Abstract
Receptor tyrosine kinases (RTKs) receive different modulation before transmitting proliferative signals. We previously identified neuronal leucine-rich repeat 1 (NLRR1) as a positive regulator of EGF and IGF-1 signals in high-risk neuroblastoma cells. Here, we show that NLRR1 is up-regulated in various adult cancers and acts as a key regulator of tumor cell proliferation. In the extracellular domains of NLRR1, fibronectin type III (FNIII) domain is responsible for its function to promote cell proliferation. We generated monoclonal antibodies against the extracellular domains of NLRR1 (N1mAb) and screened the positive N1mAbs for growth inhibitory effect. The treatment of N1mAbs reduces tumor cell proliferation in vitro and in vivo, and sensitizes the cells to EGFR inhibitor, suggesting that NLRR1 is a novel regulatory molecule of RTK function. Importantly, epitope mapping analysis has revealed that N1mAbs with growth inhibitory effect recognize immunoglobulin-like and FNIII domains of NLRR1, which also indicates the importance of FNIII domain in the function of NLRR1. Thus, the present study provides a new insight into the development of a cancer therapy by targeting NLRR1 as a modulator of proliferative signals on cellular membrane of tumor cells.
Highlights
Neuroblastoma (NB), originally arising from the sympathoadrenal lineage of the neural crest, is one of the most common extracranial solid tumors in childhood
High expression of neuronal leucine-rich repeat 1 (NLRR1) was observed in tumorous tissues; eight out of twelve adenocarcinomas and three out of nine squamous cell carcinomas showed more than two-fold higher expression of NLRR1 than normal tissues (Figure 1B)
We demonstrate that NLRR1 expression is up-regulated in adult cancer tissues including lung and breast in addition to unfavorable NBs
Summary
Neuroblastoma (NB), originally arising from the sympathoadrenal lineage of the neural crest, is one of the most common extracranial solid tumors in childhood. NBs in patients less than 1 year of age often regress spontaneously, resulting in a favorable prognosis [1]. Tumors found over 1 year of age are usually aggressive leading to poor prognosis. Targeting NLRR1 for Cancer Therapy poor prognosis is characterized by the presence of genetic aberrations, such as gain of chromosome 17q, loss of chromosome 11q, and amplification of MYCN oncogene [2, 3]. MYCN is a nuclear transcription factor and one of the most important prognostic indicators of poor clinical outcome [4]. MYCN regulates cell proliferation through transcriptional regulation of its target genes in both positive and negative manners [5, 6]. Genes contributing to tumor growth and aggressiveness of NB under MYCN regulation still remain elusive
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