title: The E3 ligase UBR5 regulates gastric cancer cell growth by destabilizing the tumor suppressor GKN1.
abstract: Gastric cancer is the most common digestive malignant tumor worldwide and the underlying mechanisms are not fully understood. The E3 ligase UBR5 (also known as EDD1) is essentially involved in diverse types of cancer. Here we aimed to study the functions of UBR5 in human gastric cancer. We first analyzed the mRNA and protein levels of UBR5 in human gastric cancer tissues and the results showed that UBR5 was markedly increased in gastric cancer tissues compared with normal gastric mucosa or matched non-cancer gastric tissues. The relationship between UBR5 and survival of gastric cancer patients was analyzed and we found that high UBR5 expression was associated with poor overall and disease-free survival. We further tried to investigate the effects of UBR5 on gastric cancer cell growth in vitro and in vivo. Therefore, we knocked down UBR5 with lentivirus-mediated shRNA and found that UBR5 knockdown repressed in vitro proliferation and colony formation of gastric cancer cells AGS, MG803 and MNK1. In vivo xenograft experiment also demonstrated that UBR5 knockdown inhibited AGS growth. Finally, we explored the mechanism by which UBR5 contributed to the growth of gastric cancer cells. We found that UBR5 bound the tumor suppressor gastrokine 1 (GKN1) and increased its ubiquitination to reduce the protein stability of GKN1. GKN1 knockdown with lentivirus-mediated shRNA increased the in vitro colony formation and in vivo growth of AGS cells, and UBR5 knockdown was unable to affect the colony formation and in vivo growth of AGS cells when GKN1 was knocked down, indicating that GKN1 contributed to the effects of UBR5 in human gastric cancer cells. Taken together, UBR5 plays an essential role in gastric cancer and may be a potential diagnosis and treatment target for gastric cancer.
authors: Department of Pathology, Qian-fo-shan Hospital Affiliated to Shandong University, No. 16766 Jingshi Road, Jinan, Shandong 250014, China.
authors: Min
authors: M
authors: Yang
authors: Department of Pathology, Qian-fo-shan Hospital Affiliated to Shandong University, No. 16766 Jingshi Road, Jinan, Shandong 250014, China.
authors: Nan
authors: N
authors: Jiang
authors: Department of Pathology, Qian-fo-shan Hospital Affiliated to Shandong University, No. 16766 Jingshi Road, Jinan, Shandong 250014, China.
authors: Qi-Wei
authors: QW
authors: Cao
authors: Shandong University, No.27, Shanda South Road, Jinan, Shandong 250100, China.
authors: Mao-Qiang
authors: MQ
authors: Ma
authors: Department of Pathology, Qian-fo-shan Hospital Affiliated to Shandong University, No. 16766 Jingshi Road, Jinan, Shandong 250014, China. Electronic address: sq167660@163.com.
authors: Qing
authors: Q
authors: Sun
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D036361:Peptide Hormones / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C477000:GKN1 protein, human; D036361:Peptide Hormones; D025521:Tumor Suppressor Proteins; C117617:UBR5 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: GKN1; Gastric cancer; UBR5; Ubiquitination