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Zinc transporter genes and urological cancers: integrated analysis suggests a role for ZIP11 in bladder cancer.

ABSTRACT: Although zinc transporters were shown to play roles in the development of prostate, bladder, and renal cancer, no study has evaluated the genetic variants in zinc transporter genes with risk of urological cancers. A candidate gene association study using genome-wide association study (GWAS) datasets was conducted for variants in 24 zinc transporter genes. Genotypes were analyzed using logistic regression models adjusted for covariates. The function of identified variants was assessed by using the Encyclopedia of DNA Elements (ENCODE). We further evaluated tumors for somatic change of the implicated gene(s) and the associations between identified variants and patient survival from data in The Cancer Genome Atlas (TCGA). A ZIP11 variant, rs8081059, was significantly associated with increased risk of renal cell carcinoma (odds ratios (OR)?=?1.28, 95 % confidence intervals (CI) (1.13-1.45), p?=?0.049). No zinc transporter variants were associated with prostate cancer risk. Four variants within ZIP11 were significantly associated with bladder cancer risk: rs11871756 (OR?=?1.43, 95 % CI (1.24-1.63), p?=?0.0002), rs11077654 (OR?=?0.76, 95 % CI (0.68-0.85), p?=?0.001), rs9913017 (OR?=?0.76, 95 % CI (0.68-0.85), p?=?0.002), and rs4969054 (OR?=?0.78, 95 % CI (0.69-0.88), p?=?0.02); the three protective variants were co-located and highly correlated. These variants were located within predicted transcribed or enhancer regions. Among the 253 bladder cancer patients in TCGA, two had tumors that contained deleterious missense mutations in ZIP11. Moreover, rs11077654 was significantly associated with survival of bladder cancer patients (p?=?0.046). In conclusion, zinc transporter gene, ZIP11, may play an important role in bladder cancer. Further studies of the gene are warranted.

SUBMITTER: Wu L

PROVIDER: S-EPMC4607554 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Zinc transporter genes and urological cancers: integrated analysis suggests a role for ZIP11 in bladder cancer.

Wu Lang L Chaffee Kari G KG Parker Alexander S AS Sicotte Hugues H Petersen Gloria M GM

Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 20150423 10

Although zinc transporters were shown to play roles in the development of prostate, bladder, and renal cancer, no study has evaluated the genetic variants in zinc transporter genes with risk of urological cancers. A candidate gene association study using genome-wide association study (GWAS) datasets was conducted for variants in 24 zinc transporter genes. Genotypes were analyzed using logistic regression models adjusted for covariates. The function of identified variants was assessed by using th ...[more]

PMID: 25900876

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Project description:Identification of the key processes involved in the tumor progression, malignancy and the molecular factors which are responsible for the transition of the cirrhotic cells to the tumor cells, contribute to the detection of biomarkers for diagnosis of hepatocellular carcinoma (HCC) at an early stage. According to clinical data, HCC is mostly characterized by a significant decrease in zinc levels. It is strongly implied that zinc deficiency is the major event required in the early stages of tumor formation and development of malignancy. Due to this reason, the definition of the molecular players which have a role in zinc homeostasis and cellular zinc level could give us a clue about the transition state of the cirrhosis to hepatic tumor formation. Despite the well-known implications of zinc in the development of HCCthe correlation of the expression of zinc transporter proteins with tumor progression and malignancy remain largely unknown. In the present study, we evaluated in detail the relationship of zinc deficiency on the prognosis of early HCC patients. In this study, we aimed to test the potential zinc transporters which contribute tothe transformation of cirrhosis to HCCand the progression of HCC. Among the 24 zinc transporter proteins, the proteins to be examined were chosen by using Gene Expression Profiling Interactive Analysis (GEPIA) webpage and RNA-seq analysis using TCGA database. ZIP14 and ZIP5 transporters were found as common differentially expressed genes from both bioinformatic analyses. ZnT1, ZnT7 and ZIP7 transporters have been associated with tumor progression. Relative abundance of ZnT1, ZIP5 and ZIP14 protein level was determined by immunohistochemistry (IHC) in surgically resected liver specimens from 16 HCC patients at different stages. IHC staining intensity was analyzed by using ImageJ software and scored with the histological scoring (H-score) method. The staining of ZnT1 was significantly higher in Grade III comparing to Grade II and Grade I. On the contrary, ZIP14 staining decreased almost 10-foldcomparing to Grade Iand Grade II. ZIP5 staining was detected almost 2-fold higher in cirrhosis than HCC. But ZnT1 staining was observed almost 3-fold lower in cirrhosis comparing to HCC. Intracellular free zinc level was measured by flow cytometry in Hep40 and Snu398 cells using FluoZin-3 dye. The intracellular free zinc level was almost 9-fold decreased in poor differentiated Snu398 HCC cells comparing to well differentiated Hep40 HCC cells.This report establishes for the first time the correlation between the expression pattern of ZIP14, ZnT1 and ZIP5 and significant zinc deficiency which occurs concurrently with the advancing of malignancy. Our results provide new molecular insight into ZnT1, ZIP14 and ZIP5 mediated regulation of cellular zinc homeostasis and indicate that zinc transporters might be important factors and events in HCC malignancy, which can lead to the development of early biomarkers.

Project description:BackgroundRole of TC2N in carcinogenesis has been largely unfathomed until recently when it was identified as a novel oncogene in lung cancer. Subsequently, a tumour suppressor role of TC2N was reported in breast cancer. It is therefore highly relevant to investigate TC2N molecular partners/mechanisms on a larger scale including a wider range of tumour types.MethodsWe investigated TC2N mRNA expression, its promoter methylation levels, effects of TC2N transcription on overall patient survival, somatic mutations in TC2N gene and correlation between TC2N mRNA expression and other cancer genes in pan-cancer by using data available from the Cancer Genome Atlas (TCGA) and the Genotype Tissue Expression (GTEx) databases.ResultsTC2N mRNA expression was differentially regulated in 9/33 TCGA tumour types. Of these 9 tumours, 5 tumour types (cholangiocarcinoma, ovarian-serous-cystadenocarcinoma, rectal-adenocarcinoma, stomach-adenocarcinoma and thymoma) had significantly higher TC2N mRNA expression while 4 (pheochromocytoma-and-paraganglioma, skin-cutaneous-melanoma, thyroid-carcinoma and uterine-carcinosarcoma) had significantly lower TC2N mRNA expression compared to matched and normal controls. TC2N promoter was hypermethylated in most cancers while hypomethylated in head-and-neck-squamous-cell-carcinoma and kidney-renal-clear-cell carcinoma. TC2N transcription was positively correlated with transcription of several other cancer genes including genes from Myc, cell-cycle, Nrf2, Wnt, PI3K, Hippo, Notch, TGFβ and RAS/RTK pathways. Poor prognosis was associated with higher TC2N mRNA levels in pancreatic-adenocarcinoma and brain-lower-grade-glioma and lower TC2N mRNA levels in kidney-renal-clear-cell-carcinoma, mesothelioma, sarcoma and skin-cutaneous melanoma. Functional protein partners of TC2N were identified as STX2, SMEK1, SMEK2, STXBP5, SCARA5, MMRN1, CATSPER2, CATSPERB, CLEC4M and STAB2. Many of these proteins are key players in carcinogenesis of various cancers. Highest pathogenic somatic mutation rates in TC2N were found in skin-cutaneous-melanoma, uterine-corpus-endometrial-carcinoma, colon-endocervical-adenocarcinoma, bladder-urothelial-carcinoma and breast-invasive-carcinoma.ConclusionOur findings unravel several un-explored avenues related to the role of TC2N in tumourigenesis of several cancers, suggesting TC2N as an important player and a potential candidate for tumour-therapy.

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Zinc transporter genes and urological cancers: integrated analysis suggests a role for ZIP11 in bladder cancer.

Publications

Zinc transporter genes and urological cancers: integrated analysis suggests a role for ZIP11 in bladder cancer.

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