1. Division of Clinical Pathology, Department of Pathology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan;
2. School of Medicine, I-Shou University, Kaohsiung, Taiwan;
3. Department of Medical Image, Chi Mei Medical Center, Tainan, Taiwan;
4. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan;
5. Department of Leisure, Recreation, and Tourism Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan;
6. Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan;
7. Division of General Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan;
8. Department of Radiation Oncology, Chi-Mei Medical Center, Tainan, Taiwan;
9. Division of Anatomical Pathology, Department of Pathology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan;
10. Department of Health & Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
* SC Lin and IW Chang contributed equally to this work
Purpose: Colorectal cancer is the third most common cancer and also the fourth most common cause of cancer mortality worldwide. For rectal cancer, neoadjuvant concurrent chemoradiotherapy (CCRT) followed by radical proctectomy is gold standard treatment for patients with stage II/III rectal cancer. By data mining a documented database of rectal cancer transcriptome (GSE35452) from Gene Expression Omnibus, National Center of Biotechnology Information, we recognized that DUOX2 was the most significantly up-regulated transcript among those related to cytokine and chemokine mediated signaling pathway (GO:0019221). Hence, the aim of this study was to assess the DUOX2 expression level and its clinicopathological correlation and prognostic significance in patients of rectal cancer.
Materials and Methods: DUOX2 immunostain was performed in 172 rectal adenocarcinomas treated with preoperative CCRT followed by radical proctectomy, which were divided into high- and low-expression subgroups. Furthermore, statistical analyses were examined to correlate the relationship between DUOX2 immunoreactivity and important clinical and pathological characteristics, as well as three survival indices: disease-specific survival (DSS), local recurrence-free survival (LRFS) and metastasis-free survival (MeFS).
Results: DUOX2 overexpression was linked to post-CCRT tumor advancement, pre- and post-CCRT nodal metastasis and poor response to CCRT (all P ≤ 0.021). Furthermore, DUOX2 high expression was significantly associated with inferior DSS, LRFS and MeFS in univariate analysis (P ≤ 0.0097) and also served as an independent prognosticator indicating shorter DSS and LRFS interval in multivariate analysis (hazard ratio (HR) = 3.413, 95% confidence interval (CI): 1.349-8.633; HR = 4.533, 95% CI: 1.499-13.708, respectively).
Conclusion: DUOX2 may play a pivotal role in carcinogenesis, tumor progression and response to neoadjuvant CCRT in rectal cancers, and serve as a novel prognostic biomarker. Additional researches to clarify the molecular and biochemical pathways are essential for developing promising DUOX2-targeted therapies for patients with rectal cancers.
Keywords: CCRT, chemoradiotherapy, dual oxidase 2, DUOX2, rectal cancer.