Department of Orthopedics, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
Int J Oncol. 2018 Apr;52(4):1198-1208. doi: 10.3892/ijo.2018.4267. Epub 2018 Feb 7.
Lymph node (LN) metastasis at an early stage of cervical cancer is often an indicator of poor prognosis and is critical for subsequent adjuvant therapy. The current study aimed to identify aberrant gene signatures and biomarkers of metastasis for patients with cervical cancer. RNA-sequencing data of 132 LN negative (N0) and 60 LN positive (N1) cervical cancer samples obtained from The Cancer Genome Atlas database were analyzed. Differentially expressed genes were identified using R packages 'edgeR' and 'limma'. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and Gene Set Enrichment Analysis (GSEA) were conducted. The GSE9750 dataset obtained from Gene Expression Omnibus was analyzed to identify genes that are persistently aberrantly expressed during the development of cervical cancer. The peroxisome proliferator-activated receptor (PPAR) signaling pathway was screened out to be significant during LN metastasis. In the two analyzed datasets, 11 genes were aberrantly expressed, while matrix metalloproteinase 1 (MMP1) was the only gene that was persistently overexpressed. Cell viability, wound healing and Transwell assays were performed to evaluate the effects of MMP1 knockdown in cervical cancer cell lines, and the expression of epithelial mesenchymal transition (EMT) markers was detected. Finally, the clinical significance of MMP1 was investigated. The current study identified that MMP1 was overexpressed and the PPAR signaling pathway was associated LN metastasis in patients with cervical cancer. Following knockdown of MMP1, the proliferation, migration and invasion of cervical cancer cell lines were weakened, the expression of epithelial marker E-cadherin was increased, and the expression of metastasis-associated gene vimentin was decreased. MMP1 was an independent prognostic factor for cervical cancer. The current study indicated that MMP1 has a key role in the regulation of cervical tumor growth and LN metastasis via EMT to a certain extent. The results suggest that MMP1 may be a biomarker for LN metastasis of cervical cancer, and further validation should be performed.
淋巴结（LN）转移是宫颈癌早期不良预后的重要指标，对后续辅助治疗至关重要。本研究旨在寻找宫颈癌转移相关的异常基因特征和生物标志物。从癌症基因组图谱（TCGA）数据库中获取了 132 例 LN 阴性（N0）和 60 例 LN 阳性（N1）宫颈癌样本的 RNA 测序数据，采用 R 包“edgeR”和“limma”分析差异表达基因。进行京都基因与基因组百科全书（KEGG）通路富集和基因集富集分析（GSEA）。分析来自基因表达综合数据库（GEO）的 GSE9750 数据集，以鉴定在宫颈癌发展过程中持续异常表达的基因。筛选出过氧化物酶体增殖物激活受体（PPAR）信号通路在 LN 转移中显著富集。在两个分析的数据集中共鉴定到 11 个差异表达基因，而基质金属蛋白酶 1（MMP1）是唯一持续过表达的基因。通过细胞活力、划痕愈合和 Transwell 实验评估 MMP1 敲低对宫颈癌细胞系的影响，并检测上皮间质转化（EMT）标志物的表达。最后，探讨了 MMP1 的临床意义。本研究发现 MMP1 过表达和 PPAR 信号通路与宫颈癌患者的 LN 转移相关。敲低 MMP1 后，宫颈癌细胞系的增殖、迁移和侵袭能力减弱，上皮标志物 E-钙黏蛋白表达增加，转移相关基因波形蛋白表达减少。MMP1 是宫颈癌的独立预后因素。本研究表明，MMP1 通过 EMT 在一定程度上调节宫颈癌肿瘤生长和 LN 转移，提示 MMP1 可能是宫颈癌 LN 转移的生物标志物，需要进一步验证。
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