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Analyzing the potential effects of small compounds involving MSR1 

and C6-ceramide on nasopharyngeal cancer using GSEA 

Dr.D.Suryadevarakonda 
1
,  D.Venkataraman Dra 

2
, Shazia 

3
, Andol Rajesh kumar 

4
,  

Assistant professor 1,2,3,4, 
Department of Pharmacy, 

Samskruti College of Pharmacy, 
Kondapur (V), Ghatkesar (M) Medchal Dist, Telangana, India. 

 

Abstract 

The goal of this study is to identify therapeutic drugs and targets that may be useful in the treatment of 

nasopharyngeal cancer (NPC).A combination of bioinformatics and in vitro experimental validation led to the 

identification of many candidate treatment drugs and NPC target genes. We found 344 differentially expressed 

genes (DGEs) that were downregulated and 26 that were upregulated after analyzing three datasets of NPC 

patients. We used KEGG pathway analysis on the DGEs and Gene Ontology (GO) to compile their descriptions. The 

identification of C6-ceramide as a small molecule with significant significance to NPC was made possible by 

independently acquiring 316 drug and small molecule target genes from the SEA database. Then, in order to get 

macrophage scavenger receptor 1 (MSR1), the genes that were differentially elevated were intersected with genes 

that may be targets of C6-ceramide small molecules. Lastly, the findings confirmed that MSR1 and C6-ceramide 

may play important roles in NPC cell lines.The outcomes are: The viability of NPC cells was dramatically reduced 

when MSR1 expressions were knocked down. A substantial decrease in NPC cell viability (p < 0.0001) was also 

seen after treatment with 10 μmol/L C6-ceramide. Moreover, the overexpression of MSR1 in NPC cells was 

accompanied by an increase in MSR1 levels, which was reduced by C6-ceramide (p < 0.0001). At the same time as 

MSR1 overexpression increased levels of AKT and PI3K, MSR1 knockdown lowered their expression.In conclusion, 

MSR1 controls PI3K and AKT expression to affect NPC cell survival.Furthermore, C6-ceramide regulates MSR1 

expression to have a therapeutic impact on NPC. These results provide fresh avenues for research into the treatment 

of NPC and novel approaches to its clinical management. These findings provide support for investigating 

ceramides and MSR1 further as potential new targets in NPC.The PI3K/AKT pathway, cell viability, macrophage 

scavenger receptor 1, and nasopharyngeal cancer are all related terms. 

 

INTRODUCTION  

The nasopharyngeal mucosa can develop a malignant 

epithelial tumor called a nasopharyngeal carcinoma 

(NPC), which is common in southern China and 

Southeast Asia. Unlike other cancers, NPC cells 

easily spread to lymph nodes and other regions even 

in the early stages of tumorigenesis [1]. The curative 

value of current treatments, such as radiation, 

chemotherapy and molecular targeted therapy, is 

limited, as evidenced by the high rates of recurrence, 

metastasis and mortality in NPC patients [2]. Thus, 

developing appropriate molecular targets for NPC 

therapy is essential. Macrophage scavenger receptor 

1 (MSR1), also known as class A scavenger receptor 

(SR-A) and cluster of differentiation 204 (CD204) 

[3], is primarily produced in macrophages. Its 

functions include scavenging and modifying 

lipoproteins. The adhesion and phagocytosis of 

macrophages are related to MSR1 [4]. The MSR1 is a 

marker of M2 tumor-associated macrophages, which 

promotes the development and metastasis of tumor. 

The MSR1 is also a prognostic biomarker for glioma 

(LGG), uveal melanoma (UVM), lung squamous cell 

carcinoma (LUSC) and other tumor types [5], but the 

function of MSR1 in NPC is not clear. In addition, 

MSR1, as a membrane receptor, binds to ligands to 

activate signaling pathways including mitogen-



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activated protein kinase, nuclear factor kappa B (NF-

κBcan) and PI3K/AKT [6], therefore affecting the 

progression of cancer. Ceramides are a class of 

bioactive sphingolipids in cell membranes that 

promotes apoptosis in response to cell stressors and 

have demonstrated antitumor activities in preclinical 

studies [7-9]. C6-ceramide is a cell-permeable 

ceramide analogue that promotes apoptosis and 

suppresses the growth of various types of tumors 

[10,11]. However, the therapeutic potential and 

mechanisms of action of ceramide analogs remain to 

be elucidated in NPC. Ceramides respond to various 

changes caused by biological factors and 

chemotherapy by inhibiting AKTdependent mitosis 

to suppress tumor cell proliferation [7]. Endogenous 

ceramides as effector molecules enhance the 

cytotoxic effects of drugs on tumor cells, while 

exogenous ceramides demonstrate greater 

cytotoxicity towards tumor cells compared to normal 

cells [8]. Additionally, ceramides inhibit tumor 

growth in breast cancer xenograft models [9]. 

Ceramides and their analogs exhibit antitumor 

potential, but their specific mechanisms of action in 

NPC warrant further investigation. This study is 

aimed to identify MSR1 as a putative target of C6-

ceramide in NPC, using a bioinformatics method. 

The study is further aimed to verify the roles of 

MSR1 and C6- ceramide in inhibiting NPC cell 

viability and modulating PI13/AKT signaling.  

EXPERIMENTAL 

Data acquisition  

The gene expression matrix of NPC was retrieved 

from the GEO database 

(https://www.ncbi.nlm.nih.gov/geo/). The desired 

genes of pharmaceuticals and small compounds were 

gathered from the SEA database 

(https://sea.bkslab.org/).  

Differential gene expression analysis  

The "Limma" pack in R was utilized to perform 

Bayesian differential expression analysis on the 

downloaded NPC dataset. DGEs were identified 

based on |log2FC| > 0.2 and adjusted p-values < 0.05.  

DEG pathway analysis  

Gene Ontology (GO) functional and KEGG pathway 

enrichment analyses were implemented by applying 

the "ClusterProfiler" package in R. Terms with 

adjusted p < 0.05 were considered significantly 

enriched.  

Potential drug analysis  

The t-values for all genes in the dataset were obtained 

through Bayesian testing and ranked. The genes in 

targets for medications and small compounds were 

acquired as SET files from the SEA database. GSEA 

was then performed to identify potential drugs and 

target genes associated with NPC [12].  

Cell culture  

The human normal nasopharyngeal epithelial cell line 

NP69 and NPC cell lines HNE-1, HONE-1, CNE2 

and CNE1 were obtained from the ATCC. HNE-1, 

HON-1 and CNE2 cells were raised in DMEM, while 

CNE1 and NP69 were raised in RPMI-1640 medium 

(both from GIBCO, USA). The media in which the 

cells were maintained was enriched with 10 % FBS 

(Hyclone, USA), 100 μg/mL streptomycin, and 100 

U/mL penicillin and maintained at 37 °C in 5 % CO 

2.  

RNA isolation and qPCR  

Total RNA was extracted from cell lines using Trizol 

reagent (Invitrogen), in line with the directions 

provided by the manufacturer. Reverse transcription 

was performed with the Reverse Transcriptase Kit 

(Madison, Wisconsin, USA) and qPCR was done by 

applying SYBR Green Supermix (Invitrogen) on an 

ABI Prism 7500 system (Applied Biosystems, Foster 

City, CA, USA). Relative mRNA transcription was 

quantified by the 2 -△△CT technique with three 

technical replicates. Based on the results obtained, 

two NPC cell lines were selected for subsequent 

experiments.  

Western blotting  

Cells were dissolved in RIPA buffer (Thermo Fisher 

Scientific) and protein concentrations measured using 

the Pierce Protein Assay Kit (Thermo Fisher 

Scientific). Proteins were separated by SDS-PAGE, 

put on PVDF membranes and detected by incubation 

with primary antibodies overnight at 4°C. Proteins 

bands were visualized using WesternBrightTM 

enhanced chemiluminescence (Bio-Rad, USA).  

Cell transfection and drug treatment  

The si-MSR1 and si-NC were separately transfected 

into cells and incubated for 24, 48, 72, and 96 h. The 

https://sea.bkslab.org/


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absorbance at 450 nm was read on a microplate 

reader following which cells were incubated with 10 

mL of CCK-8 reagent for 2 h at 37 oC with 5 % 

CO2. HONE1 and HNE1 cells were exposed to 

varied doses of C6- ceramide for 24, 48, 72 and 96 h 

before assessing cell survival by CCK-8 assay. Cells 

were transfected with pcDNA-NC, pcDNA-MSR1, 

C6-ceramide, or pcDNA-MSR1 + C6-ceramide 

according to experimental groups. The MSR1 mRNA 

levels were quantified using qPCR posttransfection. 

Cells were also transfected with MSR1 knockdown 

or overexpression vectors while PI3K and AKT 

mRNA levels were examined using qPCR.  

Statistical analysis  

Statistical analyses were done using SPSS 20.0 

software. Variations between groups were evaluated 

using Student's t-test or one-way ANOVA, Statistical 

significance was evaluated by p-values < 0.05 (*p < 

0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).  

 

 

RESULTS  

Differential gene expression and pathway analysis  

Gene expression data from three NPC datasets 

(GSE12452, GSE53819 and GSE61218) were 

obtained from the GEO database. Bayesian 

differential analysis was performed to identify DGEs 

between NPC and control samples in each dataset. In 

GSE12452 (31 NPC and 10 control), 7780 

downregulated and 297 upregulated DEGs were 

identified (Figure 1 A). 

 

 

 

Figure 1: Differential gene expression and pathway analysis. DEGs between NPC and control samples were 

identified by Bayesian analysis in three datasets: GSE12452 (A), GSE53819 (B), and GSE61218 (C); Venn 

diagrams show the overlap of upregulated (D) and downregulated (E) 



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Figure 1 continued: Differential gene expression and pathway analysis. DEGs between NPC and control samples 

were identified by Bayesian analysis in three datasets: DEGs across the three datasets; Ontology enrichment analysis 

revealed altered BP (F), CC (G) and MF (H); The top 15 enriched KEGG pathways are shown in (I)  

In GSE53819 (18 NPC and 18 control), 7426 

downregulated and 842 upregulated DEGs were 

found (Figure 1 B) while 2485 downregulated and 

344 upregulated DEGs were identified in GSE61218 

(10 NPC and 6 control; Figure 1 C). The overlap of 

DEGs across the three datasets indicated 26 

commonly upregulated and 344 commonly 

downregulated DEGs (Figure 1 D and E). GO and 

KEGG enrichment analyses were performed on the 

380 DEGs to investigate altered biological pathways 

and processes. The top 10 enriched GO terms 

included cilium assembly, cilium organization and 

microtubulebased movement for Biological Process 

(BP) (Figure 1 F); nuclear envelope and acrosome for 

Cellular Component (CC) (Figure 1 G); and dynein 

heavy chain binding for Molecular Function (MF) 

(Figure 1 H). The top 15 enriched KEGG pathways 

included thyroid hormone signaling, lipid 

metabolism, atherosclerosis, TNF signaling and 

autophagy (Figure 1 I).  

Potential drug candidates for NPC  



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To identify potential drug candidates for NPC, GSEA 

was performed using the 316 drug and small 

molecule target gene sets from the SEA database. 

The top 10 significantly enriched drugs (p < 0.05, ES 

> 0.3) were identified in NPC samples for each 

dataset (Figure 2). The top three enriched drugs in 

GSE12452 were C6- ceramide, bexarotene and 

chlorambucil (Figure 2 

A). For GSE53819, the top hits were C6- ceramide, 

cabozantinib and etoposide (Figure 2 B). In 

GSE61218，C6-ceramide, AZD6482 and ML162 

were most enriched (Figure 2 C). Venn diagram 

shows C6-ceramide as the only drug enriched across 

all three datasets (Figure 2 D). The enrichment scores 

of C6-ceramide in the three datasets are presented in 

Figure 2 E and G.  

Identification of MSR1 as a potential target of C6-

ceramide in NPC  

To identify the potential therapeutic targets of C6-

ceramide in NPC, its chemical properties were first 

analyzed. C6-ceramide has a CAS registry number of 

124753-97-5, a molecular formula of C24H47NO3 

and a molecular weight of 397.63 Da. Its chemical 

structure is shown in Figure 3 A. Differentially 

upregulated genes from the three NPC datasets were 

intersected with the potential target genes of C6-

ceramide, identifying MSR1 as a common target 

(Figure 3 B). Molecular docking using 

AutoDockTools-1.5.6 revealed the potential binding 

interaction between MSR1 and C6-ceramide (Figure 

3 C).  

Effect of MSR1 on NPC cells  

The levels of MSR1 was analyzed in four NPC cell 

types and healthy nasopharyngeal epithelial cells by 

qPCR. When compared to typical cells, MSR1 

mRNA amounts were significantly higher in NPC 

cells (Figure 4 A). Western blotting (WB) confirmed 

increased MSR1 protein expression in NPC cells 

versus normal cells (Figure 4 B) indicating that 

MSR1 is greatly upregulated in NPC. In order to 

determine the function of MSR1 in NPC, two NPC 

cell lines were transfected with si-NC or si-MSR1. 

The results of qPCR confirmed transfection with si-

MSR1 significantly reduced MSR1 mRNA compared 

to si-NC control cells, confirming the efficient 

knockdown of MSR1 (Figure 4 C). Cell viability 

results show that MSR1 knockdown inhibited cell 

viability in both NPC lines (Figure 4 D). 

 



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Figure 2: GSEA identifies C6-ceramide as a potential therapeutic for NPC (A-C) The top 10 enriched drugs in 

nasopharyngeal carcinoma samples from the three datasets 

 

Figure 2 continued: GSEA identifies C6-ceramide as a potential therapeutic for NPC (D) Venn diagram showing 

C6-ceramide as the only drug enriched across all three datasets; (E-G) Enrichment scores of C6-ceramides in the 

three datasets. 

 

Figure 3: Identification of MSR1 as a potential 

therapeutic target of C6-ceramide in nasopharyngeal 

carcinoma; (A) Chemical structure of the C6-

ceramide small molecule; (B) Venn diagram showing 

the intersection of upregulated genes in three NPC 

datasets with potential target genes of C6-ceramide; 

(C) Molecular docking diagram depicting the 



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potential binding interaction between C6-ceramide 

and MSR1  

To investigate the effect of C6-ceramide on NPC 

cells, two cell lines were exposed to increasing 

amounts of the drug. The results of CCK8 assay 

showed decreased cell viability with higher C6- 

ceramide doses (Figure 4 E), indicating that C6- 

ceramide has anti-proliferative effect. To further 

investigate if this effect involved MSR1, 

nasopharyngeal carcinoma cells were transfected 

with pcDNA-MSR1 (for MSR1 overexpression) or 

control pcDNA-NC. The results of qPCR confirmed 

increased MSR1 mRNA in pcDNA-MSR1 versus 

pcDNA-NC cells (Figure 4 F). Cells were then 

divided into four groups: pcDNA-NC, pcDNA-

MSR1, C6-ceramide treatment and pcDNA-MSR1 + 

C6-ceramide. Results of qPCR showed MSR1 

mRNA was significantly increased in the pcDNA-

MSR1 group compared to the pcDNA-NC group. 

However, MSR1 amounts were significantly lower in 

the C6-ceramide treatment category versus the 

pcDNA-MSR1 group, while the pcDNA-MSR1 + 

C6-ceramide group exhibited an intermediate level of 

MSR1 expression (Figure 4 G). These results 

indicated that C6-ceramide inhibited the upregulation 

of MSR1 gene expression in NPC cells caused by 

MSR1 overexpression. In other words, MSR1 may be 

a potential target gene of C6-ceramide on NPC cells.  

MSR1 modulates PI3K/AKT signaling in NPC 

cells  

The study previously demonstrated that MSR1 

knockdown reduces NPC cell viability. Here, the 

study investigated the interaction between MSR1 and 

the PI3K/AKT signaling pathway. Compared to 

control cells, PI3K and AKT expression reduced with 

MSR1 knockdown but increased with MSR1 

overexpression (Figure 5). These data indicate that 

modulating MSR1 reciprocally regulates PI3K and 

AKT levels in NPC cells. Thus, MSR1 appears to 

exert downstream effects on NPC cells via the 

activation of PI3K/AKT pathway. 

 



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Figure 4: Effect of MSR1 knockdown and C6-ceramide treatment on NPC cells. MSR1 mRNA (A) and protein (B) 

expression in NPC cell lines compared to NP69 cells; (C) MSR1 knockdown efficiency in NPC cells by shRNA; (D) 

Cell viability of NPC cells following MSR1 knockdown; (E) Viability of NPC cells treated with C6-ceramide; (F) 

MSR1 overexpression in NPC cells by plasmid transfection; (G) MSR1 expression in NPC cells with MSR1 

overexpression and C6-ceramide treatment  

 

Figure 5: MSR1 regulates PI3K and AKT expression in NPC cells (A) PI3K and AKT mRNA levels following 

MSR1 knockdown or overexpression in NPC cells; (B) PI3K and (C) AKT protein levels in NPC cells after MSR1 

knockdown and overexpression  



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DISCCUSION  

Nasopharyngeal carcinoma is rarely detected early 

and current therapies have limited efficacy in 

advanced disease, contributing to high mortality. 

Approximately 95.5 % of NPC cases present at late 

stages, with 5-year overall and metastatic survival 

rates of only 61 and 50 %, respectively [13]. 

Elucidating NPC pathogenesis and identifying novel 

therapeutic targets are critical to improve patient’s 

outcomes. Here, by integrating three NPC datasets, 

26 upregulated and 344 downregulated genes were 

identified. GSEA nominated the small molecule C6- 

ceramide as a top potential NPC therapeutic drug 

across datasets. By overlapping differentially 

upregulated genes with predicted C6-ceramide 

targets, the study identified MSR1 as a candidate 

downstream effector.  

The study therefore investigated the functional 

effects of C6-ceramide and MSR1 in NPC. 

Macrophage scavenger receptor 1 is expressed 

primarily in phagocytic and antigen-presenting cells, 

including dendritic cells, macrophages and lung 

endothelium [14]. It recognizes molecules and 

participate in disease pathogenesis [15]. Cluster of 

differentiation 204 (CD204) is a protein encoded by 

the MSR1 gene. Compared to normal tissues, its 

expression in various breast cancer subtypes is 

markedly higher. Furthermore, CD204 is 

overexpressed in tumorassociated macrophages 

(TAM) and is considered a potential therapeutic 

target within the tumor microenvironment [16]. Other 

studies suggest that MSR1-mediated activation of 

PI3K/AKT, NF-κB and PPARα signaling pathways 

helps macrophages adapt to diverse 

microenvironments [3,17]. Collectively, these studies 

indicate that MSR1 plays a crucial role in cancer 

treatment. Building on this prior work, this study 

examined MSR1 gene transcription in one regular 

nasal epithelial cell line and four NPC cell types. 

MSR1 mRNA amounts were much higher in the NPC 

lines in comparison to the typical cells. Western blot 

analysis further showed MSR1 overexpression in 

NPC cells. These data indicate high MSR1 

expression in NPC cells. Thereafter, the connection 

between MSR1 and NPC carcinogenesis was 

investigated. MSR1 knockdown significantly reduced 

MSR1 levels and inhibited NPC cell viability, 

indicating MSR1 is indeed involved in NPC 

carcinogenesis. Previous studies have demonstrated 

that MSR1 may boost nuclear translocation of β-

catenin, hence promoting stimulation of PI3K/AKT 

pathway [16]. The PI3K/AKT pathway activation are 

crucial for tumorigenesis.  

Therefore, the investigation further examined the 

effect of MSR1 on the PI3K/AKT pathway during 

NPC development by overexpressing or knockdown 

of MSR1 in NPC cells. MSR1 overexpression 

resulted in increased expression of MSR1, PI3K and 

AKT compared to control cells. In contrast, MSR1 

knockdown significantly reduced PI3K and AKT 

protein levels. These findings reveal that MSR1 also 

promotes NPC pathogenesis by stimulating 

PI3K/AKT signaling pathway in NPC cells. C6-

ceramide is a cell-permeable ceramide analogue that 

mimics endogenous ceramides [18]. The antitumor 

effects of C6-ceramide have been demonstrated in 

various tumor models [19], but its effects on NPC are 

unknown. In this study, GSEA analysis of three GEO 

datasets revealed C6-ceramide as a feasible NPC 

treatment. This investigation then investigated the 

implications of C6-ceramide upon NPC cells in vitro. 

Treatment with a specific C6-ceramide concentration 

decreased NPC cell viability. These data demonstrate 

C6-ceramide exerts cytotoxicity and significantly 

reduces NPC cell viability. Previous studies have also 

demonstrated C6- ceramide liposomes induce cell 

death in chronic lymphocytic leukemia cells [20]. 

Next, this study investigated links between C6-

ceramide cytotoxicity and MSR1 expression. MSR1 

overexpression alone increased MSR1 expression. In 

contrast, treatment with C6- ceramide alone markedly 

reduced MSR1 expression. Co-treatment with 

overexpression and C6-ceramide resulted in MSR1 

levels between individual treatment groups. This 

indicates C6-ceramide could mitigate increased 

MSR1 expression induced by overexpression in NPC 

cells. These studies indicate C6-ceramide may have 

therapeutic efficacy by targeting MSR1 in NPC.  

CONCLUSION  

Using GSEA, this investigation has identified C6- 

ceramide and its target gene, MSR1, as therapeutic 

candidates for NPC. The findings verified their 

functional effect in vitro, employing NPC cell line 

experiments. MSR1 knockdown inhibits NPC cell 

proliferation, while C6-ceramide exhibits anti-NPC 

effect by regulating MSR1 expression. Although this 

study lacks patient sample data and detailed 

mechanistic analysis, it provides foundational data 

and reveals new research avenues for targeting MSR1 

and ceramide signaling in NPC treatment. Going 

forward, validation in patient tumor tissues and 

elucidation of the precise molecular mechanisms 



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mediating MSR1 and C6-ceramide effect will 

provide critical insight into their therapeutic 

potential. This work establishes a rationale for further 

exploration of MSR1 and ceramides as novel targets 

in NPC. 

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