Abstract
Mutation of PPP2R1A has been observed at high frequency in endometrial serous carcinomas but at low frequency in ovarian clear cell carcinoma. However, the biological role of mutation of PPP2R1A in ovarian and endometrial cancer progression remains unclear. In this study, we found that PPP2R1A expression is elevated in high-grade primary tumor patients with papillary serous tumors of the ovary. To determine whether increased levels or mutation of PPP2R1A might contribute to cancer progression, the effects of overexpression or mutation of PPP2R1A on cell proliferation, migration, and PP2A phosphatase activity were investigated using ovarian and endometrial cancer cell lines. Among the mutations, PPP2R1A-W257G enhanced cell migration in vitro through activating SRC-JNK-c-Jun pathway. Overexpression of wild type (WT) PPP2R1A increased its binding ability with B56 regulatory subunits, whereas PPP2R1A-mutations lost the ability to bind to most B56 subunits except B56δ. Total PP2A activity and PPP2R1A-associated PP2Ac activity were significantly increased in cells overexpressing PPP2R1A-WT. In addition, overexpression of PPP2R1A-WT increased cell proliferation in vitro and tumor growth in vivo.
Highlights
Endometrial carcinoma, a heterogeneous disease, is the most frequently diagnosed gynecological cancer
PPP2R1A mRNA expression level is not elevated in various stages of ovarian serous cystadenocarcinoma in the TCGA database, indicating that PPP2R1A expression is only increased in high-grade carcinomas
In addition to overexpression of PPP2R1A, PPP2R1A mutations have been found in different cancer types (Table 2), including ovarian carcinoma, endometrial carcinoma, breast invasive carcinoma, colorectal adenocarcinoma, lung adenocarcinoma, and renal clear cell carcinoma based on cBio Portal for Cancer Genomics
Summary
Endometrial carcinoma, a heterogeneous disease, is the most frequently diagnosed gynecological cancer. PPP2R1A coding a scaffold subunit of protein phosphatase 2A (PP2A) has been found to be one recurrent mutation in both ovarian and endometrial cancers[3,7,8,9,10]. PPP2R1A somatic mutations (E64D, E64G, and R418W) have been identified in lung carcinoma, breast carcinoma, and melanoma[24] These mutations contribute to human cell transformation by disrupting the composition of PP2A complex and reducing phosphatase activity[25]. Subsequent studies have revealed that PPP2R1A mutations occur at high frequency in endometrial serous carcinomas[7,29,30] These recurrent PPP2R1A mutation sites are mainly located within the TAg binding site for polyoma virus and SV40. The objective of this study was to determine whether PPP2R1A mutations contribute to cancer progression through affecting cell proliferation, migration, and PP2A phosphatase activity
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