High expression of KCa3.1 in patients with clear cell renal carcinoma predicts high metastatic risk and poor survival
Rabjerg, M. ; Oliván-Viguera, A. ; Hansen, L.K. ; Jensen, L. ; Sevelsted-Møller, L. ; Walter, S. ; Jensen, B.L. ; Marcussen, N. ; Köhler, R.
Resumen: Background
Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival.
Methodology/Principal Findings
We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro.
Conclusions/Significance
Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative of low disease specific survival of ccRCC patients, short progression-free survival, and a high metastatic potential. Therefore, KCa3.1 is of prognostic value in ccRCC.
Idioma: Inglés
DOI: 10.1371/journal.pone.0122992
Año: 2015
Publicado en: PloS one 10, 4 (2015), e0122992[24 pp]
ISSN: 1932-6203
Factor impacto JCR: 3.057 (2015)
Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 11 / 62 = 0.177 (2015) - Q1 - T1
Factor impacto SCIMAGO: 1.427 - Agricultural and Biological Sciences (miscellaneous) (Q1) - Medicine (miscellaneous) (Q1) - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)
Financiación: info:eu-repo/grantAgreement/ES/DGA/GIPASC-B105
Financiación: info:eu-repo/grantAgreement/EC/FP7/321721/EU/Identification and validation of cerebral KCa3.1/KCa2.3 potassium channels a drug tragets for the prevention and treatment of cerebral ischemia associated with diabetes and Alzheimers disease/BRAINIK
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/RD12-0042-0014
Tipo y forma: Article (Published version)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
Exportado de SIDERAL (2021-01-21-10:54:39)
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Ca2+-activated K+ channels have been implicated in cancer cell growth, metastasis, and tumor angiogenesis. Here we hypothesized that high mRNA and protein expression of the intermediate-conductance Ca2+-activated K+ channel, KCa3.1, is a molecular marker of clear cell Renal Cell Carcinoma (ccRCC) and metastatic potential and survival.
Methodology/Principal Findings
We analyzed channel expression by qRT-PCR, immunohistochemistry, and patch-clamp in ccRCC and benign oncocytoma specimens, in primary ccRCC and oncocytoma cell lines, as well as in two ccRCC cell lines (Caki-1 and Caki-2). CcRCC specimens contained 12-fold higher mRNA levels of KCa3.1 than oncocytoma specimens. The large-conductance channel, KCa1.1, was 3-fold more highly expressed in ccRCC than in oncocytoma. KCa3.1 mRNA expression in ccRCC was 2-fold higher than in the healthy cortex of the same kidney. Disease specific survival trended towards reduction in the subgroup of high-KCa3.1-expressing tumors (p<0.08 vs. low-KCa3.1-expressing tumors). Progression-free survival (time to metastasis/recurrence) was reduced significantly in the subgroup of high-KCa3.1-expressing tumors (p<0.02, vs. low-KCa3.1-expressing tumors). Immunohistochemistry revealed high protein expression of KCa3.1 in tumor vessels of ccRCC and oncocytoma and in a subset of ccRCC cells. Oncocytoma cells were devoid of KCa3.1 protein. In a primary ccRCC cell line and Caki-1/2-ccRCC cells, we found KCa3.1-protein as well as TRAM-34-sensitive KCa3.1-currents in a subset of cells. Furthermore, Caki-1/2-ccRCC cells displayed functional Paxilline-sensitive KCa1.1 currents. Neither KCa3.1 nor KCa1.1 were found in a primary oncocytoma cell line. Yet KCa-blockers, like TRAM-34 (KCa3.1) and Paxilline (KCa1.1), had no appreciable effects on Caki-1 proliferation in-vitro.
Conclusions/Significance
Our study demonstrated expression of KCa3.1 in ccRCC but not in benign oncocytoma. Moreover, high KCa3.1-mRNA expression levels were indicative of low disease specific survival of ccRCC patients, short progression-free survival, and a high metastatic potential. Therefore, KCa3.1 is of prognostic value in ccRCC.
Idioma: Inglés
DOI: 10.1371/journal.pone.0122992
Año: 2015
Publicado en: PloS one 10, 4 (2015), e0122992[24 pp]
ISSN: 1932-6203
Factor impacto JCR: 3.057 (2015)
Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 11 / 62 = 0.177 (2015) - Q1 - T1
Factor impacto SCIMAGO: 1.427 - Agricultural and Biological Sciences (miscellaneous) (Q1) - Medicine (miscellaneous) (Q1) - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1)
Financiación: info:eu-repo/grantAgreement/ES/DGA/GIPASC-B105
Financiación: info:eu-repo/grantAgreement/EC/FP7/321721/EU/Identification and validation of cerebral KCa3.1/KCa2.3 potassium channels a drug tragets for the prevention and treatment of cerebral ischemia associated with diabetes and Alzheimers disease/BRAINIK
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/RD12-0042-0014
Tipo y forma: Article (Published version)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. Exportado de SIDERAL (2021-01-21-10:54:39)
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Record created 2017-12-13, last modified 2021-01-21