Endocrinol Metab.  2020 Sep;35(3):656-668. 10.3803/EnM.2020.667.

Liver X Receptor β Related to Tumor Progression and Ribosome Gene Expression in Papillary Thyroid Cancer

• Jeong S
• Kim IK
• Kim H
• Choi MJ
• Lee J
• Jo YS

• KMID: 2508016
• DOI: http://doi.org/10.3803/EnM.2020.667

Abstract

Background
Intracellular lipid deposition has been reported in thyroid glands in obese animal and human. To understand the regulatory mechanism of lipid metabolism in thyroid cancer, we investigated the expression status of liver X receptor (LXR) and analyzed its clinicopathological characteristics and molecular biological features.
Methods
Expression status of LXR and its transcriptional targets in human cancers were analyzed using The Cancer Genome Atlas (TCGA). The gene-sets related to high LXRβ expression was investigated by gene set enrichment analysis (GSEA) using Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways and gene ontology biologic process. Quantitative reverse transcription polymerase chain reaction was performed in thyroid cancer samples using our validation cohort.
Results
In contrast to low expression of LXRα, LXRβ was highly expressed in thyroid cancer compared to the other types of human cancers. High LXRβ expression was correlated with the expression of LXRβ transcriptional targets genes, such as apolipoprotein C1 (APOC1), APOC2, apolipoprotein E (APOE), ATP binding cassette subfamily G member 8 (ABCG8), sterol regulatory elementbinding protein 1c (SREBP1c), and SPOT14. Furthermore, High LXRβ expression group indicated poor clinicopathological characteristics and aggressive molecular biological features independently from the drive mutation status. Mechanistically, high LXRβ expression was coordinately related to ribosome-related gene sets.
Conclusion
The mechanistic link between LXRβ and ribosomal activity will be addressed to develop new diagnostic and therapeutic targets in thyroid cancers.

Keyword

Thyroid neoplasms; Obesity; Metabolism; Prognosis; Liver X receptors; Ribosomes

Figure

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  Fig. 1. Comparison of liver X receptor (LXR) expression in human cancers. (A) Comparison of LXRα mRNA expression in various human cancers. (B) Comparison of LXRβ mRNA expression in various human cancers. (C) Comparison of LXRα protein expression in various human cancers. (D) Comparison of LXRβ protein expression in various human cancers. (E) Comparison of LXRα mRNA expression between normal tissues and thyroid cancer samples by unpaired (left panel) and paired (right panel) t tests. (F) Comparison of LXRβ mRNA expression between normal tissues and thyroid cancer samples by unpaired (left panel) and paired (right panel) t tests. Comparison of LXRα and LXRβ mRNA expression levels was performed using TCGA data (n=505) and comparison of LXRα and LXRβ protein levels was conducted using Human Protein Atlas Data. Data are presented as mean±standard deviation. Mean comparisons were analyzed by an unpaired or paired t test. a P<0.01; b P<0.0001.

• 

  Fig. 2. Correlation analysis between expression of liver X receptor β (LXRβ) and its transcriptional target genes. (A) Correlation between expression of LXRβ and its transcriptional target genes in The Cancer Genome Atlas (TCGA) thyroid carcinoma (THCA). Correlation coefficients were calculated by Pearson’s method. (B) Comparison of mRNA expression level of LXRβ representative target genes between normal and cancer tissues in TCGA THCA. (C) Comparison of mRNA expression level of LXRβ representative target genes according to LXRβ expression status (n=126 for each group). Data are presented as mean±standard deviation. Mean comparisons were analyzed by an unpaired t test. APOC1, apolipoprotein C1; APOC2, apolipoprotein C2; APOE, apolipoprotein E; ABCG8, ATP binding cassette subfamily G member 8; SREBP1c, sterol regulatory element-binding protein 1c; SPOT14, thyroid hormone responsive (THRSP). a P<0.01; b P<0.0001.

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  Fig. 3. Correlation of liver X receptor β (LXRβ) with the expression of ribosome gene sets. (A) Representative results of gene set enrichment analysis (GSEA) using Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways and gene ontology (GO) term (biological process) in thyroid carcinoma (THCA) according to LXRβ expression status (low vs. high LXRβ expression group (n=126 for each group). Gene sets of interest are indicated by the name of gene sets. Red circles indicate statistically significant gene sets (nominal P value ≤0.05 and false discovery rate q-value ≤0.25). Blue circles indicate gene sets with high FDR q-values although the P value seems meaningful (nominal P value ≤0.05 and FDR q-value >0.25). (B) Detailed information of KEGG ribosome and GO ribosome gene sets coordinately enriched in the group with high LXRβ expression, with the list of gene names. NES, normalized enrichment score.

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  Fig. 4. Positive relationship of liver X receptor β (LXRβ) with the expression of representative ribosome genes. (A) Correlation analysis of LXRβ with representative ribosome genes (n=505, using thyroid carcinoma [THCA] data). Correlation coefficients were calculated by Pearson’s method. P values are indicated on the corresponding figures. (B) Selected target gene expressions were identified in THCA and GSE83520 data sets. GSE83520 is the data that performed RNA sequencing with the tumor and normal tissues of 12 papillary thyroid carcinoma patients. (C) Representative figure of reverse transcription-polymerase chain reaction (RT-PCR) validating THCA analysis using our validation samples. All RT-PCR assays were representative of at least three independent experiments. (D) Semi-quantitative analysis of RT-PCR results (each group n=8) using ImageJ software. Data are presented as mean±standard deviation. Mean comparisons were analyzed by Wilcoxon signed rank test. All experiments were repeated three times, and each experiment was performed in triplicate. N, normal; T, tumor; RPS30, ribosomal protein S30; RPL11, ribosomal protein L11; RPL15, ribosomal protein L15; RPL19, ribosomal protein L19; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. a P<0.05; b P<0.001.

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