Rhabdomyosarcoma is the most common soft-tissue sarcoma occurring in children and young adults. These tumors are unique among sarcomas in that they are thought to derive from skeletal muscle tissue. Tumors express myogenic markers, but fail to undergo terminal differentiation. Two subclasses of rhabdomyosarcomas exist, the embryonal and alveolar. Whereas the embryonal form compromises the majority of cases and is more responsive to multi-modal therapy, alveolar rhabdomyosarcoma is a more primitive malignant neoplasm where prognosis for children with advanced disease remains dismal. Therefore, effective therapies will likely hinge on our abilities to better resolve the underlying mechanisms of alveolar rhabdomyosarcoma. NF-kappaB is a transcription factor whose signaling pathway has been implicated in a variety of cancers. In skeletal muscle, NF-kappaB functions in immature cells to negatively regulate terminal differentiation. Recently we discovered that NF-kappaB functions in this capacity by participating in a regulatory circuit with the Polycomb group protein, YY1, and the microRNA, miR-29. In undifferentiated myoblasts, NF-kappaB stimulates YY1 production, which epigenetically silences miR-29. However, as differentiation ensues, NF-kappaB activity decreases causing a concomitant reduction of YY1 and a derepression of miR-29. This microRNA in turn feeds back on YY1 to further reduce its expression and favor a differentiation state. Significantly, in rhabdomyosarcoma cell lines and primary tumors NF-kappaB - YY1 - miR-29 circuitry becomes deregulated as a result of elevated levels of NF-kappaB that cause silencing of miR-29. Further results indicate that NF-kappaB activation in rhabdomyosarcoma is mediated through the NF-kappaB classical pathway that switches from the alternative pathway found in normal differentiated muscle. Inhibition of classical NF-kappaB signaling in rhabdomyosarcoma cells restores the regulatory circuit and promotes a muscle differentiation phenotype. Based on these results we hypothesize that NF-kappaB contributes to rhabdomyosarcoma by blocking terminal differentiation through deregulation of the NF-kappaB - YY1 - miR-29 circuit. To test this hypothesis, specific aims will 1) determine the relevance of the NF-kappaB classical versus alternative signaling pathway in rhabdomyosarcomagenesis, and 2) determine the requirement of NF-kappaB in the initiation and progression of alveolar rhabdomyosarcoma. Results from these studies are likely to yield significant mechanistic insight into the role of NF-kappaB signaling in alveolar rhabdomyosarcoma, which may prove useful for treatment of this lethal childhood cancer.

Public Health Relevance

Rhabdomyosarcoma is a common soft-tissue cancer in children and adolescents that in its advanced form produces an unfavorable outcome. The tumors are related to the skeletal muscle lineage, but lack the ability to undergo terminal differentiation. NF-kappaB is part of a signaling pathway that in immature muscle cells functions to inhibit differentiation. Since NF-kappaB is activated in rhabdomyosarcoma, this proposal will examine how NF-kappaB signals in these tumor cells and whether NF-kappaB activity is required for tumor development by acting as a negative regulator of the myogenic differentiation program.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA143082-02
Application #
8206637
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Yassin, Rihab R,
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$318,292
Indirect Cost
$63,109
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Yu, Peter Y; Lopez, Gonzalo; Braggio, Danielle et al. (2018) miR-133a function in the pathogenesis of dedifferentiated liposarcoma. Cancer Cell Int 18:89
Bharathy, Narendra; Berlow, Noah E; Wang, Eric et al. (2018) The HDAC3-SMARCA4-miR-27a axis promotes expression of the PAX3:FOXO1 fusion oncogene in rhabdomyosarcoma. Sci Signal 11:
Londhe, Priya; Yu, Peter Y; Ijiri, Yuichi et al. (2018) Classical NF-?B Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2. Front Oncol 8:104
Yu, Peter Y; Balkhi, Mumtaz Y; Ladner, Katherine J et al. (2016) A selective screening platform reveals unique global expression patterns of microRNAs in a cohort of human soft-tissue sarcomas. Lab Invest 96:481-91
Chen, Eleanor Y; DeRan, Michael T; Ignatius, Myron S et al. (2014) Glycogen synthase kinase 3 inhibitors induce the canonical WNT/?-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. Proc Natl Acad Sci U S A 111:5349-54
Svalina, Matthew N; Keller, Charles (2014) YAPping about differentiation therapy in muscle cancer. Cancer Cell 26:154-5
Hettmer, Simone; Li, Zhizhong; Billin, Andrew N et al. (2014) Rhabdomyosarcoma: current challenges and their implications for developing therapies. Cold Spring Harb Perspect Med 4:a025650
Keller, Charles; Guttridge, Denis C (2013) Mechanisms of impaired differentiation in rhabdomyosarcoma. FEBS J 280:4323-34
He, Wei A; Berardi, Emanuele; Cardillo, Veronica M et al. (2013) NF-?B-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia. J Clin Invest 123:4821-35
Balkhi, M Y; Balkhi, Mumtaz Y; Iwenofu, O Hans et al. (2013) miR-29 acts as a decoy in sarcomas to protect the tumor suppressor A20 mRNA from degradation by HuR. Sci Signal 6:ra63

Showing the most recent 10 out of 11 publications