ENPP1 在高级别浆液性卵巢癌中的高表达预示着不良预后，可作为一种分子治疗靶点。

High expression of ENPP1 in high-grade serous ovarian carcinoma predicts poor prognosis and as a molecular therapy target.

机构信息

Women's Reproductive Health Key Laboratory of Zhejiang Province, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P. R. China.

Department of Pathology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, P. R. China.

出版信息

PLoS One. 2021 Feb 26;16(2):e0245733. doi: 10.1371/journal.pone.0245733. eCollection 2021.

DOI:10.1371/journal.pone.0245733

PMID:33635867

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7909685/

Abstract

Recent studies have shown that the expression of ENPP1 is related to differentiation, death, dissemination and chemosensitivity of tumor cells. So far, there is no research in ovarian carcinoma. This study aimed at exploring the role of ENPP1 gene in ovarian carcinoma, the relationship with prognostic indicators and chemotherapy resistance, and investigates the possibility of molecular targeted therapy. The expression of ENPP1 in 41 normal ovarian epithelial tissues, 97 ovarian serous cystadenoma and 103 HGSOC tissues was detected by IHC. In ovarian cancer tissues and ovarian cancer cell lines, mRNA and protein expression of ENPP1 was determined by qRT-PCR and Western blot. The ENPP1 expression was knockdowned by siRNA. Cell proliferation was measured with the BrdU Cell Proliferation ELISA. Cell migration and invasion were detected by Wound-Healing, Transwell migration and Matrigel invasion assay. Caspase 3 activity was determined by the CaspACE. The expression of EMT markers such as E-cadherin, N-cadherin, and Vimentin was measured, and the expression of PCNA and MMP9 was also be detected. The results showed that the expression of ENPP1 was significantly increased in high-grade ovarian serous carcinoma, the number of strong expression was 85.4% (22.3%+63.1%) and only 1.03% (1.03%+0.0%) in serous cystadenoma, but no in normal ovarian epithelium (P< 0.05). And the stronger the expression of ENPP1, the later the FIGO stage and the poorer differentiation of cells (P = 0.001 or <0.001, respectively). However, no correlation was found between the expression of ENPP1 and chemosensitivity. ENPP1 was also highly expressed in ovarian cancer tissues and in epithelial ovarian cancer cell lines (A2780, CaoV3, OVCAR3, SKOV3 and 3ao). After down-regulation of ENPP1 expression by RNA interference, the cell proliferation, migration and invasion of ovarian cancer cell decreased significantly, the expression of apoptosis related gene caspase 3 increased significantly, while the expression of PCNA and MMP9 was significantly down regulated. In addition, EMT biological characteristics of A2780 and SKOV3 cells were also inhibited. In summary, the increased expression of ENPP1 may be related to the occurrence of HGSOC, and indicate that the disease progresses rapidly and the prognosis is poor. ENPP1 may be considered as a potential molecular therapeutic target.

摘要

最近的研究表明，ENPP1 的表达与肿瘤细胞的分化、死亡、扩散和化疗敏感性有关。到目前为止，在卵巢癌中还没有相关研究。本研究旨在探讨 ENPP1 基因在卵巢癌中的作用及其与预后指标和化疗耐药性的关系，并探讨分子靶向治疗的可能性。采用免疫组化法检测 41 例正常卵巢上皮组织、97 例卵巢浆液性囊腺瘤和 103 例 HGSOC 组织中 ENPP1 的表达。采用 qRT-PCR 和 Western blot 法检测卵巢癌组织和卵巢癌细胞系中 ENPP1 的 mRNA 和蛋白表达。用 siRNA 敲低 ENPP1 的表达。采用 BrdU 细胞增殖 ELISA 法检测细胞增殖。通过划痕愈合、Transwell 迁移和 Matrigel 侵袭实验检测细胞迁移和侵袭。通过 CaspACE 测定 Caspase 3 活性。检测 EMT 标志物如 E-钙粘蛋白、N-钙粘蛋白和波形蛋白的表达，并检测 PCNA 和 MMP9 的表达。结果表明，ENPP1 在高级别卵巢浆液性癌中的表达明显增加，强表达的比例为 85.4%（22.3%+63.1%），而浆液性囊腺瘤中仅为 1.03%（1.03%+0.0%），正常卵巢上皮组织中无表达（P<0.05）。ENPP1 表达越强，FIGO 分期越晚，细胞分化越差（P=0.001 或<0.001）。然而，ENPP1 的表达与化疗敏感性之间没有相关性。ENPP1 在卵巢癌组织和上皮性卵巢癌细胞系（A2780、CaoV3、OVCAR3、SKOV3 和 3ao）中也呈高表达。用 RNA 干扰下调 ENPP1 表达后，卵巢癌细胞的增殖、迁移和侵袭明显减少，凋亡相关基因 caspase 3 的表达明显增加，而 PCNA 和 MMP9 的表达明显下调。此外，A2780 和 SKOV3 细胞的 EMT 生物学特性也受到抑制。综上所述，ENPP1 的表达增加可能与 HGSOC 的发生有关，表明疾病进展迅速，预后不良。ENPP1 可被视为一种潜在的分子治疗靶点。