Zinc Transporters and the Progression of Breast Cancers

Takatani‐Nakase, Tomoka

doi:10.1248/bpb.b18-00086

Cited by 44 publications

(30 citation statements)

References 41 publications

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“…Intracellular and extracellular Zn levels and distributions were spatiotemporally regulated by the specific Zn transporters regulate in a tissue-specific manner [24]. Aberrant Zn transporters have been reported to be associated with specific diseases, including diabetes, Alzheimer's disease, cancers, and other pathological processes [25][26][27][28][29][30].…”

Section: Discussionmentioning

confidence: 99%

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Analysis of the prognostic significance of solute carrier (SLC) family 39 genes in breast cancer

2020

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Background: Breast cancer (BC) is the most common malignancy in females and remains a main cause of cancer-associated death worldwide. The solute carrier (SLC) groups of membrane transport proteins, which control the inﬂux of zinc, participate in ranging of physiological processes and may provide novel therapeutic targets of cancers. However, the prognostic values of individual SLC family 39 (SLC39A) genes in patients with BC are not clarified. Materials and Methods: The mRNA expression of SLC family 39 genes in BC was evaluated by using the UALCAN database. The prognostic values of overall survival (OS) of SLC family 39 genes in patients with BC were investigated by Kaplan-Meier plotter. The survival analysis of cells was determined by Project Achilles. Results: The analytic results suggested that SLC39A1, SLC39A3, SLC39A4, SLC39A5, SLC39A6, SLC39A7, SLC39A9, SLC39A10, SLC39A11 and SLC39A13 were significantly upregulated in BC tissues compared with normal breast tissues. However, SLC39A8 and SLC39A14 were expressed higher in normal tissues than in BC tissues. High expression of SLC39A2, SLC39A3, SLC39A4, SLC39A5, SLC39A7, SLC39A12 and SLC39A13 was significantly associated with worse OS in patients with BC. In contrast, high mRNA levels of SLC39A6 and SLC39A14 indicated favorable OS. Through subgroup analysis, all abnormal expressed SLC family members were correlated with prognoses of patients with specific BC. Moreover, SLC39A7 was associated with proliferation and cloning of BC. Conclusions: Our results suggested that SLC family 39 members were promising prognostic biomarkers of BC. The SLC39A7 played a key role in growth and survival of BC cells.

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Section: Discussionmentioning

confidence: 99%

“…A line of evidences has demonstrated the importance of SLC39A members in the progression of BC [24]. Knockdown of SLC39A6 blocks intracellular homeostasis of Zn level, which leads to cell survival underlying a hypoxic environment [34].…”

Section: Discussionmentioning

confidence: 99%

Analysis of the prognostic significance of solute carrier (SLC) family 39 genes in breast cancer

2020

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“…The involvement of ZIP6 in longer relapse free survival and prolonged survival of breast cancer patients with ductal carcinoma invasion has been documented [124]. Knockdown of ZIP6 in MCF-7 breast cancer cells can increase cell survival in hypoxic environments [125,126]. ZIP6 also reportedly promotes breast cancer cell invasion and metastasis, together with the high expression of E-cadherin [127,128].…”

Section: Zinc and Zinc Transporters In Other Cancersmentioning

confidence: 98%

Growth Modulatory Role of Zinc in Prostate Cancer and Application to Cancer Therapeutics

Manh

Cho

et al. 2020

IJMS

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Zinc is a group IIB heavy metal. It is an important regulator of major cell signaling pathways in most mammalian cells, functions as an antioxidant and plays a role in maintaining genomic stability. Zinc deficiency leads to severe diseases in the brain, pancreas, liver, kidneys and reproductive organs. Zinc loss occurs during tumor development in a variety of cancers. The prostate normally contains abundant intracellular zinc and zinc loss is a hallmark of the development of prostate cancer development. The underlying mechanism of this loss is not clearly understood. The knowledge that excess zinc prevents the growth of prostate cancers suggests that zinc-mediated therapeutics could be an effective approach for cancer prevention and treatment, although challenges remain. This review summarizes the specific roles of zinc in several cancer types focusing on prostate cancer. The relationship between prostate cancer and the dysregulation of zinc homeostasis is examined in detail in an effort to understand the role of zinc in prostate cancer.Int. J. Mol. Sci. 2020, 21, 2991 2 of 18 in K562 leukemia cells [11]. Withdrawal of zinc from PrEC prostate epithelial cells also stimulates breakage of single-strand DNA [12]. In addition, genes related to DNA damage response, including tumor protein p73 and MRE11, were downregulated in these cells, whereas the expression of p53 was increased. In murine fibroblasts, the addition of zinc can stimulate DNA synthesis and mitogenic signaling, whereas withdrawal of zinc reduces the secretion of growth hormone [13,14]. In Swiss 3T3 fibroblasts, ZnSO 4 can reverse the inhibitory effect of diethylenetrinitrilopentaacetate (DTPA) on thymidine incorporation into DNA, suggesting that zinc stimulates cell growth by regulating cell cycle at the G1/S phase [15]. Intracellular zinc can block the G2/M transition in human bronchial epithelial cells by upregulating p53 and p21 activity [16]. These collective findings highlight the central role of zinc in the modulation of cell proliferation, mainly by affecting DNA synthesis. Therefore, zinc homeostasis plays a key role in the development of many diseases, in which the alteration of zinc is a common event. Zinc BiologyThe human body mass contains more than 2 g of zinc. Over 90% is distributed to most tissues, with only approximately 0.1% of this metal ion circulating in plasma [17,18]. Yet, this small amount of zinc plays an important role in maintaining homeostasis in the body. Zinc is stored in most organs and tissues with approximately 60% in skeletal muscle, 30% in bone and 5% in liver and skin and the remainder distributed in other tissues that include the brain, kidneys, pancreas and heart [19] (Figure 1). Excess zinc is primarily released through gastrointestinal secretion and endogenous excretion, with minor loss through urinary excretion. Although zinc is an essential trace element used by many enzymes and transcription factors, high concentrations are toxic to the cells. Cells adapt to overcome the toxicity by maintaining the balance of ...

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“…In the prostate gland ZIPs, especially ZIP1, are considered tumor suppressors[323]. In breast cancer, increased levels of zinc correspond to upregulation of several ZIPs (and a few ZnTs as well), thus zinc transporters as a group are considered as oncogenes in breast cancer[324]. In the GI tract, the majority of reports show upregulation of both ZIPs and ZnTs in all major GI organ cancers (Table 5), although for some cancers there is clearly conflicting evidence.…”

Section: Zinc Transportersmentioning

confidence: 99%

Role of ion channels in gastrointestinal cancer

Anderson¹,

Cormier²,

Scott³

2019

WJG

145

103

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In their seminal papers Hanahan and Weinberg described oncogenic processes a normal cell undergoes to be transformed into a cancer cell. The functions of ion channels in the gastrointestinal (GI) tract influence a variety of cellular processes, many of which overlap with these hallmarks of cancer. In this review we focus on the roles of the calcium (Ca2+), sodium (Na+), potassium (K+), chloride (Cl-) and zinc (Zn2+) transporters in GI cancer, with a special emphasis on the roles of the KCNQ1 K+ channel and CFTR Cl- channel in colorectal cancer (CRC). Ca2+ is a ubiquitous second messenger, serving as a signaling molecule for a variety of cellular processes such as control of the cell cycle, apoptosis, and migration. Various members of the TRP superfamily, including TRPM8, TRPM7, TRPM6 and TRPM2, have been implicated in GI cancers, especially through overexpression in pancreatic adenocarcinomas and down-regulation in colon cancer. Voltage-gated sodium channels (VGSCs) are classically associated with the initiation and conduction of action potentials in electrically excitable cells such as neurons and muscle cells. The VGSC NaV1.5 is abundantly expressed in human colorectal CRC cell lines as well as being highly expressed in primary CRC samples. Studies have demonstrated that conductance through NaV1.5 contributes significantly to CRC cell invasiveness and cancer progression. Zn2+ transporters of the ZIP/SLC39A and ZnT/SLC30A families are dysregulated in all major GI organ cancers, in particular, ZIP4 up-regulation in pancreatic cancer (PC). More than 70 K+ channel genes, clustered in four families, are found expressed in the GI tract, where they regulate a range of cellular processes, including gastrin secretion in the stomach and anion secretion and fluid balance in the intestinal tract. Several distinct types of K+ channels are found dysregulated in the GI tract. Notable are hERG1 upregulation in PC, gastric cancer (GC) and CRC, leading to enhanced cancer angiogenesis and invasion, and KCNQ1 down-regulation in CRC, where KCNQ1 expression is associated with enhanced disease-free survival in stage II, III, and IV disease. Cl- channels are critical for a range of cellular and tissue processes in the GI tract, especially fluid balance in the colon. Most notable is CFTR, whose deficiency leads to mucus blockage, microbial dysbiosis and inflammation in the intestinal tract. CFTR is a tumor suppressor in several GI cancers. Cystic fibrosis patients are at a significant risk for CRC and low levels of CFTR expression are associated with poor overall disease-free survival in sporadic CRC. Two other classes of chloride channels that are dysregulated in GI cancers are the chloride intracellular channels (CLIC1, 3 & 4) and the chloride channel accessory proteins (CLCA1,2,4). CLIC1 & 4 are upregulated in PC, GC, gallbladder cancer, and CRC, while the CLCA proteins have been reported to be down-regulated in CRC. In summary, it is clear, from the diverse influences of ion channels, that their aberrant expression and/or activity c...

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Zinc Transporters and the Progression of Breast Cancers

Cited by 44 publications

References 41 publications

Analysis of the prognostic significance of solute carrier (SLC) family 39 genes in breast cancer

Analysis of the prognostic significance of solute carrier (SLC) family 39 genes in breast cancer

Growth Modulatory Role of Zinc in Prostate Cancer and Application to Cancer Therapeutics

Role of ion channels in gastrointestinal cancer

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