MicroRNA and gene co-expression networks characterize biological and clinical behavior of rhabdomyosarcomas

Missiaglia, Edoardo; Shepherd, Chris; Aładowicz, Ewa; Olmos, David; Selfe, Joanna; Pierron, Gaëlle; Delattre, Olivier; Walters, Zoë S.; Shipley, Janet

doi:10.1016/j.canlet.2016.10.011

Cited by 25 publications

(22 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MiR-221 is significantly reduced in FP-RMS compared to FN-RMS (Fig. 4a ) consistent with a recent study in 64 RMS patients [ 31 ]. Transient transfection of miR-221 mimic led to overexpression as evaluated by qRT-PCR, reduction of cell viability, and an increase in apoptosis in both Rh30 and Rh41 cells (Fig.…”

Section: Resultssupporting

confidence: 91%

“…In endothelial cells, miR-221/222 inhibit proliferation, migration, and angiogenesis [ 49 ]. Consistent with our findings, miR-221/222 are downregulated specifically in FP-RMS cell lines and patients [ 31 , 50 ]. Interestingly miR-221/222 expression correlates with overall survival and progression-free survival of RMS [ 31 ].…”

Section: Discussionsupporting

confidence: 92%

“…Consistent with our findings, miR-221/222 are downregulated specifically in FP-RMS cell lines and patients [ 31 , 50 ]. Interestingly miR-221/222 expression correlates with overall survival and progression-free survival of RMS [ 31 ]. In contrast, miR-221/222 are overexpressed and function as oncogenes in breast cancer, hepatocellular carcinoma, glioblastoma, and others [ 51 , 52 ].…”

Section: Discussionsupporting

confidence: 92%

See 2 more Smart Citations

PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma

et al. 2018

View full text Add to dashboard Cite

Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood and histologically resembles developing skeletal muscle. Alveolar rhabdomyosarcoma (ARMS) is an aggressive subtype with higher rate of metastasis and poorer prognosis. The majority of ARMS tumors (80%) harbor a PAX3-FOXO1 or less commonly a PAX7-FOXO1 fusion gene. The presence of either the PAX3-FOXO1 or PAX7-FOXO1 fusion gene foretells a poorer prognosis resulting in clinical re-classification as either fusion-positive (FP-RMS) or fusion-negative RMS (FN-RMS). The PAX3/7-FOXO1 fusion genes result in the production of a rogue transcription factors that drive FP-RMS pathogenesis and block myogenic differentiation. Despite knowing the molecular driver of FP-RMS, targeted therapies have yet to make an impact for patients, highlighting the need for a greater understanding of the molecular consequences of PAX3-FOXO1 and its target genes including microRNAs. Here we show FP-RMS patient derived xenografts and cell lines display a distinct microRNA expression patterns. We utilized both loss- and gain-of function approaches in human cell lines with knockdown of PAX3-FOXO1 in FP-RMS cell lines and expression of PAX3-FOXO1 in human myoblasts and identified microRNAs both positively and negatively regulated by the PAX3-FOXO1 fusion protein. We demonstrate PAX3-FOXO1 represses miR-221/222 that functions as a tumor suppressing microRNA through the negative regulation of CCND2, CDK6, and ERBB3. In contrast, miR-486-5p is transcriptionally activated by PAX3-FOXO1 and promotes FP-RMS proliferation, invasion, and clonogenic growth. Inhibition of miR-486-5p in FP-RMS xenografts decreased tumor growth illustrating a proof of principle for future therapeutic intervention. Therefore, PAX3-FOXO1 regulates key microRNAs that may represent novel therapeutic vulnerabilities in FP-RMS.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Previous studies have reported that miR-9-5p is ectopically regulated in various types of cancers. miR-9-5p levels are higher in metastatic tumors compared with non-metastatic tumors and these were demonstrated to be associated with poor prognosis of rhabdomyosarcomas (44). The homeotic gene miR-9 inhibited ovarian cancer cell growth via nuclear factor-κβ1 (45).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑9‑5p downregulates Klf4 and influences the progression of hepatocellular carcinoma via the AKT signaling pathway

et al. 2019

View full text Add to dashboard Cite

Krüppel-like factor 4 (Klf4) is a transcriptional factor involved in the progression of hepatocellular carcinoma (HCC). However, the underlying regulatory mechanisms associated with the Klf4 gene as a tumor suppressor in HCC remain unclear. microRNAs (miRNAs or miRs) are a series of small non-coding RNAs that serve a vital role in regulating gene expression via their influence on protein translation and the associated degradation of mRNA. The mRNA expression levels of the miRNA, miR-9-5p, and Klf4 were measured using reverse transcription-quantitative polymerase chain reaction. The protein expression levels of Klf4, protein kinase B (AKT), phosphorylated (p-)AKT, mechanistic target of rapamycin (mTOR), p-mTOR, B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) were determined by western blot analysis. Dual luciferase reporter assay was used to confirm a direct interaction between miR-9-5p and the 3′-untranslated region (3′-UTR) sequence of Klf4. Cell counting kit-8 assay, wound healing assay, Transwell migration assay and flow cytometric analysis were performed to evaluate the proliferative, migratory and apoptotic capabilities of the HCC cells. In the present study, miR-9-5p was revealed to be overexpressed in HCC as a novel upstream gene of Klf4. miR-9-5p expression was inversely associated with Klf4 expression in clinical samples. Additionally, Kaplan-Meier analysis revealed a markedly poor prognosis of HCC in the miR-9-5p high-expression group. Bioinformatics analysis revealed that miR-9-5p bound directly to the 3′-UTR of Klf4, which reduced the expression levels of Klf4. The miR-9-5p/Klf4 axis promoted HCC proliferation and migration, and inhibited HCC apoptosis. Furthermore, miR-9-5p upregulated the Bcl-2/Bax protein ratio and activated AKT/mTOR signaling. Taken together, these data demonstrated that the miR-9-5p/Klf4 axis was able to promote HCC progression, which may occur via regulation of the AKT signaling pathway, highlighting a potential novel target in HCC treatment.

show abstract

“…They discovered that FILNC1 represses c‐Myc‐mediated energy metabolism and inhibits renal tumor development . Additionally, studies have also demonstrated that FOXO1 has antitumor actions in spindle cell lipoma, rhabdomyosarcomas and Kaposi's sarcoma (Table ).…”

Section: Roles Of Foxo1 In Diverse Human Neoplasmsmentioning

confidence: 99%

Deciphering the roles of FOXO1 in human neoplasms

Jiang

Tian

Yang

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

Neoplasms constituted an enormous burden and contributed to an estimated 8.2 million deaths in 2012 worldwide. FOXO1 (forkhead box O1), a member of the forkhead box (FOX) family, is a transcriptional factor involved in diverse cellular functions. Herein, we concentrate on recent studies of the antineoplastic roles of FOXO1 in neoplasms. This article may serve as a guide for future research and identify FOXO1 as a potent therapeutic target in neoplasms.

show abstract

MicroRNA and gene co-expression networks characterize biological and clinical behavior of rhabdomyosarcomas

Cited by 25 publications

References 55 publications

PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma

PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma

MicroRNA‑9‑5p downregulates Klf4 and influences the progression of hepatocellular carcinoma via the AKT signaling pathway

Deciphering the roles of FOXO1 in human neoplasms

Contact Info

Product

Resources

About