Scavenger receptor class B type 1 regulates neuroblastoma cell proliferation, migration and invasion

Abstract

Neuroblastoma (NB) is an extra cranial pediatric embryonal tumor most prevalent in children less than 1 year of age. NB accounts for 7% of all pediatric cancers but accounts for 15% of all childhood cancer deaths. Scavenger receptor class B type 1 (SR-B1), a mediator of cellular cholesterol uptake, is overexpressed in and have been linked to the aggressiveness of many cancers. Nevertheless, no studies have so far investigated the relationship between SR-B1 and NB. Elucidation of receptors that promote NB may pave the way for discovery of new therapeutic targets. Here we show that inhibition of SR-B1 reduced cell survival, migration and invasion, and cholesterol content in NB cell lines. Additionally analysis of SR-B1 levels in NB patient biopsies using the R2: Genomics Analysis and Visualization Platform showed that high SR-B1 expression correlated with decreased overall and event-free survival.

Introduction

Neuroblastoma (NB) is the most common solid extra cranial tumor in children [1]. It develops along components of the sympathetic nervous system and is a complex, heterogeneous disease [2], [3]. NB patients are often grouped into three categories: low-risk, intermediate-risk and high-risk based on age at diagnosis, stage of the disease, MYCN oncogene status, and tumor histopathology [4], [5]. Most patients with high-risk NB have less than 50% chance of survival [6], [7].

Cancer cells maintain a rapid proliferative rate by altering their metabolic activity to ensure ample supply of proteins, lipids, and nucleic acids for their replication [8], [9]. The Warburg effect, where cancer cells rely on aerobic glycolysis for energy, is the best known metabolic alteration studied [10]. Interestingly, reprogramming of lipid metabolism has emerged as another pathway that cancer cells use to promote their survival [8], [11], [12].

The scavenger receptor class B Type 1 (SR-B1) is an 82 kDa membrane protein that mediates cholesterol uptake and participates in reverse cholesterol transport via extracting cholesterol from high-density lipoprotein (HDL) [13], [14]. The binding of HDL to the extracellular domain of the SR-B1 allows the selective uptake of cholesterol into the cell [15]. Consequently, the expression of SR-B1 is upregulated in many cancers including prostate, cervical, breast, and lung cancer [16], [17], [18]. Increasing evidence supports HDL as an external source of cholesterol during tumor development [16], [19], [20]. Furthermore, low levels of HDL-cholesterol have been recorded in patients with cancer [21], [22]. Accordingly, HDL, and consequently its receptor, SR-B1, appears to be implicated in oncogenic metabolism.

In this study we revealed that inhibition of SR-B1 significantly reduced cell survival, migration, invasion and cellular cholesterol content. Additionally, analysis of patient samples showed that overexpression of SR-B1 was correlated with poor overall and event-free survival in NB. These data collectively indicate the pivotal role that SR-B1 plays in NB progression and paves the way for identifying potential targets for treatment of NB by focusing on SR-B1.