Dataset Information

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

ABSTRACT:

Background

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).

Methods

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.

Results

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?ConclusionsHigher 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.

SUBMITTER: Cui R

PROVIDER: S-EPMC6664705 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

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

Cui Ran R Cao Guangming G Bai Huimin H Zhang Zhenyu Z

Cancer cell international 20190729

<h4>Background</h4>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).<h4>Methods</h4>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. ...[more]

PMID: 31384176

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Project description:BackgroundOvarian low-grade serous carcinoma (LGSC) has fewer mutations than ovarian high-grade serous carcinoma (HGSC) and a less aggressive clinical course. However, an overwhelming majority of LGSC patients do not respond to conventional chemotherapy resulting in a poor long-term prognosis comparable to women diagnosed with HGSC. KRAS and BRAF mutations are common in LGSC, leading to clinical trials targeting the MAPK pathway. We assessed the stability of targetable somatic mutations over space and/or time in LGSC, with a view to inform stratified treatment strategies and clinical trial design.MethodsEleven LGSC cases with primary and recurrent paired samples were identified (stage IIB-IV). Tumor DNA was isolated from 1-4 formalin-fixed paraffin-embedded tumor blocks from both the primary and recurrence (n = 37 tumor and n = 7 normal samples). Mutational analysis was performed using the Ion Torrent AmpliSeqTM Cancer Panel, with targeted validation using Fluidigm-MiSeq, Sanger sequencing and/or Raindance Raindrop digital PCR.ResultsKRAS (3/11), BRAF (2/11) and/or NRAS (1/11) mutations were identified in five unique cases. A novel, non-synonymous mutation in SMAD4 was observed in one case. No somatic mutations were detected in the remaining six cases. In two cases with a single matched primary and recurrent sample, two KRAS hotspot mutations (G12V, G12R) were both stable over time. In three cases with multiple samplings from both the primary and recurrent surgery some mutations (NRAS Q61R, BRAF V600E, SMAD4 R361G) were stable across all samples, while others (KRAS G12V, BRAF G469V) were unstable.ConclusionsOverall, the majority of cases with detectable somatic mutations showed mutational stability over space and time while one of five cases showed both temporal and spatial mutational instability in presumed drivers of disease. Investigation of additional cases is required to confirm whether mutational heterogeneity in a minority of LGSC is a general phenomenon that should be factored into the design of clinical trials and stratified treatment for this patient population.

Dataset Information

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

Background

Methods

Results

Publications

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

Similar Datasets

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