Seded Baatar1, Tuya Bai1, Takehiko Yokobori2,3, Navchaa Gombodorj4,5, Nobuhiro Nakazawa1, Yasunari Ubukata1, Akiharu Kimura1, Norimichi Kogure1, Akihiko Sano1, Makoto Sohda1, Makoto Sakai1, Amartuvshin Tumenjargal6, Kyoichi Ogata1, Hiroyuki Kuwano1, Ken Shirabe1, Hiroshi Saeki1. 1. Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan. 2. Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Japan. bori45@gunma-u.ac.jp. 3. Research Program for Omics-Based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Japan. bori45@gunma-u.ac.jp. 4. Research Program for Omics-Based Medical Science, Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Maebashi, Japan. 5. Department of Radiation Oncology, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia. 6. Department of Bioimaging and Information Analysis, Graduate School of Medicine, Gunma University, Maebashi, Japan.
Abstract
BACKGROUND: RAD18 plays an important role in DNA damage repair by inducing monoubiquitinated PCNA (mUB-PCNA) in both cancer and normal tissues. Previous studies have not determined the significance of RAD18 expression in clinical gastric cancer (GC) samples. Thus, this study aimed to clarify the expression and functional significance of RAD18 in GC. METHODS: Overall, 96 resected GC samples were subjected to an immunohistochemical analysis of RAD18. GC cell lines were also subjected to functional RNA interference analyses of RAD18. RESULTS: RAD18 expression was predominantly nuclear and was observed at higher levels in GC tissues than in normal tissues. In GC tissues, strong RAD18 expression was associated with progression of lymph node metastasis (p = 0.0001), lymphatic invasion (p = 0.0255), venous invasion (p < 0.0001), recurrence (p = 0.028), and disease stage (p = 0.0253). Moreover, GC patients with high tumor RAD18 expression had shorter overall survival (p = 0.0061) and recurrence-free survival durations (p = 0.035) than those with low tumor RAD18 expression. RAD18 knockdown inhibited GC proliferation and invasiveness and increased chemosensitivity by suppressing mUB-PCNA. CONCLUSIONS: RAD18 expression may be a useful marker of progression and poor prognosis of GC. Moreover, therapeutic strategies that target RAD18 might be a novel chemosensitizer to eradicate the refractory GC.
BACKGROUND:RAD18 plays an important role in DNA damage repair by inducing monoubiquitinated PCNA (mUB-PCNA) in both cancer and normal tissues. Previous studies have not determined the significance of RAD18 expression in clinical gastric cancer (GC) samples. Thus, this study aimed to clarify the expression and functional significance of RAD18 in GC. METHODS: Overall, 96 resected GC samples were subjected to an immunohistochemical analysis of RAD18. GC cell lines were also subjected to functional RNA interference analyses of RAD18. RESULTS:RAD18 expression was predominantly nuclear and was observed at higher levels in GC tissues than in normal tissues. In GC tissues, strong RAD18 expression was associated with progression of lymph node metastasis (p = 0.0001), lymphatic invasion (p = 0.0255), venous invasion (p < 0.0001), recurrence (p = 0.028), and disease stage (p = 0.0253). Moreover, GC patients with high tumorRAD18 expression had shorter overall survival (p = 0.0061) and recurrence-free survival durations (p = 0.035) than those with low tumorRAD18 expression. RAD18 knockdown inhibited GC proliferation and invasiveness and increased chemosensitivity by suppressing mUB-PCNA. CONCLUSIONS:RAD18 expression may be a useful marker of progression and poor prognosis of GC. Moreover, therapeutic strategies that target RAD18 might be a novel chemosensitizer to eradicate the refractory GC.
Authors: Freddie Bray; Jacques Ferlay; Isabelle Soerjomataram; Rebecca L Siegel; Lindsey A Torre; Ahmedin Jemal Journal: CA Cancer J Clin Date: 2018-09-12 Impact factor: 508.702