Cui Ran, Cao Guangming, Bai Huimin, Zhang Zhenyu
Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, No.8, North Road of Workers Stadium, Chaoyang District, Beijing, 100020 China.
Cancer Cell Int. 2019 Jul 29;19:201. doi: 10.1186/s12935-019-0920-0. eCollection 2019.
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.
探讨溶血磷脂酸受体1（LPAR1）在人卵巢浆液性囊腺癌（OSC）肿瘤内异质性（ITH）发生发展中的作用及其与PI3K/AKT信号通路的相关性。
采用免疫组织化学染色法检测同一患者配对的原发性和复发性病变中LPAR1的表达。使用有限稀释法和Transwell侵袭/迁移试验建立ITH细胞模型。用慢病毒颗粒使ITH细胞模型中的LPAR1表达沉默或上调，并通过各种体外和体内细胞功能评估来评价其生物学特性。检测LPAR1敲低和过表达细胞中磷酸化PI3K/AKT（p-PI3K/p-AKT）的水平。
同一患者的淋巴转移灶和复发灶中LPAR1染色的H评分明显高于原发性肿瘤灶（P = 0.024/0.031）。LPAR1高表达与无进展生存期和总生存期较差相关（P = 0.017/0.039）。LPAR1沉默的细胞在体外的生物学功能，包括侵袭、迁移和增殖，以及在体内的肿瘤形成均降低（均P < 0.05）。这些细胞功能在LPAR1过表达的细胞中在体外和体内均显著增加（均P < 0.05）。LPAR1敲低细胞中p-PI3K和p-AKT水平显著降低，而在LPAR1过表达细胞中显著升高（均P < 0.05）。
LPAR1蛋白水平较高与预后不良相关。LPAR1可能通过调节PI3K/AKT信号通路的活性，在OSC细胞系异质性亚群的侵袭、迁移和增殖以及OSC的ITH发生发展中起重要作用。
