Analysis of Zinc-Exporters Expression in Prostate Cancer

Singh, Chandra K.; Malas, Kareem M.; Tydrick, Caitlin; Siddiqui, Imtiaz A.; Iczkowski, Kenneth A.; Ahmad, Nihal

doi:10.1038/srep36772

Cited by 37 publications

(39 citation statements)

References 79 publications

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“…Furthermore, multiple studies have revealed that SLC30A family genes are dysregulated and played a critical role in various kinds of cancer, including pancreatic cancer 18 , invasive breast ductal carcinoma 18 , and esophageal cell carcinoma 20 . Previous studies have reported that SLC30A1 , 9 and 10 were significantly upregulated in prostate cancer tissues compared to normal tissues, while SLC30A5 - 6 were strongly downregulated 21 – 23 . Upregulated SLC30A5-7 expression might play a critical role in coordinating transcriptional programming associated with the increased activity of the early secretory pathway in colorectal cancer 24 .…”

Section: Introductionmentioning

confidence: 86%

Comprehensive analysis of the expression of SLC30A family genes and prognosis in human gastric cancer

Guo

2020

Sci Rep

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The solute carrier 30 (SLC30) family genes play a fundamental role in various cancers. However, the diverse expression patterns, prognostic value, and potential mechanism of SLC30A family genes in gastric cancer (GC) remain unknown. Herein, we analyzed the expression and survival data of SLC30A family genes in GC patients using multiple bioinformatic approaches. Expression data of SLC30A family genes for GC patients were extracted from the Cancer Genome Atlas (TCGA) and genetic alteration frequency assessed by using cBioportal database. And validated the expression of SLC30A family genes in GC tissues and corresponding normal tissues. The prognostic value of SLC30A family genes in gastric cancer patients were explored using Kaplan–Meier plotter database. Functional enrichment analysis performed using DAVID database and clusterProfiler package. And ssGSEA algorithm was performed to explore the relationship between the SLC30A family genes and the infiltration of immune cells. We found that the median expression levels of SLC30A1-3, 5–7, and 9 were significantly upregulated in gastric cancer tissues compared to non-cancerous tissues, while SLC30A4 was downregulated. Meanwhile, SLC30A1-7, and 9 were significantly correlated with advanced tumor stage and nodal metastasis status, SLC30A5-7, and 9–10 were significantly related to the Helicobacter pylori infection status of GC patients. High expression of five genes (SLC30A1, 5–7, and 9) was significantly correlated with better overall survival (OS), first progression survival (FPS), and post progression survival (PPS). Conversely, upregulated SLC30A2-4, 8, and 10 expression was markedly associated with poor OS, FP and PPS. And SLC30A family genes were closely associated with the infiltration of immune cells. The present study implied that SLC30A5 and 7 may be potential biomarkers for predicting prognosis in GC patients, SLC30A2 and 3 play an oncogenic role in GC patients and could provide a new strategy for GC patients treatment.

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Section: Introductionmentioning

confidence: 86%

Comprehensive analysis of the expression of SLC30A family genes and prognosis in human gastric cancer

Guo

2020

Sci Rep

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“…ZnT4 expression was reportedly localized in intracellular vesicles and plasma membranes. At the RNA level, ZnT1, ZnT9 and ZnT10 were significantly upregulated in human prostate cancer tissues compared to those in adjacent normal tissues, implying that intracellular zinc is diminished through this upregulation of zinc output transporters [110]. ZnT7 null-mutation in TRAMP mice was reported to accelerate the formation of prostate tumors compared to that in TRAMP mice retaining wild type ZnT7 [111].…”

Section: Zinc and Zinc Transporters In Prostate Cancermentioning

confidence: 99%

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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“…For example, overexpression of ZIP6 and ZIP10 has been implicated in breast cancer progression 9 . Moreover, downregulation of ZnT5 and ZnT6 mRNA is observed in the early stages of prostate cancer, and ZnT9 mRNA upregulation was observed in stage II of prostate cancer tumors 10 . Significant upregulation of ZnT1 mRNA was also observed in prostate cancer tissue, independent of tumor stage 10 .…”

Section: Introductionmentioning

confidence: 95%

“…Moreover, downregulation of ZnT5 and ZnT6 mRNA is observed in the early stages of prostate cancer, and ZnT9 mRNA upregulation was observed in stage II of prostate cancer tumors 10 . Significant upregulation of ZnT1 mRNA was also observed in prostate cancer tissue, independent of tumor stage 10 . Recently, overexpression of ZnT1 mRNA has been associated with the development and progression of bladder cancer 11 .…”

Section: Introductionmentioning

confidence: 95%

Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

et al. 2019

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Zinc is vital for the structure and function of~3000 human proteins and hence plays key physiological roles. Consequently, impaired zinc homeostasis is associated with various human diseases including cancer. Intracellular zinc levels are tightly regulated by two families of zinc transporters: ZIPs and ZnTs; ZIPs import zinc into the cytosol from the extracellular milieu, or from the lumen of organelles into the cytoplasm. In contrast, the vast majority of ZnTs compartmentalize zinc within organelles, whereas the ubiquitously expressed ZnT1 is the sole zinc exporter. Herein, we explored the hypothesis that qualitative and quantitative alterations in ZnT1 activity impair cellular zinc homeostasis in cancer. Towards this end, we first used bioinformatics to analyze inactivating mutations in ZIPs and ZNTs, catalogued in the COSMIC and gnomAD databases, representing tumor specimens and healthy population controls, respectively. ZnT1, ZnT10, ZIP8, and ZIP10 showed extremely high rates of loss of function mutations in cancer as compared to healthy controls. Analysis of the putative functional impact of missense mutations in ZnT1-ZnT10 and ZIP1-ZIP14, using homologous protein alignment and structural predictions, revealed that ZnT1 displays a markedly increased frequency of predicted functionally deleterious mutations in malignant tumors, as compared to a healthy population. Furthermore, examination of ZnT1 expression in 30 cancer types in the TCGA database revealed five tumor types with significant ZnT1 overexpression, which predicted dismal prognosis for cancer patient survival. Novel functional zinc transport assays, which allowed for the indirect measurement of cytosolic zinc levels, established that wild type ZnT1 overexpression results in low intracellular zinc levels. In contrast, overexpression of predicted deleterious ZnT1 missense mutations did not reduce intracellular zinc levels, validating eight missense mutations as loss of function (LoF) mutations. Thus, alterations in ZnT1 expression and LoF mutations in ZnT1 provide a molecular mechanism for impaired zinc homeostasis in cancer formation and/or progression.

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Analysis of Zinc-Exporters Expression in Prostate Cancer

Cited by 37 publications

References 79 publications

Comprehensive analysis of the expression of SLC30A family genes and prognosis in human gastric cancer

Comprehensive analysis of the expression of SLC30A family genes and prognosis in human gastric cancer

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

Alterations in ZnT1 expression and function lead to impaired intracellular zinc homeostasis in cancer

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