Abstract
Metallothioneins (MTs) are small cysteine-rich proteins that play important roles in metal homeostasis and protection against heavy metal toxicity, DNA damage, and oxidative stress. In humans, MTs have four main isoforms (MT1, MT2, MT3, and MT4) that are encoded by genes located on chromosome 16q13. MT1 comprises eight known functional (sub)isoforms (MT1A, MT1B, MT1E, MT1F, MT1G, MT1H, MT1M, and MT1X). Emerging evidence shows that MTs play a pivotal role in tumor formation, progression, and drug resistance. However, the expression of MTs is not universal in all human tumors and may depend on the type and differentiation status of tumors, as well as other environmental stimuli or gene mutations. More importantly, the differential expression of particular MT isoforms can be utilized for tumor diagnosis and therapy. This review summarizes the recent knowledge on the functions and mechanisms of MTs in carcinogenesis and describes the differential expression and regulation of MT isoforms in various malignant tumors. The roles of MTs in tumor growth, differentiation, angiogenesis, metastasis, microenvironment remodeling, immune escape, and drug resistance are also discussed. Finally, this review highlights the potential of MTs as biomarkers for cancer diagnosis and prognosis and introduces some current applications of targeting MT isoforms in cancer therapy. The knowledge on the MTs may provide new insights for treating cancer and bring hope for the elimination of cancer.
Highlights
Metallothioneins (MTs) are a family of low molecular weight, cysteine-rich cytosolic proteins that play a vital role in metal ion homeostasis and detoxification [1, 2]
The results suggested that MT1E downregulation was a potential biomarker of early biochemical recurrence (BCR) and poor prognosis in prostate cancer patients [10]
Numerous studies have demonstrated that the elimination of tumor suppressor gene activity by promoter methylation is responsible for carcinogenesis, a mechanism that has been confirmed in many human cancers
Summary
Metallothioneins (MTs) are a family of low molecular weight (ranging from 6 to 7 kDa), cysteine-rich cytosolic proteins that play a vital role in metal ion homeostasis and detoxification [1, 2]. This result was recently corroborated by Wülfing et al If bladder cancer cells expressed MTs, the patients treated with cisplatin chemotherapy had a significantly poor survival rate; in other words, MT overexpression may mediate resistance to cisplatin-based chemotherapy [23].
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