Abstract
Long non-coding RNA (lncRNA) are emerging as contributors to malignancies. Little is understood about the contribution of lncRNA to epithelial-to-mesenchymal transition (EMT), which correlates with metastasis. Ovarian cancer is usually diagnosed after metastasis. Here we report an integrated analysis of >700 ovarian cancer molecular profiles, including genomic data sets, from four patient cohorts identifying lncRNA DNM3OS, MEG3, and MIAT overexpression and their reproducible gene regulation in ovarian cancer EMT. Genome-wide mapping shows 73% of MEG3-regulated EMT-linked pathway genes contain MEG3 binding sites. DNM3OS overexpression, but not MEG3 or MIAT, significantly correlates to worse overall patient survival. DNM3OS knockdown results in altered EMT-linked genes/pathways, mesenchymal-to-epithelial transition, and reduced cell migration and invasion. Proteotranscriptomic characterization further supports the DNM3OS and ovarian cancer EMT connection. TWIST1 overexpression and DNM3OS amplification provides an explanation for increased DNM3OS levels. Therefore, our results elucidate lncRNA that regulate EMT and demonstrate DNM3OS specifically contributes to EMT in ovarian cancer.
Highlights
Long non-coding RNA are emerging as contributors to malignancies
To determine whether Long non-coding RNA (lncRNA) contribute to epithelial-to-mesenchymal transition (EMT) in ovarian cancer, data from high-grade serous ovarian cancer patient samples were obtained from The Cancer Genome Atlas (TCGA) and stratified into 231 epithelial and 89 mesenchymal subtypes as previously defined[5]
44 differentially expressed genes known for inducing mesenchymal features including, EMT inducing transcription factors (TWIST1, SNAI2, ZEB1, and ZEB2), matrix metalloproteinases, BMP family genes, and collagen family genes (Supplementary Table 2), were identified indicating the regression model was built on meaningful data in the context of EMT18–22
Summary
Little is understood about the contribution of lncRNA to epithelial-to-mesenchymal transition (EMT), which correlates with metastasis. We report an integrated analysis of >700 ovarian cancer molecular profiles, including genomic data sets, from four patient cohorts identifying lncRNA DNM3OS, MEG3, and MIAT overexpression and their reproducible gene regulation in ovarian cancer EMT. DNM3OS knockdown results in altered EMT-linked genes/pathways, mesenchymal-to-epithelial transition, and reduced cell migration and invasion. Our results elucidate lncRNA that regulate EMT and demonstrate DNM3OS contributes to EMT in ovarian cancer. Elevated expression of one lncRNA, ANRIL, was reported to increase proliferation, migration, and invasion of serous ovarian cancer cells[13,14]. 11 lncRNA have recently been shown to function in migration, EMT, and metastasis in multiple cancers; their role in ovarian cancer is unknown[15]. Much about lncRNA and ovarian cancer remains to be investigated
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