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Scheme describing the activation of signaling pathways involved in breast cancer progression and metastasis. Zn²⁺ dyshomeostasis results in activation of multiple pathways that affect cell morphology, migration, and proliferation. Note specifically ZIP10 and ZIP6 that interact to regulate epithelial mesenchymal transition, and ZnR/GPR39 that induces membrane protrusions and MMP2/9 release. Arrows depict established pathways, while dotted lines and question marks are putative pathways for regulation and interaction.
Source publication
Zinc (Zn2+) plays an essential role in epithelial physiology. Among its many effects, most prominent is its action to accelerate cell proliferation, thereby modulating wound healing. It also mediates affects in the gastrointestinal system, in the testes, and in secretory organs, including the pancreas, salivary, and prostate glands. On the cellular...
Citations
... As an essential trace element, zinc ions play catalytic, structural, and regulatory roles in biological systems (1), including cell signaling (2)(3)(4) and cell cycle control during meiosis and mitosis (5)(6)(7)(8)(9)(10)(11)(12). Zinc fluxes are also associated with numerous physio-pathological processes (3,5,9,(13)(14)(15)(16)(17)(18)(19). In humans, dietary zinc is absorbed in the small intestine where its transport is primarily mediated by ZIP4, a zinc transporter belonging to the Zrt/Irt-like protein (ZIP) metal transporter family (20)(21)(22)(23). ...
The essential microelement zinc is absorbed in the small intestine mainly by the zinc transporter ZIP4, a representative member of the Zrt/Irt-like protein (ZIP) family. ZIP4 is reportedly upregulated in many cancers, making it a promising oncology drug target. To date, there have been no reports on the turnover number of ZIP4, which is a crucial missing piece of information needed to better understand the transport mechanism. In this work, we used a non-radioactive zinc isotope, ⁷⁰ Zn, and inductively coupled plasma mass spectrometry (ICP-MS) to study human ZIP4 (hZIP4) expressed in HEK293 cells. Our data showed that ⁷⁰ Zn can replace the radioactive ⁶⁵ Zn as a tracer in kinetic evaluation of hZIP4 activity. This approach, combined with the quantification of the cell surface expression of hZIP4 using biotinylation or surface-bound antibody, allowed us to estimate the apparent turnover number of hZIP4 to be in the range of 0.08-0.2 s ⁻¹ . The turnover numbers of the truncated hZIP4 variants are significantly smaller than that of the full-length hZIP4, confirming a crucial role for the extracellular domain in zinc transport. Using ⁶⁴ Zn and ⁷⁰ Zn, we measured zinc efflux during the cell-based transport assay and found that it has little effect on the zinc import analysis under these conditions. Finally, we demonstrated that use of laser ablation (LA) ICP-TOF-MS on samples applied to a solid substrate significantly increased the throughput of the transport assay. We envision that the approach reported here can be applied to the studies of metal transporters beyond the ZIP family.
... Serum and intracellular zinc concentrations are altered in breast cancer patients, and it remains unclear if this redistribution is a direct consequence of zinc nutrient alteration or a tissue-specific response [21]. Zinc signaling directly controls mammary gland development and aberrant signaling has been observed in malignant cells during breast cancer progression, accumulation, or the redistribution of zinc in the mammary gland [22]. ...
It is well-known that serum and cellular concentrations of zinc are altered in breast cancer patients. Specifically, there are notable zinc hyper-aggregates in breast tumor cells when compared to normal mammary epithelial cells. However, the mechanisms responsible for zinc accumulation and the consequences of zinc dysregulation are poorly understood. In this review, we detailed cellular zinc regulation/dysregulation under the influence of varying levels of sex steroids and breast cancer tumorigenesis to try to better understand the intricate relationship between these factors based on our current understanding of the CmPn/CmP signaling network. We also made some efforts to propose a relationship between zinc signaling and the CmPn/CmP signaling network.
... The results indicate that the tumorigenesis and development of breast cancer are closely related to zinc-ion binding, which is consistent with the findings in previous studies (37)(38)(39). Many studies have found that zinc is significantly correlated with the carcinogenesis of various tissues and cells in the body, and a change in the zinc content in the human body is closely related to the occurrence and development of tumors (40)(41)(42). In addition, zinc deficiency can cause immune dysfunction, which can enhance the inflammatory effects of interleukin, inhibit the effects of interleukin on lymphocytes, and promote apoptosis, angiogenesis, and metastasis. ...
Background
With the rapid development and wide application of high-throughput sequencing technology, biomedical research has entered the era of large-scale omics data. We aim to identify genes associated with breast cancer prognosis by integrating multi-omics data.
Method
Gene-gene interactions were taken into account, and we applied two differential network methods JDINAC and LGCDG to identify differential genes. The patients were divided into case and control groups according to their survival time. The TCGA and METABRIC database were used as the training and validation set respectively.
Result
In the TCGA dataset, C11orf1, OLA1, RPL31, SPDL1 and IL33 were identified to be associated with prognosis of breast cancer. In the METABRIC database, ZNF273, ZBTB37, TRIM52, TSGA10, ZNF727, TRAF2, TSPAN17, USP28 and ZNF519 were identified as hub genes. In addition, RPL31, TMEM163 and ZNF273 were screened out in both datasets. GO enrichment analysis shows that most of these hub genes were involved in zinc ion binding.
Conclusion
In this study, a total of 15 hub genes associated with long-term survival of breast cancer were identified, which can promote understanding of the molecular mechanism of breast cancer and provide new insight into clinical research and treatment.
Zinc is essential for many physiological functions, with a major role in digestive system, skin health, and learning and memory. On the cellular level, zinc is involved in cell proliferation and cell death. A selective zinc sensing receptor, ZnR/GPR39 is a Gq‐coupled receptor that acts via the inositol trisphosphate pathway to release intracellular Ca²⁺. The ZnR/GPR39 serves as a mediator between extracellular changes in Zn²⁺ concentration and cellular Ca²⁺ signalling. This signalling pathway regulates ion transporters activity and thereby controls the formation of transepithelial gradients or neuronal membrane potential, which play a fundamental role in the physiological function of these tissues. This review focuses on the role of Ca²⁺ signalling, and specifically ZnR/GPR39, with respect to the regulation of the Na⁺/H⁺ exchanger, NHE1, and of the K⁺/Cl⁻ cotransporters, KCC1‐3, and also describes the physiological implications of this regulation. image
