RAC1 activation mediates Twist1-induced cancer cell migration

Yang, Wen Hao; Lan, Hsin Yi; Huang, Chih Chia; Tai, Shyh Kuan; Tzeng, Cheng Hwai; Kao, Shou Yen; Wu, Kou Juey; Hung, Mien Chie; Yang, Muh Hwa

doi:10.1038/ncb2455

Cited by 214 publications

(208 citation statements)

References 44 publications

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“…Modeling the mRNA degradation with the let-7 sensors suggest that the effect of a specific let-7 miR on a particular target mRNA depends on the degree of miR-mRNA complementarity and on the ratio of particular let-7 miR and its mRNA target. Although the let-7 family members are often considered to have redundant functions (21), studies in squamous cell carcinomas of the head suggest that let-7b inhibits proliferation, let-7d represses epithelial to mesenchymal transition, and let-7i mainly inhibits mesenchymal cell movement (46)(47)(48). Our observations support the possibility that the let-7 family members exhibit target selectivity and thus might promote different cell fates even when expressed in the same cell type.…”

Section: Discussionsupporting

confidence: 74%

SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

Cimadamore

Amador-Arjona

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

199

182

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The transcription factor SRY (sex-determining region)-box 2 (SOX2) is an important functional marker of neural precursor cells (NPCs) and plays a critical role in self-renewal and neuronal differentiation; however, the molecular mechanisms underlying its functions are poorly understood. Using human embryonic stem cellderived NPCs to model neurogenesis, we found that SOX2 is required to maintain optimal levels of LIN28, a well-characterized suppressor of let-7 microRNA biogenesis. Exogenous LIN28 expression rescued the NPC proliferation deficit, as well as the early but not the late stages of the neurogenic deficit associated with the loss of SOX2. We found that SOX2 binds to a proximal site in the LIN28 promoter region and regulates LIN28 promoter acetylation, likely through interactions with the histone acetyltransferase complex. Misexpression of let-7 microRNAs in NPCs reduced proliferation and inhibited neuronal differentiation, phenocopying the loss of SOX2. In particular, we identified let-7i as a novel and potent inhibitor of neuronal differentiation that targets MASH1 and NGN1, two well-characterized proneural genes. In conclusion, we discovered the SOX2-LIN28/let-7 pathway as a unique molecular mechanism governing NPC proliferation and neurogenic potential.neural stem cells | mechanisms of pluripotency S elf-renewing, multipotent neural precursor cells (NPCs) are capable of terminally differentiating into neuronal and glial lineages during development and in the adult nervous system (1, 2). Disruption of the pathways controlling NPC biology has been implicated in various pathologies, including autism (3), Treacher Collins syndrome (4), and neural tube defects (5), emphasizing the importance of gaining a better understanding of the underlying molecular events and how they may be manipulated to treat and prevent such pathologies. The HMG-box transcription factor SOX2 is ubiquitously expressed in NPCs and supports their self-renewal (6). SOX2 is also required for neurogenesis in the central nervous system (7-10). Recently, we used human embryonic stem cells (hESCs) and mouse models to demonstrate a critical requirement for SOX2 for sensory neurogenesis in dorsal root ganglia (11). However, the mechanisms by which SOX2 functions in self-renewal and neuronal differentiation remain poorly understood.Small, noncoding microRNAs (miRNAs) are transcribed as long precursors (pri-miRNAs) that are sequentially processed by the RNases Drosha/Pasha to form pri-miRNAs and by Dicer to form the mature miRNAs of ∼20-25 nucleotides. The miRNAs function through imperfect base-pairing with hundreds of target mRNAs to trigger their degradation (or block their translation) by the RNA-induced silencing complex, RISC (12). In some cases, miRNA maturation is tightly controlled; for example, the RNA-binding protein LIN28 regulates the biogenesis of the let-7 miRNA family by inhibiting their maturation at both the primiRNA (13, 14) and premiRNA (15, 16) processing steps. Intriguingly, LIN28 protein was found to be associated with SO...

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Section: Discussionsupporting

confidence: 74%

SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

Cimadamore

Amador-Arjona

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

199

182

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“…Twist1 is an established repressor of E-cadherin gene transcription during EMT, 14,15 and it directly induces N-cadherin expression in PC cells. 16 Moreover, Twist1 has been shown to induce RAC1 activity 22 and formation of invadopodia in cancer cells. 24 The regulatory regions of the Twist1 gene contain the g-interferoneactivated sequence, 85 a binding element shared by Stat3 and Stat5a/ b, and Stat3 has been shown to up-regulate Twist1 gene expression in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Talati

Ellsworth

et al. 2015

The American Journal of Pathology

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Active Stat5a/b predicts early recurrence and disease-specific death in prostate cancer (PC), which both typically are caused by development of metastatic disease. Herein, we demonstrate that Stat5a/b induces epithelial-to-mesenchymal transition (EMT) of PC cells, as shown by Stat5a/b regulation of EMT marker expression (Twist1, E-cadherin, N-cadherin, vimentin, and fibronectin) in PC cell lines, xenograft tumors in vivo, and patient-derived PCs ex vivo using organ explant cultures. Jak2-Stat5a/b signaling induced functional end points of EMT as well, indicated by disruption of epithelial cell monolayers and increased migration and adhesion of PC cells to fibronectin. Knockdown of Twist1 suppressed Jak2-Stat5a/beinduced EMT properties of PC cells, which were rescued by re-introduction of Twist1, indicating that Twist1 mediates Stat5a/b-induced EMT in PC cells. While promoting EMT, Jak2-Stat5a/b signaling induced stemlike properties in PC cells, such as sphere formation and expression of cancer stem cell markers, including BMI1. Mechanistically, both Twist1 and BMI1 were critical for Stat5a/b induction of stem-like features, because genetic knockdown of Twist1 suppressed Stat5a/b-induced BMI1 expression and sphere formation in stem cell culture conditions, which were rescued by re-introduction of BMI1. By using human prolactin knock-in mice, we demonstrate that prolactin-Stat5a/b signaling promoted metastases formation of PC cells in vivo. In conclusion, our data support the concept that Jak2-Stat5a/b signaling promotes metastatic progression of PC by inducing EMT and stem cell properties in PC cells. Most prostate cancer (PC)erelated deaths are because of development of metastatic disease. A central process in metastatic dissemination of PC is epithelial-to-mesenchymal transition (EMT), during which cancer cells attain more motile and invasive properties, invade through the basement membrane, and survive in systemic circulation. 1e3 Extravasation at distant organ sites is followed by adhesion of cancer cells to extracellular matrix proteins, such as fibronectin, 4e6 leading to formation of premetastatic niches and subsequent formation of macroscopic metastases. 7e9 Hallmarks of EMT in PC include disruption of adherens junctions through down-regulation of E-cadherin, 2 concomitant with a development of a migratory phenotype and up-regulation of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin. 10,11 Loss of E-cadherin results from mutations, DNA methylation, or silencing of E-cadherin promoter

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“…61 Additionally, Rho family GTPases are well recognized for their complex interaction networks and multiple roles played in regulation of actin cytoskeleton assembly. 62 It has also been reported that two of the Rho family GTPases, cell division control protein 42 (Cdc42) and Rac1, can regulate cell motility, [63][64][65] phagocytosis, 66 and macropinocytosis. 67 Therefore, we hypothesized that electrotransfection could lead to actin remodeling and enhance macropinocytosis through activation of Cdc42 and Rac1.…”

Section: Dna Uptake By Electrotransfection-induced Macropinocytosis Imentioning

confidence: 99%

Involvement of a Rac1-Dependent Macropinocytosis Pathway in Plasmid DNA Delivery by Electrotransfection

et al. 2017

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RAC1 activation mediates Twist1-induced cancer cell migration

Cited by 214 publications

References 44 publications

SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

Jak2-Stat5a/b Signaling Induces Epithelial-to-Mesenchymal Transition and Stem-Like Cell Properties in Prostate Cancer

Involvement of a Rac1-Dependent Macropinocytosis Pathway in Plasmid DNA Delivery by Electrotransfection

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