Identification of α-N-catenin as a novel tumor suppressor in neuroblastoma

Jingbo Qiao, Eric J. Rellinger, Kwang Woon Kim, Camille M. Powers, Sora Lee, Hernan Correa, Dai H. Chung

Research output: Contribution to journalArticle

Abstract

The lost expression of α-catenin has been found in cancers, and reinstalling α-catenin inhibits tumor growth. Here we hypothesized that the α-N-catenin, a homologous member of α-catenin and neural-specific expressed, functions as a novel tumor suppressor in neural crest-derived tumor, neuroblastoma. We correlated CTNNA2 (encodes α-N-catenin) expression to neuroblastoma disease relapse-free survival probability using publicly accessible human neuroblastoma datasets in R2 platform. The result showed that it negatively correlated to relapse-free survival probability significantly in patients with neuroblastoma with non-MYCN amplified tumor. Conversely, overexpressing CTNNA2 suppressed the neuroblastoma cell proliferation as measuring by the clonogenesis, inhibited anchorage-independent growth with soft agar colony formation assay. Forced expression of CTNNA2 decreased cell migration and invasion. Further, overexpression of CTNNA2 reduced the secretion of angiogenic factor IL-8 and HUVEC tubule formation. Our results show, for the first time, that α-N-catenin is a tumor suppressor in neuroblastoma cells. These findings were further corroborated with in vivo tumor xenograft study, in which α-N-catenin inhibited tumor growth and reduced tumor blood vessel formation. Interestingly, this is only observed in SK-N-AS xenografts lacking MYCN expression, and not in BE(2)-C xenografts with MYCN amplification. Mechanistically, α-N-catenin attenuated NF-κB responsive genes by inhibiting NF-κB transcriptional activity. In conclusion, these data demonstrate that α-N-catenin is a tumor suppressor in non-MYCN-amplified neuroblastomas and it inhibits NF-κB signaling pathway to suppress tumor growth in human neuroblastomas. Therefore, restoring the expression of α-N-catenin can be a novel therapeutic approach for neuroblastoma patients who have the deletion of CTNNA2 and lack of MYCN amplification.

Original languageEnglish (US)
Pages (from-to)5028-5040
Number of pages13
JournalOncotarget
Volume10
Issue number49
StatePublished - Jan 1 2019

Keywords

  • CTNNA2 (α-N-catenin)
  • Neuroblastoma
  • NF-κB
  • Tumor suppressor

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Qiao, J., Rellinger, E. J., Kim, K. W., Powers, C. M., Lee, S., Correa, H., & Chung, D. H. (2019). Identification of α-N-catenin as a novel tumor suppressor in neuroblastoma. Oncotarget, 10(49), 5028-5040.