000063434 001__ 63434
000063434 005__ 20210121114506.0
000063434 0247_ $$2doi$$a10.1371/journal.pone.0122992
000063434 0248_ $$2sideral$$a103186
000063434 037__ $$aART-2015-103186
000063434 041__ $$aeng
000063434 100__ $$aRabjerg, M.
000063434 245__ $$aHigh expression of KCa3.1 in patients with clear cell renal carcinoma predicts high metastatic risk and poor survival
000063434 260__ $$c2015
000063434 5060_ $$aAccess copy available to the general public$$fUnrestricted
000063434 5203_ $$aBackground
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.
000063434 536__ $$9info:eu-repo/grantAgreement/ES/ISCIII/RD12-0042-0014$$9info: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$$9info:eu-repo/grantAgreement/ES/DGA/GIPASC-B105
000063434 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000063434 590__ $$a3.057$$b2015
000063434 591__ $$aMULTIDISCIPLINARY SCIENCES$$b11 / 62 = 0.177$$c2015$$dQ1$$eT1
000063434 592__ $$a1.427$$b2015
000063434 593__ $$aAgricultural and Biological Sciences (miscellaneous)$$c2015$$dQ1
000063434 593__ $$aMedicine (miscellaneous)$$c2015$$dQ1
000063434 593__ $$aBiochemistry, Genetics and Molecular Biology (miscellaneous)$$c2015$$dQ1
000063434 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000063434 700__ $$0(orcid)0000-0001-5348-924X$$aOliván-Viguera, A.
000063434 700__ $$aHansen, L.K.
000063434 700__ $$aJensen, L.
000063434 700__ $$aSevelsted-Møller, L.
000063434 700__ $$aWalter, S.
000063434 700__ $$aJensen, B.L.
000063434 700__ $$aMarcussen, N.
000063434 700__ $$aKöhler, R.
000063434 773__ $$g10, 4 (2015), e0122992[24 pp]$$pPLoS One$$tPloS one$$x1932-6203
000063434 8564_ $$s8566099$$uhttps://zaguan.unizar.es/record/63434/files/texto_completo.pdf$$yVersión publicada
000063434 8564_ $$s109923$$uhttps://zaguan.unizar.es/record/63434/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000063434 909CO $$ooai:zaguan.unizar.es:63434$$particulos$$pdriver
000063434 951__ $$a2021-01-21-10:54:39
000063434 980__ $$aARTICLE