High Expression of KCa3.1 in Patients with Clear Cell Renal Carcinoma Predicts High Metastatic Risk and Poor Survival

Abstract

BackgroundCa2+-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 FindingsWe 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/SignificanceOur 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.

Synthesis of Small‐Molecule Fluorescent Probes for the In Vitro Imaging of Calcium‐Activated Potassium Channel KCa3.1

“…[2,3] Inhibition of the K Ca 3.1 channel leads in many different tumor entities to reduced proliferation, migration, and metastasis. [4][5][6] Overexpression of this channel directly correlates with tumor grade and metastatic status and is often related to poor prognosis for tumor patients and high lethality rates. [7] Moreover,e xpression of K Ca 3.1 channels is dysregulated in many tumor entities.When patients are stratified according to K Ca 3.1 channel expression, patient survival is worse for those with elevated K Ca 3.1 expression.…”

The potassium channel KCa3.1 promotes cell proliferation by activating SKP2 and metastasis through the EMT pathway in hepatocellular carcinoma

“…KCa3.1 plays an important role not only in regulating cell volume but also in maintaining intracellular calcium homeostasis . The expression of KCa3.1 has been found to be correlated with malignancy in a variety of human cancers, such as glioblastoma, lung cancer, breast cancer, colorectal cancer, and kidney cancer . In addition, pharmacological blockade or gene silencing of KCa3.1 can inhibit proliferation, migration, and invasiveness in pancreatic cancer, endometrial carcinoma, and breast cancer …”

Intermediate-Conductance-Ca2-Activated K Channel IKCa1 Is Upregulated and Promotes Cell Proliferation in Cervical Cancer

“…TRAM-34, a specific IKCa1 blocker, can suppress cellular growth [10]. Together, these studies support that IKCa1 could be potential molecular marker for tumor growth and tumor progression, as well as a potential treatment target [14,28,29]. However, the impact of IKCa1 on the growth of human cervical cancer cells is unknown.…”