ALX1 Induces Snail Expression to Promote Epithelial-to-Mesenchymal Transition and Invasion of Ovarian Cancer Cells

Yuan, Hong; Kajiyama, Hiroaki; Ito, Satoko; Yoshikawa, Nobuhisa; Hyodo, Toshinori; Asano, Eri; Hasegawa, Hitoki; Maeda, Masao; Shibata, Kiyosumi; Hamaguchi, Michinari; Kikkawa, Fumitaka; Senga, Takeshi

doi:10.1158/0008-5472.can-12-2377

Cited by 60 publications

(46 citation statements)

References 42 publications

(47 reference statements)

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“…In vertebrates, alx1 (also known as cart1) mutations have long been associated with craniofacial defects and neural tube defects without any known involvement in EMT (Zhao et al, 1996;Uz et al, 2010). However, recent vertebrate evidence shows a role for alx1 in EMT; in ovarian cancer cells, alx1 is reported to be upstream of snail-promoting EMT (Yuan et al, 2013). In the sea urchin de-adhesion sub-circuit, alx1 is upstream of both twist and snail, with twist also positively regulating alx1.…”

Section: Apical Constriction and Ab Polaritymentioning

confidence: 99%

Sub-circuits of a gene regulatory network control a developmental epithelial-mesenchymal transition

2014

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Epithelial-mesenchymal transition (EMT) is a fundamental cell state change that transforms epithelial to mesenchymal cells during embryonic development, adult tissue repair and cancer metastasis. EMT includes a complex series of intermediate cell state changes including remodeling of the basement membrane, apical constriction, epithelial de-adhesion, directed motility, loss of apical-basal polarity, and acquisition of mesenchymal adhesion and polarity. Transcriptional regulatory state changes must ultimately coordinate the timing and execution of these cell biological processes. A wellcharacterized gene regulatory network (GRN) in the sea urchin embryo was used to identify the transcription factors that control five distinct cell changes during EMT. Single transcription factors were perturbed and the consequences followed with in vivo time-lapse imaging or immunostaining assays. The data show that five different sub-circuits of the GRN control five distinct cell biological activities, each part of the complex EMT process. Thirteen transcription factors (TFs) expressed specifically in pre-EMT cells were required for EMT. Three TFs highest in the GRN specified and activated EMT (alx1, ets1, tbr) and the 10 TFs downstream of those (tel, erg, hex, tgif, snail, twist, foxn2/3, dri, foxb, foxo) were also required for EMT. No single TF functioned in all five sub-circuits, indicating that there is no EMT master regulator. Instead, the resulting sub-circuit topologies suggest EMT requires multiple simultaneous regulatory mechanisms: forward cascades, parallel inputs and positive-feedback lock downs. The interconnected and overlapping nature of the sub-circuits provides one explanation for the seamless orchestration by the embryo of cell state changes leading to successful EMT.

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Section: Apical Constriction and Ab Polaritymentioning

confidence: 99%

Sub-circuits of a gene regulatory network control a developmental epithelial-mesenchymal transition

2014

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“…In addition, cell proliferation and EMT are always accompanied by the dynamic changes of gene expression. One of the hallmarks to evaluate EMT is the reduction in E‐cadherin expression, which is considered an active suppressor of invasion and growth of many epithelial cancers 8, 9, 10, 11.…”

Section: Introductionmentioning

confidence: 99%

MiR‐138 inhibits cell proliferation and reverses epithelial‐mesenchymal transition in non‐small cell lung cancer cells by targeting GIT1 and SEMA4C

Wang

Wen

et al. 2015

J Cellular Molecular Medi

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Non‐small‐cell lung cancer (NSCLC) is one of the most common and lethal malignant tumours worldwide with a poor 5‐year survival rate. Recent studies indicated that miRNAs have been involved in the tumorigenic driver pathways in NSCLC, but the relevant molecular mechanisms are not well‐understood. In this study, we investigated the biological functions and molecular mechanisms of miR‐138 in human NSCLC. The effects of miR‐138 on the NSCLC cell growth and epithelial‐mesenchymal transition (EMT) were first examined. Then the targeting connections of miR‐138 with G‐protein‐coupled receptor kinase‐interacting protein 1 (GIT1) and semaphorin 4C (SEMA4C) were confirmed by dual luciferase reporter assays. Finally, the effects of GIT1 and SEMA4C on the NSCLC cell growth and EMT were investigated respectively. We found that the ectopic expression of miR‐138 resulted in a significant inhibition of NSCLC growth and reversion of EMT. GIT1 and SEMA4C were identified as two novel targets of miR‐138. Furthermore, GIT1 and SEMA4C knockdown inhibited the cell growth and reversed EMT, just like the effects of miR‐138 overexpression on NSCLC cells, whereas ectopic expression of GIT1 and SEMA4C partly rescued the suppressive effects of miR‐138 in NSCLC cells. These data represent a crucial step towards the understanding of the novel roles and molecular mechanism of miR‐138, GIT1 and SEMA4C in NSCLC progression, which may provide some new targets or prognostic biomarkers for NSCLC treatment, thus having implications in translational oncology.

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“…Knockdown (KD) of Alx1 in the sea urchin embryo results in decreased numbers of PMCs, delayed ingression of PMCs, failure to complete epithelial-to-mesenchymal transition (EMT) at mesenchyme blastula stage [24 h post fertilization (hpf )] due to the defects in de-adhesion, and a complete lack of skeletal rod formation (Ettensohn et al, 2003;Saunders and McClay, 2014). One of the downstream genes activated by Alx1 is Snail, which encodes an evolutionarily conserved TF that plays a key role in cell migration and EMT in sea urchin and other animals by inhibiting the transcription of cadherin gene and promoting its endocytosis (Batlle et al, 2000;Wu and McClay, 2007;Yuan et al, 2013;Saunders and McClay, 2014).…”

Section: Introductionmentioning

confidence: 99%

microRNA-31 modulates skeletal patterning in the sea urchin embryos

Stepicheva

Song

2015

Development

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MicroRNAs (miRNAs) are small non-coding RNAs that repress the translation and reduce the stability of target mRNAs in animal cells. microRNA-31 (miR-31) is known to play a role in cancer, bone formation and lymphatic development. However, studies to understand the function of miR-31 in embryogenesis have been limited. We examined the regulatory role of miR-31 in early development using the sea urchin as a model. miR-31 is expressed at all stages of development and its knockdown (KD) disrupts the patterning and function of primary mesenchyme cells (PMCs), which form the embryonic skeleton spicules. We identified that miR-31 directly represses Pmar1, Alx1, Snail and VegfR7 within the PMC gene regulatory network using reporter constructs. Further, blocking the miR-31-mediated repression of Alx1 and/or VegfR7 in the developing embryo resulted in defects in PMC patterning and skeletogenesis. The majority of the mislocalized PMCs in miR-31 KD embryos did not express VegfR10, indicating that miR-31 regulates VegfR gene expression within PMCs. In addition, miR-31 indirectly suppresses Vegf3 expression in the ectoderm. These results indicate that miR-31 coordinately suppresses genes within the PMCs and in the ectoderm to impact PMC patterning and skeletogenesis. This study identifies the novel function and molecular mechanism of miR-31-mediated regulation in the developing embryo.

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ALX1 Induces Snail Expression to Promote Epithelial-to-Mesenchymal Transition and Invasion of Ovarian Cancer Cells

Cited by 60 publications

References 42 publications

Sub-circuits of a gene regulatory network control a developmental epithelial-mesenchymal transition

Sub-circuits of a gene regulatory network control a developmental epithelial-mesenchymal transition

MiR‐138 inhibits cell proliferation and reverses epithelial‐mesenchymal transition in non‐small cell lung cancer cells by targeting GIT1 and SEMA4C

microRNA-31 modulates skeletal patterning in the sea urchin embryos

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