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Osteopontin facilitates tumor metastasis by regulating epithelial-mesenchymal plasticity.

ABSTRACT: Tumor metastasis leads to high mortality; therefore, understanding the mechanisms that underlie tumor metastasis is crucial. Generally seen as a secretory protein, osteopontin (OPN) is involved in multifarious pathophysiological events. Here, we present a novel pro-metastatic role of OPN during metastatic colonization. Unlike secretory OPN (sOPN), which triggers the epithelial-mesenchymal transition (EMT) to initiate cancer metastasis, intracellular/nuclear OPN (iOPN) induces the mesenchymal-epithelial transition (MET) to facilitate the formation of metastases. Nuclear OPN is found to interact with HIF2? and impact the subsequent AKT1/miR-429/ZEB cascade. In vivo assays confirm that the progression of metastatic colonization is accompanied by the nuclear accumulation of OPN and the MET process. Furthermore, evidence of nuclear OPN in the lung metastases is exhibited in clinical specimens. Finally, VEGF in the microenvironment was shown to induce the translocation of OPN into the nucleus through a KDR/PLC?/PKC-dependent pathway. Taken together, our results describe the pleiotropic roles of OPN in the tumor metastasis cascade, which indicate its potential as an effective target for both early and advanced tumors.

SUBMITTER: Jia R

PROVIDER: S-EPMC5261026 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Osteopontin facilitates tumor metastasis by regulating epithelial-mesenchymal plasticity.

Jia Rongjie R Liang Yingchao Y Chen Rui R Liu Guoke G Wang Hao H Tang Min M Zhou Xuyu X Wang Huajing H Yang Yang Y Wei Huafeng H Li Bohua B Song Yipeng Y Zhao Jian J

Cell death & disease 20161229 12

Tumor metastasis leads to high mortality; therefore, understanding the mechanisms that underlie tumor metastasis is crucial. Generally seen as a secretory protein, osteopontin (OPN) is involved in multifarious pathophysiological events. Here, we present a novel pro-metastatic role of OPN during metastatic colonization. Unlike secretory OPN (sOPN), which triggers the epithelial-mesenchymal transition (EMT) to initiate cancer metastasis, intracellular/nuclear OPN (iOPN) induces the mesenchymal-epi ...[more]

PMID: 28032860

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Project description:BackgroundOvarian cancer is one of the most widespread malignant diseases of the female reproductive system worldwide. The plurality of ovarian cancer is diagnosed with metastasis in the abdominal cavity. Epithelial-mesenchymal transition (EMT) exerts a vital role in tumor cell metastasis. However, it remains unclear whether long non-coding RNA (lncRNA) are implicated in EMT and influence ovarian cancer cell invasion and metastasis. This study was designed to investigate the impacts of lncRNA AC005224.4 on ovarian cancer.MethodsLncRNA AC005224.4, miR-140-3p, and snail family transcriptional repressor 2 ( SNAI2 ) expression levels in ovarian cancer and normal ovarian tissues were determined using real-time quantitative polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) and Transwell (migration and invasion) assays were conducted to measure SKOV3 and CAOV-3 cell proliferation and metastasis. E-cadherin, N-cadherin, Snail, and Vimentin contents were detected using Western blot. Nude mouse xenograft assay was utilized to validate AC005224.4 effects in vivo . Dual-luciferase reporter gene assay confirmed the targeted relationship between miR-140-3p and AC005224.4 or SNAI2 .ResultsAC005224.4 and SNAI2 upregulation and miR-140-3p downregulation were observed in ovarian cancer tissues and cells. Silencing of AC005224.4 observably moderated SKOV3 and CAOV-3 cell proliferation, migration, invasion, and EMT process in vitro and impaired the tumorigenesis in vivo . miR-140-3p was a target of AC005224.4 and its reduced expression level was mediated by AC005224.4. miR-140-3p mimics decreased the proliferation, migration, and invasion of ovarian cancer cells. SNAI2 was identified as a novel target of miR-140-3p and its expression level was promoted by either AC005224.4 overexpression or miR-140-3p knockdown. Overexpression of SNAI2 also facilitated ovarian cancer cell viability and metastasis.ConclusionAC005224.4 was confirmed as an oncogene via sponging miR-140-3p and promoted SNAI2 expression, contributing to better understanding of ovarian cancer pathogenesis and shedding light on exploiting the novel lncRNA-directed therapy against ovarian cancer.

Dataset Information

Osteopontin facilitates tumor metastasis by regulating epithelial-mesenchymal plasticity.

Publications

Osteopontin facilitates tumor metastasis by regulating epithelial-mesenchymal plasticity.

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