1. Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52# Fu-Cheng-Lu, Hai-Dian District, Beijing, 100142, China;
2. Department of Gastroenterology, The Chengdu Military General Hospital, Chengdu, China;
3. Department of Sugary, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52# Fu-Cheng-Lu, Hai-Dian District, Beijing, 100142, China;
4. Department of Pathology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 52# Fu-Cheng-Lu, Hai-Dian District, Beijing, 100142, China;
5. Department of Genetics, Case Western Reserve University, Cleveland, OH 44106, USA;
6. Department of Medicine, The George Washington University School of Medicine and Health Sciences, 2300 Eye Street, N.W. Ross Hall 402C, Washington, DC 20037, USA.
*These authors contributed equally to this work.
Increased expression of progesterone receptor (PR) has been reported in gastric cancer (GC). We have previously identified a functional T889C point mutation in DNA polymerase beta (POLB), a DNA repair gene in GC. To provide a detailed analysis of molecular changes associated with the mutation, human cDNA microarrays focusing on 18 signal transduction pathways were used to analyze differential gene expression profiles between GC tissues with T889C mutant in POLB gene and those with wild type. Among the differentially expressed genes, notably, PR was one of the significantly up-regulated genes in T889C mutant POLB tissues, which were subsequently confirmed in POLB gene transfected AGS cell line. Interestingly, patients with T889C mutation and PR positivity were associated with higher incidence of intraperitoneal metastasis (IM). In vitro studies indicate that PR expression was upregulated in AGS cell line when transfected with T889C mutant expression vector. Cotransfection of T889C mutant allele and PR gene induced cell migration in the cell line. These data demonstrated that T889C mutation-associated PR overexpression results in increased IM. Therefore, T889C mutation-associated PR overexpression may serve as a biomarker for an adverse prognosis for human GC.
Keywords: Gastric cancer, DNA polymerase beta, progesterone receptor, metastasis.