Overexpression of FXYD-3 Is Involved in the Tumorigenesis and Development of Esophageal Squamous Cell Carcinoma

Zhu, Zhen-Long; Yan, Bowei; Yang, Yankun; Wang, Mingwei; Zentgraf, Hanswalter; Zhang, Xianghong; Sun, Xiao‐Feng

doi:10.1155/2013/740201

Cited by 12 publications

(10 citation statements)

References 46 publications

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“…FXYD5 is a transmembrane auxiliary subunit of the Na + -K + -ATPase; it shows a 2.5-fold increase in glioblastoma. No direct link with glioblastoma has been reported to date, however it has been found up-regulated in adamantinomatous craniopharyngiomas in children [ 57 ] and other members of the FXYD family are known to be associated with different cancer types such as urothelial carcinoma [ 58 ], esophageal squamous cell carcinoma [ 59 ] and cholangiocarcinoma [ 60 ]. FXYD channels are involved in the anti-oxidative stress in vascular smooth muscle, thus controlling the vascular tone [ 61 ] and blood pressure [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Ion channels expression and function are strongly modified in solid tumors and vascular malformations

et al. 2016

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BackgroundSeveral cellular functions relate to ion-channels activity. Physiologically relevant chains of events leading to angiogenesis, cell cycle and different forms of cell death, require transmembrane voltage control. We hypothesized that the unordered angiogenesis occurring in solid cancers and vascular malformations might associate, at least in part, to ion-transport alteration.MethodsThe expression level of several ion-channels was analyzed in human solid tumor biopsies. Expression of 90 genes coding for ion-channels related proteins was investigated within the Oncomine database, in 25 independent patients-datasets referring to five histologically-different solid tumors (namely, bladder cancer, glioblastoma, melanoma, breast invasive-ductal cancer, lung carcinoma), in a total of 3673 patients (674 control-samples and 2999 cancer-samples). Furthermore, the ion-channel activity was directly assessed by measuring in vivo the electrical sympathetic skin responses (SSR) on the skin of 14 patients affected by the flat port-wine stains vascular malformation, i.e., a non-tumor vascular malformation clinical model.ResultsSeveral ion-channels showed significantly increased expression in tumors (p < 0.0005); nine genes (namely, CACNA1D, FXYD3, FXYD5, HTR3A, KCNE3, KCNE4, KCNN4, CLIC1, TRPM3) showed such significant modification in at least half of datasets investigated for each cancer type. Moreover, in vivo analyses in flat port-wine stains patients showed a significantly reduced SSR in the affected skin as compared to the contralateral healthy skin (p < 0.05), in both latency and amplitude measurements.ConclusionsAll together these data identify ion-channel genes showing significantly modified expression in different tumors and cancer-vessels, and indicate a relevant electrophysiological alteration in human vascular malformations. Such data suggest a possible role and a potential diagnostic application of the ion–electron transport in vascular disorders underlying tumor neo-angiogenesis and vascular malformations.

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Section: Discussionmentioning

confidence: 99%

Ion channels expression and function are strongly modified in solid tumors and vascular malformations

et al. 2016

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“…The FXYD genes encode for proteins that function to regulate the transport functions of N a+ /K + ATPases in a variety of normal cell systems (Crambert et al 2005 ; Yamamoto et al 2009 ). One member of this family, FXYD3, not only serves to regulate ATPase function in normal physiological systems, but several studies have shown that overexpression of this member of the FXYD family is associated with a number of cancers, and has been implicated in direct action in the formation of at least one type of cancer (Yamamoto et al 2009 ; Li et al 2014 ; Zhu et al 2013 ; Grzmil et al 2004 ). While increased expression of FXYD3 has been associated with breast cancer, the factors that promote up-regulation of this protein in mammary cells have not been identified.…”

Section: Discussionmentioning

confidence: 99%

“…FXYD3 protein is expressed in a number of cells in normal, untransformed tissues, including the bladder, lung, stomach and skin, but has been reported to be highly overexpressed in many tumors such as breast, androgen-dependent prostate, pancreatic, and colon cancer (Yamamoto et al 2009 ; Li et al 2014 ). Overexpression of FXYD3 is also believed to be involved in the tumorigenesis and development of esophageal squamous cell carcinoma (Zhu et al 2013 ). Although increased expression of FXYD3 is associated with various cancers, the relevant biological factors and their associated mechanisms of actions through which FXYD3 is increased in transforming and cancer cell systems have not been identified.…”

Section: Introductionmentioning

confidence: 99%

Estrogen and tamoxifen up-regulate FXYD3 on breast cancer cells: assessing the differential roles of ER α and ZEB1

Herrmann

Aronica

2015

SpringerPlus

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Increased expression of the FXYD3 family of proteins has been associated with lung, colorectal, bladder and pancreatic cancers, and recent evidence suggests that elevated FXYD3 may promote tumor cell proliferation in breast cancer as well. However, factors involved in up-regulating the expression of FXYD3 in breast cancer have not been identified. We evaluated whether estrogen and the selective estrogen receptor modulator tamoxifen could regulate the expression of FXYD3 on breast cancer cells. Estrogen receptor (ER) α-positive MCF-7 and ER α-negative MDA-MB-231 human breast cancer cells used in our studies were treated with estrogen, tamoxifen or the combination of these agents. Relative expression of FXYD3 was assessed using fluorochrome-tagged antibodies and a fluorescence cytometer. We found that estrogen and tamoxifen, used alone or in combination, significantly increased FXYD3 on MCF-7 cells. FXYD3 levels did not increase compared to the control samples when ER α-negative 231 cells were treated with estrogen or tamoxifen, alone or in combination, indicating that ER α was required for the increased FXYD3 response. We showed that ER α associates with the transcription factor ZEB1 in MCF-7 cells, and that decreasing ZEB1 protein expression using siRNA disrupts the ability of estrogen, but not tamoxifen, to increase FXYD3 in MCF-7 cells. Our results indicate that there may be two mechanisms, both involving ER α and one requiring ZEB1, through which FXYD3 may be increased by estrogen and tamoxifen in breast cancer cells. Ongoing research endeavors are focusing on identifying cellular components through which estrogen and tamoxifen, alone or in combination, differentially regulate FXYD3 expression in human breast cancer cells.

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“…A series of studies have reported that FXYD3 is expressed in numerous types of cancer. FXYD3 expression was initially described in breast cancer ( 7 ), and subsequently detected in prostate cancer, CRC, pancreatic cancer and ESCC, in which FXYD3 was reported to be significantly upregulated in tumor tissues compared with normal adjacent mucosal tissues ( 11 – 17 ). However, in lung cancer and glioma, FXYD3 was demonstrated to be expressed at low levels compared with healthy paracancerous tissues ( 18 – 20 ).…”

Section: Discussionmentioning

confidence: 99%

“…FXYD3 is expressed in numerous healthy tissues, including the uterus, stomach, colon and skin ( 9 , 10 ). However, FXYD3 expression has also been identified in various types of cancer, including breast cancer ( 7 ), prostate cancer ( 11 , 12 ), colorectal cancer (CRC) ( 13 ), pancreatic cancer ( 14 – 16 ), esophageal squamous carcinoma (ESCC) ( 17 ), lung cancer ( 18 , 19 ) and glioma ( 20 ). Furthermore, FXYD3 was demonstrated to be associated with the clinical prognoses of these types of cancer.…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of sodium-potassium ATPase regulator, FXYD3, in human hepatocellular carcinoma

Wang

et al. 2017

Oncol Lett

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The clinical significance of the sodium-potassium ATPase regulator FXYD domain-containing ion transport regulator 3 (FXYD3) has been demonstrated in a number of types of cancer. However, the role of this protein in human hepatocellular carcinoma (HCC) remains to be elucidated. In the present study, 217 HCC tissue samples were analyzed to evaluate the expression and prognostic significance of FXYD3 in HCC. Reverse transcription-quantitative polymerase chain reaction was used to analyze the mRNA expression of FXYD3 in 80 primary HCC specimens and paired non-cancerous liver tissue samples, while western blotting was used to analyze the protein expression level of FXYD3 in another 24 pairs. These analyses demonstrated that the expression level of FXYD3 was significantly increasedb at the mRNA and protein levels in HCC tumor tissues compared with adjacent non-cancerous tissues. Immunohistochemical analysis of 137 paraffin-embedded HCC tissue samples indicated that the expression of FXYD3 was associated with HCC clinicopathological characteristics. Kaplan-Meier analysis demonstrated that patients with high FXYD3 protein expression (n=60) experienced significantly poorer overall survival time compared with patients with low FXYD3 protein expression (n=77) (P<0.001). Multivariate analysis demonstrated that FYXD3 protein expression level (hazard ratio, 2.137; 95% confidence interval, 1.224–3.732; P=0.008) was an independent prognostic factor in patients with HCC. Overall, the results indicated that FXYD3 expression levels were higher in HCC tumor tissues than in adjacent non-cancerous tissues, and that the FXYD3 protein may serve as a prognostic marker for HCC.

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Overexpression of FXYD-3 Is Involved in the Tumorigenesis and Development of Esophageal Squamous Cell Carcinoma

Cited by 12 publications

References 46 publications

Ion channels expression and function are strongly modified in solid tumors and vascular malformations

Ion channels expression and function are strongly modified in solid tumors and vascular malformations

Estrogen and tamoxifen up-regulate FXYD3 on breast cancer cells: assessing the differential roles of ER α and ZEB1

Prognostic significance of sodium-potassium ATPase regulator, FXYD3, in human hepatocellular carcinoma

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