SLC34A2 Up-regulation And SLC4A4 Down-regulation Correlates With Invasion, Metastasis, And The MAPK Signaling Pathway In Papillary Thyroid Carcinomas.

Abstract

Papillary thyroid carcinoma (PTC) is one of the fastest growing endocrine system malignant carcinomas detected over the past decade. Unfortunately, more than 25% of PTC patients are characterized by their aggressiveness and subsequent metastasis; these characteristics usually indicate poor prognosis. Recently, increasing evidence has suggested that solute carrier (SLC) transporters may play a pivotal role in the initiation, invasion and metastasis of human carcinoma. However, the expression and clinicopathological significance of SLC transporters in patients with PTC remains undetermined. In this study, we aimed to elucidate how the differential expression of SLC transporters affects clinicopathological features, as well as determine the possible regulatory signaling pathways involved. Three differentially expressed SLC transporters were screened from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database using a bioinformatics approach. The results indicated that high SLC34A2 and low SLC4A4 protein expression exhibited a higher percentage of capsular invasion and extra-thyroid metastasis in patients. Logistic regression analysis showed that high SLC34A2 expression in tumors was identified as an independent risk factor for capsular invasion [odds ratio (OR)=11.400, 95% confidence interval (CI)=1.733-74.995, P=0.011] and extra-thyroid metastasis (OR=4.920, 95%CI=1.234-19.623, P=0.024), while low SLC4A4 expression in tumors was only identified as independent risk factors for extra-thyroid metastasis (OR=8.568, 95%CI =1.186-61.906, P=0.033). Specifically, for tumors with capsular invasion and extra-thyroid metastasis, the protein expression staining of SLC34A2 was markedly enhanced in the cytoplasm of follicular epithelial cells, contrastingly, SLC4A4 expression was notably weakened in the cytomembrane and nucleus. Intriguingly, both high SLC34A2 and low SLC4A4 protein expression were significantly linked to a high urinary iodine concentration in patients with PTC. Mechanistically, compared with adjacent normal thyroids, p-ERK was significantly up-regulated by 17.8% in the invading tumor; p-ERK, p-JNK, and p-P38 were markedly up-regulated by 29.2%, 67.1%, and 38.9% for metastatic tumors, respectively. Importantly, SLC4A4 negatively correlated with p-JNK (r=-0.696, P= 0.004) and p-P38 (r=-0.534, P=0.049). In conclusion, we suggest that up-regulated SLC34A2 (mainly in the cytoplasm) and down-regulated SLC4A4 (mainly in the cytomembrane and nucleus), which might be attributed to excess iodine intake, were closely linked to extra-thyroid metastasis in PTCs. Furthermore, this effect of SLC4A4 may be through the activation of JNK/P38 MAPK signaling pathway. Future in vivo and in vitro gain- or loss-of-function experiments are needed to verify these findings and further elucidate the deeper molecular mechanisms.