CCL22 and CCL26 are potential biomarkers for predicting distant metastasis in thyroid carcinoma

Abstract

Objectives: Chemokines have been suggested to play significant roles in the progression of malignant cancers. This study aimed to identify the chemokines related to malignant progression in thyroid carcinoma.

Methods: The mRNA expression levels of 52 chemokines were compared between differentiated thyroid cancer (DTC) samples and normal thyroid tissues from The Cancer Genome Atlas database; survival analysis was then performed on the basis of differentially expressed chemokines. A retrospective study was conducted on the level of differentially expressed chemokines in 76 DTC patients. Functional pathway analysis was performed to explore chemokine-related regulatory mechanisms.

Results: We identified 20 chemokines with differentially expressed mRNA levels through publicly available data. High levels of CCL22 and CCL26 were found to be related with metastasis in clinical DTC samples. High levels of CCL22 were found to be significantly related to poor prognosis in DTC patients. Pathway analyses revealed that cytokines might affect cancer progression through cytokine-cytokine receptor and cytokine-interleukin interactions.

Conclusions: CCL22 and CCL26 could serve as prognostic biomarkers in thyroid carcinoma.

Keywords: CCL22; CCL26; Thyroid carcinoma; biomarker; chemokine; distant metastasis.

Figure 1.

Expression of chemokines in a public database and screening for differentially expressed chemokines. (a) Clustering heatmap of 52 expressed chemokine mRNAs in 567 thyroid samples. The ordinate axis indicates the chemokine names. (b) Volcano plot showing the chemokine mRNAs. Red represents high expression, and blue represents low expression and (c) The 14 upregulated chemokine mRNAs in thyroid tumor tissues were CCL11, CXCL6, CCL13, CCL17, CXCL5, CCL26, CXCL8, CCL1, CCL7, CXCL1, CX3CL1, CCL15, CCL22, and CXCL16. (d) The six downregulated chemokine mRNAs in thyroid tumor tissues were CCL21, CCL19, IL2, IL6, CXCL13, and CCL2.

Figure 2.

CCL22 and CCL26 expression in 76 DTC patients stratified by the presence or absence of metastatic lesions. (a) CCL22 expression in non-metastatic and metastatic differentiated thyroid cancer (DTC) patients. (b) CCL22 expression in DTC patients without metastases, with only lymph node metastasis, and with distant metastases. (c) CCL26 expression in non-metastatic and metastatic DTC patients. (d) CCL26 expression in DTC patients without metastases, with only lymph node metastasis, and with distant metastases. (e) Combined prognostic value of CCL22 and CCL26 in 76 DTC patients. (f) The prognostic value of CCL22 in thyroid carcinoma patients from The Kaplan–Meier Plotter database. (g) The prognostic value of CCL26 in thyroid carcinoma patients from The Kaplan–Meier Plotter database.

Figure 3.

CCL22 and CCL26 transcript expression levels in subgroups of patients with thyroid carcinoma, stratified by histology, sex, age, and other criteria (UALCAN). (a) Relative CCL22 expression in thyroid cancers of different histological grades. (b) Relative CCL22 expression in healthy controls and thyroid carcinoma patients aged 21–40, 41–60, 61–80, or 81–100 years. (c) Relative CCL22 expression in healthy controls and in thyroid carcinoma patients with or without nodal metastasis. (d) Relative CCL22 expression in healthy controls and stage I to stage IV thyroid carcinoma patients. (e) Relative CCL22 expression in thyroid cancers of different histological grades. (f) Relative CCL22 expression in healthy controls and thyroid carcinoma patients aged 21–40, 41–60, 61–80, or 81–100 years. (g) Relative CCL22 expression in healthy controls and thyroid carcinoma patients with or without nodal metastasis and (h) Relative CCL22 expression in healthy controls and stage I to stage IV thyroid carcinoma patients. Data are expressed as mean ± standard error; *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 4.

(a) The protein-protein interaction (PPI) network significantly coregulated with CCL22 (CCR7, CCR4, IL13, CXCR3, CCR8, IL4, CCR2, CCR1, STAT3, and IL10). (b) The PPI network significantly coregulated with CCL26 (CCR1, CX3CR1, CXCR3, CCR3, CCR2, CCR8, IL13, IL4, STAT6, and SLC12A2). (c) GeneMANIA was used to validate the genes co-expressed with CCL22 and CCL26 and (d–g) Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the co-expressed genes with CCL22 and CCL26. P-values are displayed on the x-axis and GO functional enrichment and KEGG pathways are shown on the y-axis.