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

Abstract

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.

Keywords: DHRS9; biomarker; epithelial cell differentiation; keratan sulfate; mucin; rectal cancer.

FIGURE 1

Transcriptome analysis of genes associated with epithelial cell differentiation and the response to CCRT. The expression levels of downregulated and upregulated genes are marked in green and red, respectively. We identified DHRS9 as the most remarkably upregulated gene in relation to epithelial cell differentiation (GO: 0030855) among CCRT-resistant rectal cancer patients.

FIGURE 2

Immunohistochemical staining of DHRS9. (A) Non-tumor mucosa displayed no DHRS9 immunoexpression. Rectal cancer specimens presented (B) low DHRS9 immunoexpression in patients who responded to CCRT and (C) high DHRS9 immunoexpression in patients with CCRT resistance.

FIGURE 3

Kaplan–Meier survival analysis. Kaplan–Meier curves were created and showed that high DHRS9 immunoexpression was considerably correlated with worse (A) disease-specific survival, (B) local recurrence-free survival, and (C) metastasis-free survival.

FIGURE 4

The Gene Ontology (GO) terms enriched in DHRS9 overexpression. The genes that were coexpressed with DHRS9 in the colorectal adenocarcinoma dataset (n = 594) from The Cancer Genome Atlas (TCGA) database were obtained employing the cBioPortal online platform (http://cbioportal.org). The top 200 genes co-upregulated with DHRS9 were further analyzed applying the GO classification system (http://pantherdb.org) based on (A) biological processes, (B) molecular functions, or (C) cellular components and ranked by fold enrichment for functional annotation.