MicroRNA‑126‑3p suppresses HeLa cell proliferation, migration and invasion, and increases apoptosis via the PI3K/PDK1/AKT pathway

Abstract

We previously reported that relative to normal cervical mucus, microRNA 126-3p (miR-126-3p) is present in significantly greater amounts in the cervical mucus of patients with overt cervical cancer or precursor lesions. Here, we investigated the effects of enforced miR-126-3p expression in the cervical cancer cell line, HeLa, on proliferation, migration, invasion, apoptosis and protein expression. We transfected HeLa cells with miR-126-3p miRNA and found that proliferation, migration and invasion by cell counting, wound healing, cell migration and invasion assay were significantly reduced in these cells relative to those transfected with a negative control mimic. The levels of phosphoinositide 3 kinase (PI3K), phosphorylated 3-phosphoinositide-dependent protein kinase-1 (p-PDK1) and p-AKT proteins were lower in the miR-126-3p-transfected cells. Phosphorylated 70S6K (p-p70S6K), phosphorylated glycogen synthase kinase 3β (p-GSK3β), phosphorylated S6K (p-S6K), cyclin D1, phosphorylated p21-activated kinase 1 (p-PAK1), Rho associated coiled-coil containing protein kinase 1 (ROCK1), myotonic dystrophy-related CDC42-binding kinases α (MRCKα) and phospholipase C γ1 (p-PLCγ1) were also downregulated. This suggests that downstream effectors of the PI3K/PDK1/AKT pathway are targets for inhibition by miR-126-3p. In contrast, apoptotic-related proteins including the BCL-2-associated agonist of cell death (Bad), B-cell lymphoma-extra-large (Bcl-xL) and BCL-2-associated X (Bax), were all upregulated by miR-126-3p, resulting in increased caspase 3/7 activity and apoptosis. Thus, enforced expression of miR-126-3p inhibited cell migration and invasion and also induced apoptosis by regulating the PI3K/PDK1/AKT pathway in HeLa cells. Hence, high levels of miR-126-3p may inhibit cervical carcinogenesis, and targeting the PI3K/PDK1/AKT pathway via miR-126-3p could represent a new approach for treating patients with cervical cancer.

"Regulatory Roles for miR-126 in Inflammatory Response and Programmed Death of Cardiac Myocytes Driven by Acidosis During Simulated Ischemia"

“…As shown in (Figure 4a,4b), Bcl-2 levels decreased markedly in cardiac myocytes subjected to hypoxia/ acidosis or aerobic acidosis, and the effects were blocked by KD of miR-126 in parallel with reduced apoptosis. The results suggest negative regulation of anti-apoptotic Bcl-2 by miR-126 in this model that is consistent with some previous results [41,43,44]. We quantified the expression levels of p38-MAPK and JNK in hypoxic/acidotic and aerobic-acidotic cardiac myocytes in the presence and absence of miR-126 KD.…”

“…Previous work from others and ourselves established key roles for Bcl-2, mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) in apoptosis pathways of cardiac myocytes exposed to redox stress, acidosis and simulated ischemia with and without reperfusion [35][36][37][38][39]. Regulatory roles for miR-126 have also been described in cancer cells undergoing Bcl-2-mediated apoptosis [40][41][42]. Therefore, we investigated a possible role for Bcl-2 in the miR-126/pH sensitive apoptotic pathway of cardiac myocytes described herein.…”

A transcription factor that promotes proliferation, migration, invasion, and epithelial–mesenchymal transition of ovarian cancer cells and its possible mechanisms

“…Previous research has revealed that PI3K/AKT signaling is a well-known driver of tumorigenesis, and activation of this pathway is closely associated with cancer migration, invasion, and EMT, making it accountable for the high aggressiveness of cancers [ 23 – 25 ]. PDK1 is one of the main components of the PI3K/AKT pathway.…”

Astragaloside regulates lncRNA LOC100912373 and the miR‑17‑5p/PDK1 axis to inhibit the proliferation of fibroblast‑like synoviocytes in rats with rheumatoid arthritis

“…More specifically, as an important protein of the PI3K/AKT signaling pathway, PDK1 can bind to the product of activated PI3K, PIP3. Afterwards, PDK1/PIP3 complex transfers to the cell membrane, in order to phosphorylate AKT and activate AKT signaling pathway ( 52 ). AKT signaling pathway activation can accelerate the release of pro-inflammatory factors and thus may lead to abnormal cell biological processes, such as excessive cell proliferation, decrease in cell proliferation and increase in cell necrosis ( 53 , 54 ).…”