Rhabdomyosarcomas are oncogene addicted to the activation of AVIL

Xie, Zhongqiu; Janczyk, Paweł; Shi, Xinrui; Wang, Qiong; Singh, Sandeep; Cornelison, Robert; Xu, Jingjing; Mandell, James W.; Barr, Frederic G.

doi:10.1073/pnas.2118048119

Cited by 2 publications

(5 citation statements)

References 27 publications

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“…In brief, 1 × 10 7 cells were collected and washed two times using PBS. Ribosomes were obtained according to the kit instructions, and then RNA was extracted from ribosomes using TRIzol as previously descried 52 .…”

Section: Methodsmentioning

confidence: 99%

A protein-encoding CCDC7 circular RNA inhibits the progression of prostate cancer by up-regulating FLRT3

Wang,

Cheng,

Singh

et al. 2024

npj Precis. Onc.

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Circular RNAs (circRNAs) are a family of endogenous RNAs that have become a focus of biological research in recent years. Emerging evidence has revealed that circRNAs exert biological functions by acting as transcriptional regulators, microRNA sponges, and binding partners with RNA-binding proteins. However, few studies have identified coding circRNAs, which may lead to a hidden repertoire of proteins. In this study, we unexpectedly discovered a protein-encoding circular RNA circCCDC7(15,16,17,18,19) while we were searching for prostate cancer related chimeric RNAs. circCCDC7(15,16,17,18,19) is derived from exon 19 back spliced to exon 15 of the CCDC7 gene. It is significantly downregulated in patients with high Gleason score. Prostate cancer patients with decreased circCCDC7(15,16,17,18,19) expression have a worse prognosis, while linear CCDC7 had no such association. Overexpressed circCCDC7(15,16,17,18,19) inhibited prostate cancer cell migration, invasion, and viability, supporting classification of circCCDC7(15,16,17,18,19) as a bona fide tumor suppressor gene. We provide evidence that its tumor suppressive activity is driven by the protein it encodes, and that circCCDC7(15,16,17,18,19) encodes a secretory protein. Consistently, conditioned media from circCCDC7(15,16,17,18,19) overexpressing cells has the same tumor suppressive activity. We further demonstrate that the tumor suppressive activity of circCCDC7(15,16,17,18,19) is at least partially mediated by FLRT3, whose expression also negatively correlates with Gleason score and clinical prognosis. In conclusion, circCCDC7(15,16,17,18,19) functions as a tumor suppressor in prostate cancer cells through the circCCDC7-180aa secretory protein it encodes, and is a promising therapeutic peptide for prostate cancer.

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Section: Methodsmentioning

confidence: 99%

A protein-encoding CCDC7 circular RNA inhibits the progression of prostate cancer by up-regulating FLRT3

Wang,

Cheng,

Singh

et al. 2024

npj Precis. Onc.

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“…These have shown promising effects in some actin-binding targets traditionally considered “undruggable”, such as Rho-GTPases. The ABP AVIL is of particular interest among actin-binding proteins because it is significantly overexpressed in RMS cancer cells while showing low level expression in very few normal cells [ 61 ]. Amplification at the AVIL locus has been shown not only in RMS but in other sarcomas as well, suggesting broader oncogenic properties.…”

Section: Targeting Actin Polymerization and Depolymerizationmentioning

confidence: 99%

“…The AVIL gene is overexpressed in nearly 100% of glioblastomas and was identified as a bona fide oncogene that is crucial for glioblastoma tumorigenesis [ 71 ]. In recent studies, we have shown that AVIL expression is abnormally upregulated in RMS, where silencing this gene results in a dramatic reduction in proliferation and migration, killing cancer cells and preventing tumor formation [ 61 ]. Therefore, AVIL seems to be a viable therapeutic target in glioblastoma and RMS.…”

Section: Advillin Backgroundmentioning

confidence: 99%

“…AVIL is thought to activate the RAS signaling pathway, which is a major cell proliferation pathway and a hallmark of ERMS. Interestingly, an oncogenic cooperativity assay found no difference in foci formation between overexpressing AVIL alone, RAS alone, or both [ 61 ]. Furthermore, AVIL overexpression in mesenchymal stem cells is sufficient to differentially express many RAS targets, increase p-MEK1/2 and p-ERK1/2, and mimic published gene signatures for RAS signaling.…”

Section: Avil Functionality In Erms and Arms Subtypesmentioning

confidence: 99%

“…AVIL is reported to be significantly expressed in many cell lines of both ARMS and ERMS, mimicking pathways upstream of both RMS subtypes including PAX3–FOXO1 and RAS. It may, therefore, serve as a connecting node for the major pathways associated with ARMS and ERMS [ 61 ]. Given its differential overexpression in numerous cancers including RMS, and its ability to activate both RAS and PAX3–FOXO1 signaling pathways, AVIL demonstrates promising therapeutic potential as a target for both ERMS and ARMS.…”

Section: Avil Functionality In Erms and Arms Subtypesmentioning

confidence: 99%

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The Potential for Targeting AVIL and Other Actin-Binding Proteins in Rhabdomyosarcoma

Cornelison,

Marrah,

Fierti

et al. 2023

IJMS

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Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue cancer with a survival rate below 27% for high-risk children despite aggressive multi-modal therapeutic interventions. After decades of research, no targeted therapies are currently available. Therapeutically targeting actin-binding proteins, although promising, has historically been challenging. Recent advances have made this possibility more salient, including our lab’s identification of advillin (AVIL), a novel oncogenic actin-binding protein that plays a role in many cytoskeletal functions. AVIL is overexpressed in many RMS cell lines, patient-derived xenograft models, and a cohort of 30 clinical samples of both the alveolar (ARMS) and embryonal (ERMS) subtypes. Overexpression of AVIL in mesenchymal stem cells induces neoplastic transformation both in vitro and in vivo, and reversing overexpression through genetic modulation reverses the transformation. This suggests a critical role of AVIL in RMS tumorigenesis and maintenance. As an actin-binding protein, AVIL would not traditionally be considered a druggable target. This perspective will address the feasibility of targeting differentially expressed actin-binding proteins such as AVIL therapeutically, and how critical cell infrastructure can be damaged in a cancer-specific manner.

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Rhabdomyosarcomas are oncogene addicted to the activation of AVIL

Cited by 2 publications

References 27 publications

A protein-encoding CCDC7 circular RNA inhibits the progression of prostate cancer by up-regulating FLRT3

A protein-encoding CCDC7 circular RNA inhibits the progression of prostate cancer by up-regulating FLRT3

The Potential for Targeting AVIL and Other Actin-Binding Proteins in Rhabdomyosarcoma

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