Review ArticleReview

Zinc dysregulation in cancers and its potential as a therapeutic target

Jie Wang, Huanhuan Zhao, Zhelong Xu and Xinxin Cheng
Cancer Biology & Medicine August 2020, 17 (3) 612-625; DOI: https://doi.org/10.20892/j.issn.2095-3941.2020.0106

Article Figures & Data

Figures

  • Figure 1
    Figure 1

    Representative structural domains of zinc-related proteins. (A, B) The predicted topologies of ZIP and ZnT transporters. The His-rich cluster of zinc transporters is indicated by a blue solid circle. (C) Schematic drawing of the metallothionein structure. It contains seven zinc ions bound in two independent domains. (D) Schematic diagram of human MTF-1. It has one zinc finger DNA-binding domain and three transcriptional activation domains. A cysteine cluster is also found at the C-terminus.

  • Figure 2
    Figure 2

    Subcellular localization of zinc transporters. The localizations of ZIPs and ZnTs are shown based on available information. The arrow indicates the direction of zinc mobilization. ZIPs import zinc into the cytoplasm from the extracellular compartments or intracellular organelles, while ZnTs move zinc in the opposite direction.

  • Figure 3
    Figure 3

    Dysregulation of zinc signaling pathways in different cancers. The transporter-mediated imbalance of intracellular zinc can contribute to the development and progression of cancer, including prostate cancer (A), breast cancer (B), pancreatic cancer (C), esophageal cancer, and metastatic cancers (D). Zinc fluctuations contribute to the disturbance of certain signaling pathways involved in the malignant properties of cancer cells. For clarity, blue arrows are used to indicate ZIP7-mediated pathways, and red arrows are used to represent ZIP6-mediated pathways in breast cancer.

  • Figure 4
    Figure 4

    Summary of zinc signaling in pathogenesis. Intracellular zinc fluctuations can be triggered by zinc release from intracellular stores, or transcriptional regulation of proteins required for zinc metabolism and homeostasis. Then, zinc modulates multiple zinc-requiring proteins or phosphorylation-dependent signaling cascades, which contribute to numerous cellular events, such as survival, differentiation, proliferation, and migration, ultimately causing the initiation or progression of cancer.

Tables

  • Table 1

    Zinc dysregulation in cancers

    CancersSerumTissueAberrant transporterReferences
    Prostate cancerContradiction†DecreasedZIP1, ZIP2, ZIP3, ZIP4, ZIP9, ZnT434,41,43–45
    Breast cancerDecreasedIncreasedZIP6, ZIP7, ZIP9, ZIP10, ZnT231,33,60,65,67
    Pancreatic cancerNR‡DecreasedZIP3, ZIP477,79
    Hepatocellular cancer (HCC)DecreasedDecreasedZIP4, ZIP14, ZnT986,89,90
    Esophageal squamous cell carcinoma (ESCC)DecreasedDecreasedZIP5, ZIP611,91,92
    Ovarian cancerDecreasedDecreasedZIP431,93
    Cervical cancerDecreasedDecreasedZIP794,95
    Kidney cancerNRDecreasedZIP1, ZIP1096–98
    Gastric cancerDecreasedIncreasedContradiction†99,100
    Lung cancerDecreasedIncreasedZIP4101–103
    Bladder cancerDecreasedNRZIP11, ZnT195,104,105
    Oral squamous cell carcinoma (OSCC)NRNRZIP4106
    Nasopharyngeal carcinoma (NPC)NRIncreasedZIP4107,108

    †Conflicting results are reported in several articles. ‡Not reported.

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