J Cancer 2020; 11(3):533-541. doi:10.7150/jca.34303

Research Paper

Inhibition of Carbonyl Reductase 1 Enhances Metastasis of Head and Neck Squamous Cell Carcinoma through β-catenin-Mediated Epithelial-Mesenchymal Transition

Miyong Yun1, Ae Jin Choi2, Seon Rang Woo2, Joo Kyung Noh3, Ji-Youn Sung4, Jung-Woo Lee5, Young-Gyu Eun2✉

1. Department of Bioindustry and Bioresource Engineering, College of Life Sciences, Sejong University;
2. Department of Otolaryngology-Head & Neck Surgery, School of Medicine, Kyung Hee University;
3. Department of Biomedical Science and Technology, Graduate School, Kyung Hee University;
4. Department of Pathology, School of Medicine, Kyung Hee University,
5. Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.

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Citation:
Yun M, Choi AJ, Woo SR, Noh JK, Sung JY, Lee JW, Eun YG. Inhibition of Carbonyl Reductase 1 Enhances Metastasis of Head and Neck Squamous Cell Carcinoma through β-catenin-Mediated Epithelial-Mesenchymal Transition. J Cancer 2020; 11(3):533-541. doi:10.7150/jca.34303. Available from http://www.jcancer.org/v11p0533.htm

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Abstract

Objective: Human carbonyl reductase 1 (CBR1) plays key roles in the regulation of oxidative stress and tumor progression. However, the detailed mechanism and clinical correlation between CBR1 and tumor progression in head and neck squamous cell carcinoma (HNSCC) is largely unexplored. This study will focus the effects of CBR1 on head and neck cancer progression and explore the possible mechanisms.

Materials and Methods: CBR1 mRNA expression was analyzed according to lymph node metastasis (LNM) status in patients with HNSCC from publicly available databases. CBR1 protein levels were measured and compared in HNSCC patient tissues, with or without metastasis, using immunohistochemistry (IHC). The invasive ability of HNSCC with modulated CBR1 expression was assayed using an invasion assay. Expression levels of EMT marker proteins were analyzed using immunoblotting.

Results: HNSCC patients with LNM showed lower expression of CBR1 than those without LNM. In addition, IHC in tissues indicated that patients with LNM had relatively lower levels of CBR1 in cancer tissue. Consistently, in vitro invasion assay, we found that CBR1 inhibition using specific short interfering RNA treatment resulted in two- to three-fold increased invasion ability of HNSCC cell lines. Also, we proved that depletion of CBR1 activated marker proteins participating in epithelial-mesenchymal transition (EMT) signaling. CBR1 inhibition increased levels of intracellular reactive oxygen species (ROS) in HNSCC cells leading to upregulation of β-catenin, one of main transcription factors that induce EMT-related genes.

Conclusion: Our findings suggested that CBR1 plays an important role in metastasis of HNSCC tumors via regulation of ROS-mediated β-catenin activity, and that CBR1 may be marker for progression of HNSCC to metastasis.

Keywords: Carbonyl reductase, metastasis, head and neck squamous cell carcinoma, reactive oxygen species, epithelial-mesenchymal transition