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SIX1 coordinates with TGF? signals to induce epithelial-mesenchymal transition in cervical cancer.

ABSTRACT: Epithelial-mesenchymal transition (EMT) plays a critical role in promoting tumor invasion and metastasis. However, the key cofactors that modulate the signal transduction to induce EMT have note been fully explored to date. The present study reports that sine oculis homeobox homolog 1 (SIX1) is able to promote EMT of cervical cancer by coordinating with transforming growth factor (TGF)?-SMAD signals. The expression of SIX1 was negatively correlated with the expression of the epithelial marker E-cadherin in two independent groups of cervical cancer specimens. SIX1 could promote the transition of mesenchymal phenotype in the presence of active TGF? signals in vitro and in vivo. TGF?-SMAD signals were required for the SIX1-mediated promotion of EMT and metastatic capacity of cervical cancer cells. Together, SIX1 and TGF? cooperated to induce more remarkable changes in the transition of phenotype than each of them alone, and coordinated to promote cell motility and tumor metastasis in cervical cancer. These results suggest that the coordination of SIX1 and TGF? signals may be crucial in the EMT program, and that SIX1/TGF? may be considered a valuable marker for evaluating the metastatic potential of cervical cancer cells, or a therapeutic target in the treatment of cervical cancer.

SUBMITTER: Sun SH

PROVIDER: S-EPMC4950046 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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SIX1 coordinates with TGFβ signals to induce epithelial-mesenchymal transition in cervical cancer.

Sun Shu-Hua SH Liu Dan D Deng Yun-Te YT Zhang Xiao-Xue XX Wan Dong-Yi DY Xi Bi-Xin BX Huang Wei W Chen Qian Q Li Meng-Chen MC Wang Ming-Wei MW Yang Fei F Shu Ping P Wu Ke-Zhi KZ Gao Qing-Lei QL

Oncology letters 20160628 2

Epithelial-mesenchymal transition (EMT) plays a critical role in promoting tumor invasion and metastasis. However, the key cofactors that modulate the signal transduction to induce EMT have note been fully explored to date. The present study reports that sine oculis homeobox homolog 1 (SIX1) is able to promote EMT of cervical cancer by coordinating with transforming growth factor (TGF)β-SMAD signals. The expression of SIX1 was negatively correlated with the expression of the epithelial marker E- ...[more]

PMID: 27446426

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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.

Dataset Information

SIX1 coordinates with TGF? signals to induce epithelial-mesenchymal transition in cervical cancer.

Publications

SIX1 coordinates with TGFβ signals to induce epithelial-mesenchymal transition in cervical cancer.

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