Loss of <i>miR-203</i> regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness

Le, Lily Thao-Nhi; Cazares, Oscar; Mouw, Janna K.; Chatterjee, Sharmila; Macias, Hector; Moran, Angel; Ramos, Jillian; Keely, Patricia J.; Weaver, Valerie M.; Hinck, Lindsay

doi:10.1083/jcb.201507054

Cited by 42 publications

(33 citation statements)

References 51 publications

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“…For instance, small nucleolar RNA (snoRNA) base pair with pre-RNA to guide folding and splicing of transcripts, and some evidence even suggests snoRNAs can affect translation ofmRNA similar to microRNAs (miRNAs) (Ender et al, 2008; Gerbi & Borovjagin, 2004). We found ECM stiffness can regulate miRNAs, which modulate gene expression posttranscriptionally, downstream of activated integrins and through signaling cascades initiated by Robo-Slit interactions (Le et al, 2016; Mouw, Yui, et al, 2014). However, these were not broad regulatory effects, rather, we noted that a subgroup of miRNAs is highly sensitive to ECM stiffness, implying there may be a level of specificity to which sets of genes can be epigenetically regulated by miRNAs in response to stiffness.…”

Section: Summary and Future Directionsmentioning

confidence: 94%

The Physical and Biochemical Properties of the Extracellular Matrix Regulate Cell Fate

Muncie

Weaver

2018

Current Topics in Developmental Biology

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The extracellular matrix is a complex network of hydrated macromolecular proteins and sugars that, in concert with bound soluble factors, comprise the acellular stromal microenvironment of tissues. Rather than merely providing structural information to cells, the extracellular matrix plays an instructive role in development and is critical for the maintenance of tissue homeostasis. In this chapter, we review the composition of the extracellular matrix and summarize data illustrating its importance in embryogenesis, tissue-specific development, and stem cell differentiation. We discuss how the biophysical and biochemical properties of the extracellular matrix ligate specific transmembrane receptors to activate intracellular signaling that alter cell shape and cytoskeletal dynamics to modulate cell growth and viability, and direct cell migration and cell fate. We present examples describing how the extracellular matrix functions as a highly complex physical and chemical entity that regulates tissue organization and cell behavior through a dynamic and reciprocal dialogue with the cellular constituents of the tissue. We suggest that the extracellular matrix not only transmits cellular and tissue-level force to shape development and tune cellular activities that are key for coordinated tissue behavior, but that it is itself remodeled such that it temporally evolves to maintain the integrated function of the tissue. Accordingly, we argue that perturbations in extracellular matrix composition and structure compromise key developmental events and tissue homeostasis, and promote disease.

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Section: Summary and Future Directionsmentioning

confidence: 94%

The Physical and Biochemical Properties of the Extracellular Matrix Regulate Cell Fate

Muncie

Weaver

2018

Current Topics in Developmental Biology

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220

153

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“…It is well known that miRNAs have emerged as key mediators of tumorigenesis and development, as they broadly participate in cellular processes, including invasion, proliferation, senescence, extracellular matrix (ECM) synthesis and death [38][39][40]. MiR-744 was one of the microRNAs that changed after the interference of a metastasis related gene in NSCLC cells, which was the rst time that miR-744 caught our attention [3].…”

Section: Discussionmentioning

confidence: 99%

MiR-744 facilitates non-small cell lung cancer progression by direct transcriptional regulation and indirect MAPK pathway activation mediated upregulation of C-FOS

Zhu

2020

Preprint

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Background: Metastasis is the leading cause of lung cancer associated death. Here, we focused on the function and molecular mechanism of miR-744 and its potential clinical application in lung carcinoma. Methods: The clinical cohort and data from TCGA were analyzed for the correlation of miR-744 and outcomes. Multiple NSCLC cell lines and a xenograft model were applied for the functional studies. Reporter assays were explored for transcriptional regulatory mechanism.Results: It was confirmed that the overexpression of miR-744 was significantly correlated with lymph node metastasis and poor prognosis in NSCLC. Both in vitro and in vivo studies revealed that miR-744 overexpression aggravated the growth, invasion and metastasis of NSCLC cells. MiR-744 enhanced the resistance of lung cancer cells to radiotherapy and paclitaxel. MiR-744 positively regulated C-FOS by directly binding to the promoter of C-FOS and -1195 to -1227 and -298 to -323 bp upstream of C-FOS gene were the direct and efficient miR-744 binding sites. MiR-744 could also indirectly upregulate c-FOS protein by activating MAPK pathway.Conclusion: Our findings uncover the function and a novel mechanism of miR-744 in mediating growth and metastasis of NSCLC cells. Our data suggests that miR-744 may serve as a possible therapeutic target for NSCLC.

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“…For example, stiff substrates were found to control cell contractility by downregulating the microRNA, miR-203, through a Roundabout Guidance Receptor 1 (ROBO1)/ Rac1 GTPase/FAK signaling axis (105). ROBO1 is involved in RhoA-mediated cell migration and miR-203 targets ROBO1 transcripts for degradation.…”

Section: Forcing Tumor Aggressionmentioning

confidence: 99%

“…ROBO1 is involved in RhoA-mediated cell migration and miR-203 targets ROBO1 transcripts for degradation. Thus, its downregulation represents a strategy for cells to maintain RhoA signaling, cell shape and adhesion during periods of high mechanical pressure (105). …”

Section: Forcing Tumor Aggressionmentioning

confidence: 99%

Tissue Force Programs Cell Fate and Tumor Aggression

2017

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Biomechanical and biochemical cues within a tissue collaborate across length scales to direct cell fate during development and are critical for the maintenance of tissue homeostasis. Loss of tensional homeostasis in a tissue not only accompanies malignancy but may also contribute to oncogenic transformation. High mechanical stress in solid tumors can impede drug delivery, and may additionally drive tumor progression and promote metastasis. Mechanistically, biomechanical forces can drive tumor aggression by inducing a mesenchymal-like switch in transformed cells so that they attain tumor initiating or stem-like cell properties. Given that cancer stem cells have been linked to metastasis and treatment resistance, this raises the intriguing possibility that the elevated tissue mechanics in tumors could promote their aggression by programming their phenotype towards that exhibited by a stem-like cell.

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Loss of miR-203 regulates cell shape and matrix adhesion through ROBO1/Rac/FAK in response to stiffness

Abstract: Increased stiffness in the tumor microenvironment generates forces on cells that promote cancer development. A signaling circuit is identified through which cells sense and respond to these changes. Patients whose tumors express these genes exhibit a better overall survival prognosis.

Cited by 42 publications

References 51 publications

The Physical and Biochemical Properties of the Extracellular Matrix Regulate Cell Fate

The Physical and Biochemical Properties of the Extracellular Matrix Regulate Cell Fate

MiR-744 facilitates non-small cell lung cancer progression by direct transcriptional regulation and indirect MAPK pathway activation mediated upregulation of C-FOS

Tissue Force Programs Cell Fate and Tumor Aggression

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