LPAR1 regulates the development of intratumoral heterogeneity in ovarian serous cystadenocarcinoma by activating the PI3K/AKT signaling pathway

摘要

To explore the role of lysophosphatidic acid receptor 1 (LPAR1) and its correlation with the PI3K/AKT pathway in the development of intratumoral heterogeneity (ITH) in human ovarian serous cystadenocarcinoma (OSC). Immunohistochemical staining was performed to detect LPAR1 expression in matched primary and recurrent lesions from the same patients. Cell models of ITH were established using the limiting dilution methodology and Transwell invasion/migration assays. LPAR1 expression in the ITH cell models was silenced or upregulated with lentiviral particles, and the biological characteristics were evaluated using various in vitro and in vivo assessments of cell function. The levels of phosphorylated PI3K/AKT (p-PI3K/p-AKT) in LPAR1 knockdown and LPAR1-overexpressing cells were detected. The H-scores for LPAR1 staining in the lymphatic metastatic and recurrent lesions were noticeably higher than in the primary tumor lesions from the same patients (P?=?0.024/0.031). High LPAR1 expression was associated with worse progression-free survival and overall survival (P?=?0.017/0.039). Biological functions in vitro, including invasion, migration, and proliferation, and tumor formation in vivo were decreased in the LPAR1-silenced cells (all P??0.05). These cellular functions were significantly increased in the LPAR1-overexpressing cells in vitro and in vivo (all P??0.05). The levels of p-PI3K and p-AKT were significantly decreased in the LPAR1 knockdown cells and significantly increased in the LPAR1-overexpressing cells (all P??0.05). Higher levels of the LPAR1 protein were associated with a poor prognosis. LPAR1 plays essential roles in the invasion, migration, and proliferation of heterogeneous subsets of OSC cell lines and the development of ITH of OSC, possibly by modulating the activity of the PI3K/AKT signaling pathway.