Abstract 1168: The codon 389 polymorphism of PICT-1 is a risk factor for human cervical cancer

Abstract

Abstract The uterine cervical cancers profoundly involve in the infection with human papillomavirus (HPV), and cause the deaths of more than 250,000 women all over the world. To date, the carcinogenesis of uterine cervical cancers was not fully understood, then we have to investigate more precise genetic and molecular events to develop early diagnosis and identify new therapeutic targets. The PICT-1 (Protein Interacting with Carboxyl Terminus-1), one of the nucleolar proteins, has tumor suppressor functions, but its association with uterine cervical carcinogenesis has been unknown. So we investigate PICT-1 gene mutations, polymorphism on codon 389 (rs184994), and protein expression levels to investigate the association with pathogenesis of uterine cervical cancers. Firstly we found missense mutations of functionally important regions of PICT-1 in one of seven uterine cervical cancer cell lines (14%) and one of 10 surgical samples (10%). Next we focused on codon 389 polymorphism (Gln to Arg) which located in important regions of PICT-1 function. In result there was a statistically significant association between PICT-1 codon 389 polymorphism and the risk of uterine cervical cancers: A/G (odds ratio 6.48, 95% confidence interval 1.98-21.22, P = 0.0012), G/G (odds ratio 3.15, 95% confidence interval 1.03-9.61, P = 0.0403), and A/G or G/G (odds ratio 4.44, 95% confidence interval 1.62-12.23, P = 0.0026). We also identified PICT-1 protein level was reduced in uterine cervical cancer cell lines by Western blotting and cervical cancer tissues by immunohistochemistry staining (IHC). In IHC analysis, expression of PICT-1 in adjacent normal cervix was found in nucleus, especially nucleolus, but in differentiating cells layers located upper parabasal cell layer, PICT-1 also expressed in cytoplasm and gradually reduced the expression of nucleolus. In patient tissues, compared to normal epithelium, we found reduction of PICT-1 expression in most samples found even in uterine cervical cancers at early invasive lesions, and weaker PICT-1 expression was observed in more invasive lesions. Interestingly, we also detected high expressed and/or re-expressed PICT-1 in cytoplasm and/or nucleolus of keratinized lesions of cervical cancers. Our results indicate that disruption of PICT-1 by gene mutation and/or reduction of protein level may associate with the pathogenesis of uterine cervical cancers, and its codon 389 polymorphism may increase the risk of uterine cervical cancers. And also we suggested that PICT-1 located in cytoplasm may be important to squamous cell differentiation, and we speculated the further study of association between PICT-1 and cell differentiation would be of value to the field of the differentiation-inducing therapy for many hard-to-treat patients of many cancers, including uterine cervical cancers. Citation Format: Masafumi Yoshimoto, Aoi Tokuda, Shoko Takahashi, Yuji Yaginuma. The codon 389 polymorphism of PICT-1 is a risk factor for human cervical cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1168.