High RAD18 Expression is Associated with Disease Progression and Poor Prognosis in Patients with Gastric Cancer

• Published in: Annals of surgical oncology Vol. 27; no. 11; pp. 4360 - 4368
• Main Authors: Baatar, Seded, Bai, Tuya, Yokobori, Takehiko, Gombodorj, Navchaa, Nakazawa, Nobuhiro, Ubukata, Yasunari, Kimura, Akiharu, Kogure, Norimichi, Sano, Akihiko, Sohda, Makoto, Sakai, Makoto, Tumenjargal, Amartuvshin, Ogata, Kyoichi, Kuwano, Hiroyuki, Shirabe, Ken, Saeki, Hiroshi
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2020; Springer Nature B.V
• Subjects: Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Cell Line, Tumor; Disease Progression; DNA damage; DNA repair; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Gastric cancer; Humans; Invasiveness; Lymph nodes; Medical prognosis; Medicine; Medicine & Public Health; Metastases; Neoplasm Invasiveness; Oncology; Prognosis; Proliferating cell nuclear antigen; RNA-mediated interference; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Surgery; Surgical Oncology; Translational Research and Biomarkers; Ubiquitin-Protein Ligases - biosynthesis; Ubiquitin-Protein Ligases - genetics
• ISSN: 1068-9265; 1534-4681
• DOI: 10.1245/s10434-020-08518-2

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.