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

Abstract

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.

Intracellular Chloride Channels: Novel Biomarkers in Diseases

“…Similar to gastric cancer cells, CLIC1 is shown to regulate ROS accumulation and pH changes in human glioblastoma stem cells influencing their proliferation as well as their motility, and therefore could be a crucial therapeutic target (Gritti et al, 2014;Peretti et al, 2018). CLIC1 was one among the nine genes identified in a screen for ion channels strongly modified in solid tumors and vascular malformations, especially in glioblastoma and bladder cancers (Biasiotta et al, 2016). CLIC1 expression is also correlated with the expression of drug resistance protein MRP1, whereas CLIC1 knockdown decreased its expression in human choriocarcinoma cell lines (Wu and Wang, 2017).…”

The Role of p16INK4a Pathway in Human Epidermal Stem Cell Self-Renewal, Aging and Cancer

“…Further analyses concerning expression of epigenetic modulators and transcription factors (described in paragraph 3) are needed to study p16 INK4a expression in-depth in NMSCs, independently from HPV infection. Here, we examined the expression of 50 genes, including p16 INK4 , downstream pRb pathway proteins and p16 INK4 promoter modulators, as reported in human skin cancer datasets available at Oncomine ( ) as previously described [ 176 , 177 ]. Two independent datasets (Nindl skin and Riker melanoma) [ 178 , 179 ] from epidermal cancers (AKs, cSCCs and BCCs) were investigated as indicated in details in Table 1 and Table 2 .…”

DNA methylation landscape of triple-negative ductal carcinoma in situ (DCIS) progressing to the invasive stage in canine breast cancer

“…The latter was the most highly hypermethylated gene in invasive breast cancer (DiffMeth = 0.43) (Table S1). Genes involved in transport such as ATOX1, a copper chaperone protein that functions as an antioxidant and is involved in breast cancer cell migration 41,42 and FXYD2, a sodium/potassium-transporting ATPase subunit whose increased expression in tumors may contribute to angiogenesis 43 , were hypomethylated in TN-DCIS and invasive breast cancer. Hypomethylation of signal transduction-related genes BDNF and CALCB have the potential to lead to a myriad of cellular responses associated with cancer such as cell growth and proliferation, angiogenesis, and inflammation 44,45 .…”