Dataset Information

High FMNL3 expression promotes nasopharyngeal carcinoma cell metastasis: role in TGF-?1-induced epithelia-to-mesenchymal transition.

ABSTRACT: Formin-like 3 (FMNL3) plays a crucial role in cytoskeletal mediation and is potentially a biomarker for cell migration; however, its role in cancer metastasis remains unknown. In this study, we found elevated FMNL3 protein expression in clinical nasopharyngeal carcinoma (NPC) tissues. FMNL3 expression positively correlated to the clinical stage, T (tumour), N (lymph node metastasis) and M (distant metastasis) classification of NPC patients. Moreover, FMNL3 positively correlated to Vimentin expression and negatively correlated to E-cadherin expression in clinical NPC samples. In vitro experiments showed that FMNL3 expression was inversely related to NPC cell differentiation status. Overexpression of FMNL3 led to epithelial-to-mesenchymal transition (EMT) in well differentiated CNE1 cells. TGF-?1-treated poorly differentiated CNE2 cells showed changes in EMT accompanied by enhanced FMNL3 expression and cell migration. On the contrary, knockdown of FMNL3 partially attenuated the TGF-?1-promoted CNE2 cell migration, together with associated changes in EMT markers. Finally, knockdown of FMNL3 also weakened EMT in tumours in xenographs. Our study indicates for the first time that TGF-?1/FMNL3 signalling may be a novel mechanism mediating EMT in NPC, which is closely associated with NPC metastasis.

SUBMITTER: Wu Y

PROVIDER: S-EPMC5309845 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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High FMNL3 expression promotes nasopharyngeal carcinoma cell metastasis: role in TGF-β1-induced epithelia-to-mesenchymal transition.

Wu Yanxia Y Shen Zhihua Z Wang Keke K Ha Yanping Y Lei Hong H Jia Yanan Y Ding Ranran R Wu Dongmei D Gan Siyuan S Li Rujia R Luo Botao B Jiang Hanguo H Jie Wei W

Scientific reports 20170215

Formin-like 3 (FMNL3) plays a crucial role in cytoskeletal mediation and is potentially a biomarker for cell migration; however, its role in cancer metastasis remains unknown. In this study, we found elevated FMNL3 protein expression in clinical nasopharyngeal carcinoma (NPC) tissues. FMNL3 expression positively correlated to the clinical stage, T (tumour), N (lymph node metastasis) and M (distant metastasis) classification of NPC patients. Moreover, FMNL3 positively correlated to Vimentin expre ...[more]

PMID: 28198387

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Project description:Transforming growth factor (TGF)‑β1 is a key cytokine affecting the pathogenesis and progression of cervical cancer. Tumor‑derived exosomes contain microRNAs (miRNAs/miRs) that interact with cancer and stromal cells, thereby contributing to tissue remodeling in the tumor microenvironment (TME). The present study was designed to clarify how TGF‑β1 affects tumor biological functions through exosomes released by cervical cancer cells. Deep RNA sequencing found that TGF‑β1 stimulated cervical cancer cells to secrete more miR‑663b‑containing exosomes, which could be transferred into new target cells to promote metastasis. Further studies have shown that miR‑663b directly targets the 3'-untranslated regions (3'‑UTR) of mannoside acetylglucosaminyltransferase 3 (MGAT3) and is involved in the epithelial‑mesenchymal transition (EMT) process. Remarkably, the overexpression of MGAT3 suppressed cervical cancer cell metastasis promoted by exosomal miR‑663b, causing increased expression of epithelial differentiation marker E‑cadherin and decreased expression of mesenchymal markers N‑cadherin and β‑catenin. Throughout our study, online bioinformation tools and dual luciferase reporter assay were applied to identify MGAT3 as a novel direct target of miR‑663b. Exosome PKH67‑labeling experiment verified that exosomal miR‑663b could be endocytosed by cervical cancer cells and subsequently influence its migration and invasion functions which were measured by wound healing and Transwell assays. The expression of miR‑663b and MGAT3 and the regulation of the EMT pathway caused by MGAT3 were detected by quantitative real‑time transcription‑polymerase chain reaction (qPCR) and western blot analysis. These results, thus, provide evidence that cancer cell‑derived exosomal miR‑663b is endocytosed by cervical cancer cells adjacent or distant after TGF‑β1 exposure and inhibits the expression of MGAT3, thereby accelerating the EMT process and ultimately promoting local and distant metastasis.

Project description:Rationale: Metastasis is the leading cause of disease-related death among patients with nasopharyngeal carcinoma (NPC). Mounting evidence suggest that epithelial-mesenchymal transition (EMT) is crucial for cancer cells to acquire metastatic ability. In this study, we aim to clarify the extent to which EMT is involved in various cancer properties and identify novel markers for predicting the prognosis of NPC patients. Methods: Two cellular models derived from the same NPC cell line with distinct metastasis ability were used for microarray analysis to identify key transcriptional factors that drive metastasis. Cell migration and invasion were analyzed by wound healing and Transwell analysis. Lung metatasis was determined by tail vein injection assay. Cancer stemness was analyzed using colony formation and xenograft assay. The EMT extent was evaluated using immunoblotting, RT-qPCR and immunofluorescence of EMT markers. The value of OVOL2 in prognosis was determined by immunohistochemistry in NPC biopsies. Results: OVOL2 was the most significantly down-regulated EMT transcription factor (EMT-TF) in cellular models of NPC metatasis. Low levels of OVOL2 were associated with poor overall survival of NPC patients and the reduced expression is partly due to promoter methylation and epithelial dedifferentiation. Knockout of OVOL2 in epithelial-like NPC cells partially activates EMT program and significantly promotes cancer stemness and metastatic phenotypes. Conversely, ectopically expression of OVOL2 in mesenchymal-like cells leads to a partial transition to an epithelial phenotype and reduced malignancy. Reversing EMT by depleting ZEB1, a major target of OVOL2, does not eliminate the stemness advantage of OVOL2-deficient cells but does reduce their invasion capacity. A comparison of subpopulations at different stages of EMT revealed that the extent of EMT is positively correlated with metastasis and drug resistance; however, only the intermediate EMT state is associated with cancer stemness. Conclusion: Distinct from other canonical EMT-TFs, OVOL2 only exhibits modest effect on EMT but has a strong impact on both metastasis and tumorigenesis. Therefore, OVOL2 could serve as a prognostic indicator for cancer patients.

Dataset Information

High FMNL3 expression promotes nasopharyngeal carcinoma cell metastasis: role in TGF-?1-induced epithelia-to-mesenchymal transition.

Publications

High FMNL3 expression promotes nasopharyngeal carcinoma cell metastasis: role in TGF-β1-induced epithelia-to-mesenchymal transition.

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