 15 lung tissue samples from patients in COPD-E and COPD-NE groups, respectively, were used as the validation cohort to verify the proteomic analysis results using western blotting. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted for DAPs. A total of 4,343 proteins were identified, of which 25 were upregulated and 11 were downregulated in the COPD-E group. GO and KEGG analyses showed that wound repair and retinol metabolism-related pathways play an essential role in the molecular mechanism of COPD emphysematous phenotype. Three proteins, namely, KRT17, DHRS9, and FMO3, were selected for validation. While KRT17 and DHRS9 were highly expressed in the lung tissue samples of the COPD-E group, FMO3 expression was not significantly different between both groups. In conclusion, KRT17 and DHRS9 are highly expressed in the lung tissue of patients with COPD emphysematous phenotype. Therefore, these proteins might involve in wound healing and retinol metabolism in patients with emphysematous phenotype and can be used as phenotype-specific markers.

Are Mutations in the DHRS9 Gene Causally Linked to Epilepsy? A Case Report.

The DHRS9 gene is involved in several pathways including the synthesis of allopregnanolone from progesterone. Allopregnanolone is a positive modulator of gamma aminobutyric acid (GABA) action and plays a role in the control of neuronal excitability and seizures. Whole-exome sequencing performed on a girl with an early onset epilepsy revealed that she was a compound heterozygote for two novel missense mutations of the DHRS9 gene likely to disrupt protein function. No previous studies have reported the implication of this gene in epilepsy. We discuss a new potential pathogenic mechanism underlying epilepsy in a child, due to a defective progesterone pathway.

Downregulation of DHRS9 is associated with poor prognosis in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) has a high potential for local invasion and nodal metastasis. Therefore, early detection and elucidation of the detailed molecular mechanisms underlying OSCC are essential. Dehydrogenase/reductase member 9 (DHRS9) is downregulated in recurrent OSCC. Although DHRS9 is reported to act as a tumour suppressor in several malignancies, its expression in OSCC cells is unknown. In this study, we examined DHRS9 expression immunohistochemically in specimens from a sample of 98 OSCC patients. Reduced DHRS9 expression was observed in 68 of 98 patients (69.4%) with OSCC. A significant association was found between low DHRS9 expression and local progression (T factor) (p = 0.0135). Furthermore, patients with low DHRS9 expression had a significantly poorer prognosis than those with high DHRS9 expression (p = 0.0443). In multivariate analysis using the Cox proportional hazards model, decreased DHRS9 expression strongly correlated with worse prognosis. The study findings suggest that DHRS9 might be a useful diagnostic and prognostic marker for OSCC.

Downregulation of DHRS9 expression in colorectal cancer tissues and its prognostic significance.

Dehydrogenase/reductase (SDR family) member 9 (DHRS9) is aberrantly expressed in colorectal cancer (CRC), but its prognostic value is unknown. The aim of the work was to investigate the prognostic significance of DHRS9 expression in CRC. We found that DHRS9 was frequently downregulated in CRC clinical samples at both the messenger RNA (mRNA) and protein levels. Decreased expression of DHRS9 was significantly correlated with increased lymph node metastasis (p = 0.032), advanced tumor-node-metastasis (TNM) stage (p = 0.021), increased disease recurrence (p = 0.001), and death (p = 0.014). Kaplan-Meier analysis indicated that low DHRS9 expression predicted poor disease-free survival (p = 0.003) and disease-specific survival (p = 0.021). Cox multivariate analysis revealed that reduced expression of DHRS9 was an independent unfavorable prognostic indicator for CRC. Furthermore, combination of DHRS9 with TNM stage was a more powerful predictor of poor prognosis than either of the two parameters alone. Our results suggest that decreased expression of DHRS9 correlates with tumor progression and may serve as a potential prognostic biomarker in CRC.