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TRIM21 Polymorphisms Are Associated with Susceptibility And Int. J. Med. Sci. 2021, Vol. 18 2997 Ivyspring International Publisher International Journal of Medical Sciences 2021; 18(13): 2997-3003. doi: 10.7150/ijms.56614 Research Paper TRIM21 Polymorphisms are associated with Susceptibility and Clinical Status of Oral Squamous Cell Carcinoma patients Chun-Yi Chuang1,2#, Yi-Chung Chien3,4,5,6,7#, Chiao-Wen Lin8,9, Chia-Hsuan Chou10,11, Shuo-Chueh Chen12, Chun-Lin Liu13, Li-Yuan Bai14, Shun-Fa Yang10,11, Yung-Luen Yu3,4,5,6,7,15 1. School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. 2. Department of Otolaryngology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. 3. Graduate Institute of Biomedical Sciences, China Medical University, Taichung 40402, Taiwan. 4. Ph.D. Program for Translational Medicine, China Medical University, Taichung 40402, Taiwan. 5. Institute of New Drug Development, China Medical University, Taichung, 404, Taiwan. 6. Drug Development Center, Research Center for Cancer Biology, China Medical University, Taichung, 404, Taiwan. 7. Center for Molecular Medicine, China Medical University Hospital, Taichung 40402, Taiwan. 8. Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan. 9. Department of Dentistry, Chung Shan Medical University Hospital 40201, Taichung, Taiwan. 10. Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan. 11. Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan. 12. Division of Chest Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan. 13. Department of Neurosurgery, China Medical University Hospital, Taichung 40402, Taiwan. 14. Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan. 15. Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung 41354, Taiwan. #Equal contributions to this work. Corresponding authors: [email protected] (S.F.Y.); [email protected] (Y.L.Y.). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.12.01; Accepted: 2021.04.21; Published: 2021.06.11 Abstract Squamous cell cancer of head and neck (HNSCC) is the sixth most common malignancy worldwide. One of the most common HNSCC types is oral squamous cell carcinoma (OSCC), which is the fifth leading cause of cancer death in Taiwan. Tripartite motif 21 (TRIM21) has been reported to play an important role in different cancer types. We found a correlation between TRIM21 and survival of HNSCC patients, but little information exists about how altered TRIM21 expression contributes to tumorigenesis. Thus, we investigated the combined effect of TRIM21 polymorphisms and exposure to environmental carcinogens on the susceptibility and clinicopathological characteristics of OSCC. Two single-nucleotide polymorphisms (SNPs) of TRIM21 (rs4144331, rs915956) from 1194 healthy controls and 1192 OSCC patients were analyzed by real-time PCR. Among 1632 smokers, TRIM21 polymorphism carriers with the betel-nut chewing habit had a ~4.8-fold greater risk of OSCC than TRIM21 wild-type carriers without the betel-nut chewing habit. After adjusting for other covariants, OSCC patients with G/T at TRIM21 rs4144331 had a high risk for distant metastasis compared with G/G homozygotes. This study is the first to examine the risk factors associated with TRIM21 SNPs in OSCC progression and development. Thus, our findings suggest that this study is the first to examine the risk factors associated with TRIM21 SNPs in OSCC progression and development and suggest that interactions between mutant genes may alter the susceptibility to OSCC. Key words: tripartite motif 21 (TRIM21); oral squamous cell carcinoma (OSCC); single-nucleotide polymorphism (SNP) Introduction Squamous cell cancer of head and neck types is oral squamous cell carcinoma (OSCC) [1]. (HNSCC) is the sixth most common malignancy Despite comprehensive treatment that includes worldwide, and one of the most common HNSCC surgery, radiation, and chemotherapy, the 5-year http://www.medsci.org Int. J. Med. Sci. 2021, Vol. 18 2998 survival rate for OSCC patients remains poor [2, 3]. types of polymorphisms. Moreover, it occurs at a The poor prognosis is attributable to the development frequency of approximately 1 per 1000 base pairs in of distant metastasis and local recurrences [4, 5]. the entire genome [27]. Several studies have been OSCC occurs through a variety of genetic changes shown that the genomic level of humans is similar to ascribed to long-term exposure to environmental chimpanzees. But there are differences between carcinogens. Chronic inflammation, tobacco use, human and chimpanzees. For example, several alcohol consumption, betel-nut chewing, and viral diseases and cancers are common in humans but rare infection are all considered risk factors for OSCC [6-9]. in chimpanzees. It is indicated that SNPs may provide Recently, we found a correlation between Tripartite important clues of cancer progression. In recent years, motif 21 (TRIM21) and HNSCC with respect to patient various researchers have reported evidence for the survival. TRIM proteins are composed of involvement of certain genetic predisposing factors multidomain ubiquitin E3 ligases characterized by the for OSCC or HNSCC. Among genetic factors, SNPs presence of the N-terminal tripartite motif, which are the most common type of DNA sequence variation includes three zinc-binding domains – a RING, a and may predict cancer risk [28, 29]. For instance, B-box, and a coiled-coil region [10]. Therefore, TRIM patients with HCC who carried at least one C allele at proteins are considered key regulators of cellular rs6950683 or rs3757441 have a higher risk of lymph homeostasis. Recent evidence has shown that TRIM node metastasis but a lower risk of liver cirrhosis than proteins can affect cell proliferation, differentiation, patients who carried the wild-type allele [24]. TRIM21 migration, innate immunity, and apoptosis regulation polymorphisms are also associated with autoimmune [11-15]. disease, and there may be a correlation between TRIM21 has E3 ligase activity and functions in TRIM21 polymorphisms and disease susceptibility ubiquitination. It is also known as Ro52, SSA1, or and increased production of TRIM21 antibodies in RNF81 [16]. In the past few years, studies of TRIM21 systemic lupus erythematosus and Sjogren's have been focused on its role in immunity, such as syndrome. The rs660 C/T SNP has been shown to be neutralizing viral infections, regulating the related to systemic lupus erythematosus among production of cytokine and chemokine, and African Americans [30, 31]. In a Norwegian regulating inflammatory signaling pathways. [17-19]. population, the rs5030767 C/T, rs5030768 A/G, TRIM21 was first identified as an antibody-binding rs915956 C/T, and rs4144331 C/A SNPs were shown protein. The functions of TRIM21 is as an Fc receptor to be associated with anti-TRIM21–positive primary that recognizes antibodies that bind to intracellular Sjogren’s syndrome, among which rs915956 shows pathogens and catalyzes the synthesis of K63 the strongest association [32]. However, the effects of ubiquitin chains resulting in activating the innate TRIM21 polymorphisms are still unknown in OSCC. immune system and antiviral response during In the present study, we aimed to investigate the pathogen invasion [20, 21]. Recent studies have association of TRIM21 polymorphisms with OSCC. shown that TRIM21 plays a role in the occurrence and We analyzed two SNPs, rs4144331 and rs915956 for prognosis of various tumors. Studies have reported associations with demographic, etiological, and that reduced expression of TRIM21 in hepatocellular clinical characteristics and with susceptibility to carcinoma, breast cancer and diffuse large B-cell OSCC. lymphoma implicated in a poor prognosis [22-25]. In addition, TRIM21 inhibits the epithelial-mesenchymal Materials and Methods transition (EMT) in breast cancer through the Study subjects and specimen collection ubiquitination and degradation of Snail [24]. Interestingly, it is also reported that increased This hospital-based case-control study recruited expression of TRIM21 in glioma suppressed cellular 1,192 OSCC patients as the case group between 2010 senescence via the p53-p21 pathway, increased drug and 2019 from Sun Yat-sen Medical University resistance in glioma cells and is implicated in a poor Hospital in Taichung, Taiwan. The diagnosis of OSCC prognosis [26]. However, whether TRIM21 is was performed according to the standards specified expressed and functions in OSCC remains unknown. the national guidelines for OSCC. According to the Between two randomly selected human tumor/lymph node metastasis criteria of the genomes, 99.9% of the DNA sequences is individuals. American Joint Committee on Cancer, OSCC patients The remaining 0.1% is considered to include some were clinically staged at the time of diagnosis (2002). differences or variations in the genome between For the control group, all 1,194 controls were received individuals. This variation is called polymorphism in the same hospital, and these control individuals did and is caused by mutation. Single-nucleotide not have a self-reported medical history of any cancer polymorphisms (SNPs) are more common than other type. The patients' clinicopathological
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