BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway

Abstract

BackgroundThe large-conductance, voltage-gated, calcium (Ca (2+))-activated potassium channel (BKCa) plays an important role in regulating Ca (2+) signaling and cell physiological function, and is aberrantly expressed in some types of cancers. The present study focuses on identifying the oncogenic potential and clinical significance of BKCa in endometrial adenocarcinoma, as well as exploring the mechanistic relevance by 17β -estradiol (E2) inducing aberrant activation of MEK1/2 and ERK1/2 via BKCa.MethodsThe expression of BKCa, ERK1/2 and p-ERK1/2 were examined by immunohistochemical staining in 263 cases, including 185 primary types I endometrial cancer tissues, 38 atypical endometrial hyperplasia tissues and 40 normal endometrium tissues. Cell growth, cycle, apoptosis rate, migration and invasion was separately tested in Ishikawa cells using siRNA-BKCa and/or E2 treatment, as well as the expression of these interested proteins by western blot analysis.ResultsWe showed that expression of BKCa is significantly elevated in 185 types I endometrial adenocarcinoma tissues compared to those of the normal endometrium and atypical endometrial hyperplasia tissues. Furthermore, in vitro observations revealed that down-regulation of BKCa expression inhibited cell growth by both enhancing apoptosis and blocking G1/S transition, suppressed cell migration and invasion in Ishakiwa cells, and decreased the expression of p-MEK1/2 and p-ERK1/2. Additionally, RNAi-mediated knockdown of BKCa attenuated the increased cellular growth and invasion, as well as the elevated expression of p-MEK1/2 and p-ERK1/2 proteins, induced by E2 stimulation. More importantly, the aberrant expression of BKCa and p-ERK1/2 were closely related with poor prognostic factors in type I endometrial cancer, and up-regulated expression of p-ERK1/2 was significantly associated with shorter disease-free survival (DFS) and overall survival (OS) and was an independent prognostic factor in type I endometrial cancer patients.ConclusionOur results demonstrated that BKCa and the key downstream effectors p-ERK1/2 could be involved in important signaling pathways in initiation and development of endometrial adenocarcinoma and may provide a new therapeutic approach for women with endometrial cancer.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5027-9) contains supplementary material, which is available to authorized users.

Ion Channel Regulation by Sex Steroid Hormones and Vitamin D in Cancer: A Potential Opportunity for Cancer Diagnosis and Therapy

“…Additionally, p-ERK up-regulated expression was significantly associated with FIGO stage ≥ II, cervical stromal involvement, lymphovascular space invasion (LVSI), and LNM. These results suggest that up-regulated expression of KCa1.1 channels and p-ERK is related with poor prognosis in type I endometrial cancer (Wang et al, 2018). In summary, ion channel detection in hormone-sensitive tissues or extracellular fluids may serve as potential early markers of SSH-associated cancers.…”

“…17-b estradiol also regulates the expression of KCa1.1 channels in endometrial cancer cells. Wang et al (2018) observed that Ishikawa cells (a human ERa positive endometrial adenocarcinoma cell line) treated with 17-b estradiol (1 nM) presented an increased expression of the KCa1.1 channel protein, as well as phosphorylated ERK (p-ERK) and MEK (p-MEK). Remarkably, by knocking-down the expression of the KCa1.1 channel, the protein levels of p-ERK and p-MEK were also down-regulated.…”

lncRNA RHPN1‐AS1 promotes the progression of endometrial cancer through the activation of ERK/MAPK pathway

“…MAPKs are reported to minclude three key groups: p38 mitogen‐activated protein kinase (p38 MAPK), c‐Jun N‐terminal kinase (JNK) and ERK 26 . ERK, one of the key effectors in MEK/ERK pathway, can be phosphorylated and translocated into the nucleus that activating downstream transcription factors to participate in the modulation of cell growth, development and differentiation 27 . Previous studies have demonstrated that the activation of MAPK pathway is associated with the progression of hormonally driven malignancies, such as EC and breast cancer 13,25 .…”

“…26 ERK, one of the key effectors in MEK/ERK pathway, can be phosphorylated and translocated into the nucleus that activating downstream transcription factors to participate in the modulation of cell growth, development and differentiation. 27 Previous studies have demonstrated that the activation of MAPK pathway is associated with the progression of hormonally driven malignancies, such as EC and breast cancer. 13,25 Moreover, ERK/MAPK pathway is highly activated in EC, correlated with the EC FIGO stage and affected proliferation and apoptosis of EC cells.…”

MALAT1 plays important role in MEK inhibitor, RG7420, on the proliferation and migration of endometrial cancer cell through sponging miR-129-5p/ TAK1

“…MEK1/2 activates ERK1/2 by first catalyzing the phosphorylation of Y204/187 and then T202/185, after that ERK1/2 catalyze the phosphorylation of many cytoplasmic and nuclear substrates including transcription factors and regulatory molecules, which triggers many biological process such as proliferation, migration, apoptosis, aging and so on. Wang [17] reported p-ERK1/2 were closely related with poor prognostic factors in type I endometrial cancer. It was an independent prognostic factor in type I endometrial cancer patients.…”