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

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

doi:10.18632/oncotarget.27096

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.

Highlights

Neuroblastoma is a highly virulent extracranial neural crest-derived solid tumor that affects infants and children
We found that Catenin Alpha 1 (CTNNA1) and Catenin Alpha 2 (CTNNA2) had higher expressions, while Catenin Alpha 3 (CTNNA3) had consistently lower expression in both Wolf and Seeger datasets from patients with neuroblastoma (Figure 1A and 1B)
We found that expression of CTNNA1 and CTNNA2 correlated to relapse-free survival only in non-Neuroblastoma MYC Oncogene (MYCN)-amplified groups (Figure 1E and 1H), but not in MYCN-amplified groups (Figure 1D and 1G)

Summary

INTRODUCTION

Neuroblastoma is a highly virulent extracranial neural crest-derived solid tumor that affects infants and children. Genetic alterations have been identified in neuroblastomas, including segmental chromosome 1p, 3p, 4p, and 11q deletions, and 1q and 17q gain; gene mutations including MYCN amplification, ALK amplification and mutation, and LIN28B amplification and polymorphism. These genetic aberrations are associated with disease initiation and progression in neuroblastoma, and correlated with a clinical outcome such as overall mortality rate [1]. We identified one novel tumor suppressor, α-Ncatenin (CTNNA2), a cell adhesion molecule, silenced in some non-MYCN amplified neuroblastomas, correlated to low event-free survival probability. Others reported that α-catenin suppressed tumor growth by inhibiting NF-κB signaling in E-cadherin-negative basal-like breast cancer cells [16]. We investigated the role of α-N-catenin in neuroblastomas and identified that α-N-catenin acts as a tumor suppressor by inhibiting tumor aggressiveness and tumor angiogenesis

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS