At present, it is increasingly necessary to explore more pathogenesis of thyroid cancer. By exploring the correlation between serum essential elements and thyroid nodules and their malignant tendency, this study found that CL, Mg, Na and P are potential influencing factors related to malignant tendency of thyroid nodules, and the imbalance of Na elements in females may disturb the balance of thyroid function and increase the occurrence of malignant tendency of thyroid nodules. It provides an effective reference for judging the malignant tendency of thyroid nodules.
Serum CL, Mg, Na, P may be the potential factors related to the malignant tendency of thyroid nodules. Our study found that in the general population, the detection levels of CL, Mg, Na were significantly decreased and the level of P was significantly increased in the MTNs compared with the BTNs. On this basis, the serum CL, Mg, and Na concentrations were negatively correlated with the malignant tendency of thyroid nodules in the general population through logistic regression analysis, while the serum P concentration was positively correlated with the malignant tendency of thyroid nodules. It showed that low serum CL, Mg and Na concentrations emerged as consistent risk factors for thyroid nodules malignant tendency in both genders, whereas low P concentrations emerged as consistent protective factor.
It has been shown that CL ion were involved in various physiological and pathophysiological processes such as cell proliferation, cell cycle regulation, apoptosis, and cell volume regulation[4, 17]. CL channels regulate cell volume by an efflux of chloride ions in response to osmotic stresses. These have been shown to play a role in cancer invasion. Studies have found that intracellular MQAE fluorescence intensity increased immediately after cell compression, demonstrating induction of Cl- efflux by mechanical force. Furthermore, Cl- efflux ability showed correlation with the breast cancer metastatic potential[18, 19]. Alterations of cell volume played a vital role in both cell proliferation and cell apoptosis. The signals for cell proliferation required an increase of cell volume at some stage, while cell apoptosis was paralleled by cell shrinkage[20]. Chloride ion transporters were expressed in the cell membrane, which could modify ion activity, mediate osmolyte flux, and alter cell volume. The chloride channels could release HCO3−, contributing to cytosolic acidification, which suppressed cell proliferation and promoted cell apoptosis[20–22].
Mg plays a central role in thyroid disease and may influence carcinogenic effects through two mechanisms. First, Mg is related to the stabilization of the structure of nucleic acids and seems involved in DNA replication, transcription, and repair. Therefore, any Mg deficiency can lead to the development of tumors through DNA mutations[23]. Second, Mg may influence the development of cancer through its association with inflammation and/or free radicals, which may lead to DNA oxidative damage and cancer formation. Mg-deficient animals show a higher sensitivity to oxidative stress in vivo and their tissues are more susceptible to peroxides in vitro[12]. Pooled analysis indicated that subjects with thyroid cancer had lower serum levels of Mg, it is considered to play a role in preventing cancer[24].
The main role of vitamin D is to regulate Ca and P homeostasis, and the abnormal P metabolism in thyroid nodules may be mediated by vitamin D. Vitamin D can directly or indirectly regulate a variety of signaling pathways such as cell proliferation, differentiation, apoptosis, inflammation, invasion, angiogenesis and metastasis. Therefore, it has the potential to influence the development and growth of cancer. In addition, vitamin D also regulates microRNA expression and may influence the biology of cancer stem cells[25]. Vitamin D has the effect of raising blood P, and impaired vitamin D signaling has been reported in thyroid cancers, which may lead to lower blood P[26, 27].
Na imbalances can lead to several cancer features, including changes in growth signaling, proliferation, angiogenesis, invasion, and metastasis[28]. In addition, the accumulation of extracellular Na ion in cancer due to inflammation contributes to tumor immunogenicity. Thus, alterations in the Na ion concentration may potentially be used as a biomarker for malignant tumor diagnosis and prognosis[29]. Na element imbalance increases the malignant tendency of thyroid nodules in female, which may be caused by disturbing the balance of thyroid function. Our study found that in female, serum Na concentration and FT3 were significantly lower in the MTNs than in the BTNs, and there was a significant correlation between serum Na concentration and FT3 by multiple linear regression. Ma etl results showed that serum FT3 level was significantly decreased in patients with lung cancer, it were used in combination with CEA and were identified as potential diagnostic biomarkers of stage 0 lung cancer (Tis)[30]. Cirrhotic patients with FT3 < 3.03 pmol/L showed lower sodium levels and a higher incidence of frailty[31].
In this study, we conducted a case-control study based on the epidemiology of thyroid malignancy and nodular goiter, and the sample size was large enough to have certain representative significance. Secondly, we stratified the samples by sex to demonstrate the association between serum essential elements and thyroid hormone and malignant tendency of thyroid nodules. However, there are still some limitations, the first is this study could not confirm the causal relationship between serum essential elements and the malignant tendency of thyroid nodules, which will be further explored to clarify the mechanism of action. Second, this study only explored the association between essential elements and papillary thyroid carcinoma, and did not evaluate the association with other subtypes like follicular, medullary, and anaplastic thyroid cancer.