MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11

Bockhorn, Jessica; Dalton, Rachel; Nwachukwu, Chika; Huang, Simo; Prat, Aleix; Yee, Kathy; Chang, Yi‐Han; Huo, Dezheng; Wen, Yujia; Swanson, Kaitlin E.; Qiu, Tyler; Lü, Jun; Park, Seo Young; Dolan, M. Eileen; Perou, Charles M.; Olopade, Olufunmilayo I.; Clarke, Michael F.; Greene, Geoffrey L.; Liu, Huiping

doi:10.1038/ncomms2393

Cited by 210 publications

(200 citation statements)

References 32 publications

(52 reference statements)

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“…To study the in vivo role of twinfilin-phosphoinositide interaction in the future, it will be important to identify twinfilin mutants that specifically inhibit its lipid-binding activity. Because twinfilin is linked to several diseases, such as lymphoma (26) and breast cancer (30) progression and chemoresistance, it will be also important to elucidate the possible role of twinfilinphosphoinositide interactions, as well as other regulatory mechanisms of twinfilin, in these disorders.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Twinfilins are involved in several actin-dependent cellular and developmental processes, such as cell migration (26, 27), endocytosis (28, 29), epithelialto-mesenchymal transition (30), morphology of inner ear stereocilia (31), axonal growth of neurons (27), and platelet activation (32). Moreover, human twinfilin-1 has been shown to facilitate resistance to chemotherapy agents in breast cancer and lymphoma (26,30).Twinfilins contribute to cytoskeletal dynamics through a complex mechanism that involves interactions with actin monomers, actin filaments, and heterodimeric capping protein. Both yeast and mammalian twinfilins bind ADP-actin monomers with high affinity, and inhibit their nucleotide exchange and assembly into filament ends (23,33,34).…”

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confidence: 99%

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Molecular mechanism for inhibition of twinfilin by phosphoinositides

Hakala

Vattulainen

Lappalainen

2018

Journal of Biological Chemistry

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Membrane phosphoinositides control organization and dynamics of the actin cytoskeleton by regulating the activities of several key actin-binding proteins. Twinfilin is an evolutionarily conserved protein, which contributes to cytoskeletal dynamics by interacting with actin monomers, filaments, and the heterodimeric capping protein. Twinfilin also binds phosphoinositides, which inhibit its interactions with actin, but the underlying mechanism has remained unknown. Here we show that the highaffinity binding site of twinfilin for phosphoinositides is located at the carboxy-terminal tail-region, while the two ADF/cofilin like ADF-H domains of twinfilin bind phosphoinositides only with low affinity. Mutagenesis and biochemical experiments combined with atomistic molecular dynamics simulations reveal that the carboxy-terminal tail of twinfilin interacts with membranes through a multivalent electrostatic interaction with a preference towards PI(3,5)P 2 , PI(4,5)P 2 , and PI(3,4,5)P 3 . This initial interaction places the actin-binding ADF-H domains of twinfilin to a close proximity of the membrane and subsequently promotes their association with the membrane, thus leading to inhibition of the actininteractions. In support to this model, a twinfilin mutant lacking the carboxy-terminal tail inhibits actin filament assembly in a phosphoinositide-insensitive manner. Our mutagenesis data also reveal that the phosphoinositide-and capping proteinbinding sites overlap in the carboxy-terminal tail of twinfilin, suggesting that phosphoinositide-binding additionally inhibits the interactions of twinfilin with the heterodimeric capping protein. The results demonstrate that the conserved carboxy-terminal tail of twinfilin is a multi-functional binding motif, which is crucial for interaction with the heterodimeric capping protein and for tethering twinfilin to phosphoinositiderich membranes.The dynamic interplay between the actin cytoskeleton and plasma membrane is critical for several cellular processes, such as migration, morphogenesis, endocytosis, and phagocytosis. Coordinated polymerization of actin filaments provides a force for generation of membrane invaginations in endocytic processes (1, 2). In migrating cells, polymerization of actin filaments against the plasma membrane at the leading edge pushes the membrane forward to generate plasma membrane protrusions, such as lamellipodia and filopodia (3-6).While actin polymerization controls the geometry of cellular membranes, membrane phospholipids, especially PI(4,5)P 2 , reciprocally regulate the organization and the dynamics of the actin cytoskeleton. Typically an increase in the plasma membrane PI(4,5)P 2 density leads to actin filament assembly beneath the membrane, whereas a decrease in PI(4,5)P 2 concentration results in diminished actin Mechanism of twinfilin-PI(4,5)P 2 interaction filament assembly (7-10). Phosphoinositides regulate actin filament assembly and disassembly by directly interacting with several actin-binding proteins (11). The activities and the pl...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Molecular mechanism for inhibition of twinfilin by phosphoinositides

Hakala

Vattulainen

Lappalainen

2018

Journal of Biological Chemistry

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“…The importance of noncoding genes, including miRNA and lncRNA, in drug responses has also been demonstrated (Majidinia and Yousefi, 2016; Mishra, 2012). For example, miR‐30c, a prognostic marker in human breast cancer, can control doxorubicin resistance by directly targeting TWF1 and IL‐11, which are two protein‐coding genes that regulate drug sensitivity (Bockhorn et al ., 2013). The p53‐regulated lincRNA‐p21 plays a physiological role in regulating cell viability following DNA damage (Huarte et al ., 2010).…”

Section: Introductionmentioning

confidence: 99%

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

Zhang

Zhou

et al. 2018

Molecular Oncology

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Differences in individual drug responses are an obstacle to progression in cancer treatment, and predicting responses would help to plan treatment. The accumulation of cancer molecular profiling and drug response data provides opportunities and challenges to identify novel molecular signatures and mechanisms of tumor responsiveness to drugs. This study evaluated drug responses with a competing endogenous RNA (ceRNA) system that depended on competition between diverse RNA species. We identified drug response‐related ceRNA (DRCEs) by combining the sequence and expression data of long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA), and the survival data of cancer patients treated with drugs. We constructed a patient–drug two‐layer integrated network and used a linear weighting method to predict individual drug responses. DRCEs were found to be significantly enriched in known cancer and drug‐associated data resources, involved in biological processes known to mediate drug responses, and correlated to drug activity in cancer cell lines. The dysregulation of DRCE expression influenced drug response‐associated functions and pathways, suggesting DRCEs as potential therapeutic targets affecting drug responses. A further case study in breast invasive carcinoma (BRCA) found that DRCE expression was consistent with the drug response pattern and the aberrant expression of the two NEAT1‐related DRCEs may lead to poor response to tamoxifen therapy for patients with TP53 mutations. In summary, this study provides a framework for ceRNA‐based evaluation of clinical drug responses across multiple cancer types. Understanding the underlying molecular mechanisms of drug responses will allow improved response to chemotherapy and outcomes of cancer treatment.

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“…miR-30c is known to interfere with epithelial-tomesenchymal transition (EMT) in breast cancer through regulation of TWF1 and IL11 [19] and has been identified as a key indicator of reproductive competence [2]. EMT is an essential part of the first lineage fate decision when during asymmetric cell division one of the daughter cells is pushed inwards, losing polarity and forming ICM [20,21].…”

Section: Microrna Profile In Sbms Is Similar Among Twins a And B Butmentioning

confidence: 99%

Human Embryos Created by Embryo Splitting Secrete Significantly Lower Levels of miRNA-30c

Noli

Capalbo

Dajani

et al. 2016

Stem Cells and Development

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Studies reporting term pregnancy and the production of genetically identical offspring from isolated blastomeres of early stage embryos have been carried out in small and large animals. However, very little is known about the effects of embryo splitting on the development and reproductive competency of human embryos. In this study, we investigated the effects of embryo splitting on profile of microRNAs (miRNAs) detected in their spent blastocyst medium (SBM) by comparative analysis of miRNA profiles in SBM of human twin embryos created by blastomere biopsy and SBM of blastocysts that resulted in a healthy pregnancy and live birth following embryo transfer. The profile of miRNA secretion in in vitro culture media consistently distinguishes twin from control embryos. We found that six miRNAs are significantly more abundant in SBM from twin embryos, while nine are significantly more abundant in SBM from euploid implanted blastocysts. These nine include miRNA-30c, a previously reported marker of blastocyst implantation potential. Furthermore, 22.9% of miRNAs secreted by twin embryos were never detected in SBM from normal reproductively competent blastocysts, or from trophectoderm (TE) samples from normal blastocysts donated for the research. The miRNA profile, unique to twin blastocysts, might be a result of differential lineage commitment in these embryos.

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MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11

Cited by 210 publications

References 32 publications

Molecular mechanism for inhibition of twinfilin by phosphoinositides

Molecular mechanism for inhibition of twinfilin by phosphoinositides

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

Human Embryos Created by Embryo Splitting Secrete Significantly Lower Levels of miRNA-30c

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