Zinc and Copper Homeostasis in Head and Neck Cancer: Review and Meta-Analysis

Abstract

Metals are known for playing essential roles in human physiology. Copper and zinc are trace elements closely dependent on one another and are involved in cell proliferation, growth, gene expression, apoptosis and other processes. Their homeostasis is crucial and tightly controlled by a resourceful system of transporters and transport proteins which deliver copper and zinc ions to their target sites. Abnormal zinc and copper homeostasis can be seen in a number of malignancies and also in head and neck cancer. Imbalance in this homeostasis is observed as an elevation or decrease of copper and zinc ions in serum or tissue levels in patients with cancer. In head and neck cancer these altered levels stand out from those of other malignancies which makes them an object of interest and therefore zinc and copper ions might be a good target for further research of head and neck cancer development and progression. This review aims to summarize the physiological roles of copper and zinc, its binding and transport mechanisms, and based on those, its role in head and neck cancer. To provide stronger evidence, dysregulation of levels is analysed by a meta-analytical approach.

Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice

“…Perturbed metal homeostasis, in particular excess of essential metals, has been associated with carcinogenesis and metastasis [ 33 ]. A meta-analysis revealed that Zinc (Zn 2+ ) and copper (Cu 2+ ) seem to play a particular role in head and neck cancer [ 34 ]. In HT-29 cells it is known that extracellular Zn 2+ supports HT-29 cell growth at 10 μM and inhibits it at 100 μM through a Zn 2+ -sensing receptor that does not seem to alter intracellular Zn 2+ concentrations and involves the ERK pathway [ 35 ].…”

Zinc promotes cell apoptosis via activating the Wnt-3a/β-catenin signaling pathway in osteosarcoma

“…Zinc in human trace elements correlates with the occurrence and development of malignant tumors, such as rectal cancer, gastric cancer, and breast cancer. Zinc imbalance also affects the occurrence of head and neck cancer [24]. Zinc oxide nanoparticles exert selective cytotoxicity against tumor cells and can serve as an innovative antitumor agent [25].…”

β-Naphthoflavone, an exogenous ligand of aryl hydrocarbon receptor, disrupts zinc homeostasis in human hepatoma HepG2 cells

“…Additionally, an epidemiological analysis in humans found that chronic or accidental exposure to low doses of dioxins is a potential risk factor for type 2 diabetes (Bertazzi et al, 2001;Wang et al, 2008) and cancer (Leng et al, 2014;Wang et al, 2013). Furthermore, recent findings have demonstrat-ed a relationship between zinc homeostasis disruption and the onset of disease, such as type 2 diabetes (Chu et al, 2017;Yary et al, 2016), Alzheimer's disease (Kawahara et al, 2018;Li and Wang, 2016;Portbury and Adlard, 2015), and cancer (Bafaro et al, 2017;Kolenko et al, 2013;Ressnerova et al, 2016). The precise physiological consequence of disrupted zinc homeostasis by AHR ligands remains to be determined.…”

“…Zinc homeostasis is precisely regulated by the balanced actions of zinc-binding proteins, metallothioneins, and zinc transporters (Hara et al, 2017;Hojyo and Fukada, 2016). Given the critical functions of zinc, perturbation of zinc levels would thus be detrimental to cell survival, and several studies have revealed alterations of serum, tissue, and cellular zinc concentrations during the onset of certain diseases, including type 2 diabetes (Yary et al, 2016), Alzheimer's disease (Li and Wang, 2016;Portbury and Adlard, 2015), senile dementia (Kawahara et al, 2014), and cancer (Kolenko et al, 2013;Ressnerova et al, 2016). These findings suggest that zinc homeostasis plays an important role in the onset and progression of disease.…”