Increased expression of zinc transporter ZIP4, ZIP11, ZnT1, and ZnT6 predicts poor prognosis in pancreatic cancer

Zhu, Bo; Huo, Ruwei; Qiao, Zhi; Zhan, Mingjie; Xiao, Chen; Hua, Zichun

doi:10.1016/j.jtemb.2021.126734

Cited by 29 publications

(28 citation statements)

References 35 publications

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“…Previously, we have shown that the tumors derived from transformed UROtsa cells displayed gene expression profiles similar to the basal subtype of muscle invasive bladder carcinomas [36,37], while our microarray data using the Affymetrix 133 Plus 2.0 chip indicated that at least 285 genes are up-regulated and 215 genes are down regulated [38]. Indeed, dysregulated intracellular zinc homeostasis and abnormal expression of specific zinc transporters such as ZnT1, ZIP1, ZIP4, ZIP6, ZIP7, and ZIP10 have been observed in various types of cancer, including urinary bladder, prostate, pancreatic, and breast cancers [39][40][41][42][43][44][45][46][47][48].…”

Section: Introductionmentioning

confidence: 82%

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Aberrant Expression of ZIP and ZnT Zinc Transporters in UROtsa Cells Transformed to Malignant Cells by Cadmium

et al. 2021

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Maintenance of zinc homeostasis is pivotal to the regulation of cell growth, differentiation, apoptosis, and defense mechanisms. In mammalian cells, control of cellular zinc homeostasis is through zinc uptake, zinc secretion, and zinc compartmentalization, mediated by metal transporters of the Zrt-/Irt-like protein (ZIP) family and the Cation Diffusion Facilitators (CDF) or ZnT family. We quantified transcript levels of ZIP and ZnT zinc transporters expressed by non-tumorigenic UROtsa cells and compared with those expressed by UROtsa clones that were experimentally transformed to cancer cells by prolonged exposure to cadmium (Cd). Although expression of the ZIP8 gene in parent UROtsa cells was lower than ZIP14 (0.1 vs. 83 transcripts per 1000 β-actin transcripts), an increased expression of ZIP8 concurrent with a reduction in expression of one or two zinc influx transporters, namely ZIP1, ZIP2, and ZIP3, were seen in six out of seven transformed UROtsa clones. Aberrant expression of the Golgi zinc transporters ZIP7, ZnT5, ZnT6, and ZnT7 were also observed. One transformed clone showed distinctively increased expression of ZIP6, ZIP10, ZIP14, and ZnT1, with a diminished ZIP8 expression. These data suggest intracellular zinc dysregulation and aberrant zinc homeostasis both in the cytosol and in the Golgi in the transformed UROtsa clones. These results provide evidence for zinc dysregulation in transformed UROtsa cells that may contribute in part to their malignancy and/or muscle invasiveness.

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Section: Introductionmentioning

confidence: 82%

“…Likewise, increased ZIP6 expression in human cervical cancer cells was associated with invasive properties through the MAPK/Snail-Slug signaling pathway [50]. Increased expression of ZIP4, ZIP11, ZnT1, or ZnT6 has been associated with poor prognosis in patients with pancreatic adenocarcinoma [40].…”

Section: Discussionmentioning

confidence: 98%

Aberrant Expression of ZIP and ZnT Zinc Transporters in UROtsa Cells Transformed to Malignant Cells by Cadmium

et al. 2021

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“…Likewise, increased ZIP6 expression in human cervical cancer cells was associated with invasive properties through the MAPK/Snail-Slug signaling pathway [96]. Increased expression of ZIP4, ZIP11, ZnT1, or ZnT6 has been associated with poor prognosis in patients with pancreatic adenocarcinoma [29]. The UTCd1 had a doubling time similar to parental UROtsa cells and it was the only clone in which ZIP8 expression was reduced concomitantly with an increased ZnT1.…”

Section: Insights From Transformed Urotsa Cellsmentioning

confidence: 97%

“…Among ten SLC30A (ZnT) members, ZnT1 is solely responsible for Zn efflux, and overexpression of ZnT1 results in low intracellular Zn levels [25]. Of note, dysregulated cellular Zn homeostasis and aberrant expression of ZnT1, ZIP1, ZIP4, ZIP6, ZIP7, and ZIP10 have increasingly been observed in various types of cancer, including urinary bladder, prostate, pancreatic and breast cancers [25][26][27][28][29][30].…”

Section: Zinc Transporters Deranged Zinc Homeostasis and Cancermentioning

confidence: 99%

The Evolving Role for Zinc and Zinc Transporters in Cadmium Tolerance and Urothelial Cancer

2021

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Cadmium (Cd) is an environmental toxicant with serious public health consequences due to its persistence within arable soils, and the ease with which it enters food chains and then, accumulates in human tissues to induce a broad range of adverse health effects. The present review focuses on the role of zinc (Zn), a nutritionally essential metal, to protect against the cytotoxicity and carcinogenicity of Cd in urinary bladder epithelial cells. The stress responses and defense mechanisms involving the low-molecular-weight metal binding protein, metallothionein (MT), are highlighted. The efflux and influx transporters of the ZnT and Zrt-/Irt-like protein (ZIP) gene families are discussed with respect to their putative role in retaining cellular Zn homeostasis. Among fourteen ZIP family members, ZIP8 and ZIP14 mediate Cd uptake by cells, while ZnT1 is among ten ZnT family members solely responsible for efflux of Zn (Cd), representing cellular defense against toxicity from excessively high Zn (Cd) intake. In theory, upregulation of the efflux transporter ZnT1 concomitant with the downregulation of influx transporters such as ZIP8 and ZIP14 can prevent Cd accumulation by cells, thereby increasing tolerance to Cd toxicity. To link the perturbation of Zn homeostasis, reflected by the aberrant expression of ZnT1, ZIP1, ZIP6, and ZIP10, with malignancy, tolerance to Cd toxicity acquired during Cd-induced transformation of a cell model of human urothelium, UROtsa, is discussed as a particular example.

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“…Another mechanism that contributes to cachexia is related to alterations of the zinc homeostasis and the upregulation of the zinc transporters ZIP4 and ZIP14. Zinc deficiency is a common occurrence in several cancers, including PC [ 47 ]. Tumor cells exhibit dysregulated zinc uptake and efflux due to alterations in the activity of many zinc transporters [ 48 ].…”

Section: Pdac-associated Cachexiamentioning

confidence: 99%

Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives

Cortez

Mackenzie

2021

Nutrients

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and extremely therapy-resistant cancer. It is estimated that up to 80% of PDAC patients present with cachexia, a multifactorial disorder characterized by the involuntary and ongoing wasting of skeletal muscle that affects therapeutic response and survival. During the last decade, there has been an increased interest in exploring dietary interventions to complement the treatment of PDAC and associated cachexia. Ketogenic diets (KDs) have gained attention for their anti-tumor potential. Characterized by a very low carbohydrate, moderate protein, and high fat composition, this diet mimics the metabolic changes that occur in fasting. Numerous studies report that a KD reduces tumor growth and can act as an adjuvant therapy in various cancers, including pancreatic cancer. However, research on the effect and mechanisms of action of KDs on PDAC-associated cachexia is limited. In this narrative review, we summarize the evidence of the impact of KDs in PDAC treatment and cachexia mitigation. Furthermore, we discuss key cellular mechanisms that explain KDs’ potential anti-tumor and anti-cachexia effects, focusing primarily on reprogramming of cell metabolism, epigenome, and the gut microbiome. Finally, we provide a perspective on future research needed to advance KDs into clinical use.

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Increased expression of zinc transporter ZIP4, ZIP11, ZnT1, and ZnT6 predicts poor prognosis in pancreatic cancer

Cited by 29 publications

References 35 publications

Aberrant Expression of ZIP and ZnT Zinc Transporters in UROtsa Cells Transformed to Malignant Cells by Cadmium

Aberrant Expression of ZIP and ZnT Zinc Transporters in UROtsa Cells Transformed to Malignant Cells by Cadmium

The Evolving Role for Zinc and Zinc Transporters in Cadmium Tolerance and Urothelial Cancer

Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives

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