Anti-invasive effect of Cyclamen pseudibericum extract on A549 non-small cell lung carcinoma cells via inhibition of ZEB1 mediated by miR-200c

Abstract

Scientists are increasingly focusing attention on natural products of plant origin for use as agents in cancer protection and treatment. Cyclamen L. tuber extracts contain saponin glycosides that have been shown to have anti-cancer and other biological activities. The epithelial-to-mesenchymal transition (EMT) is thought to enhance malignant tumour progress. The transcriptional repressor zinc-finger E-box binding homeobox 1 (ZEB1) is an important inducer of EMT in different human tumours and has recently been shown to boost invasion by tumour cells. In this study, we investigated the effects of endemic Cyclamen pseudibericum (CP) saponin-rich tuber extract on the capacity of non-small cell lung cancer line A549 cells to proliferate, invade and migrate and also examined the expression levels of several invasion-migration-related microRNAs (miRNAs) to identify those which directly targeted ZEB1. The cytotoxicity effect of the CP extract on the A549 cancer cells was determined by the luminometric method. The half-minimal (50%) inhibitory concentration dose in the A549 cells was determined to be 41.64 ± 2.35 µg/mL. Using the Matrigel invasion chamber system and the wound healing assay we observed that the CP extract suppressed the invasion and migration capacity of A549 cells, respectively. The expression of miRNAs in A549 cells was evaluated by real-time PCR. Our data showed that overexpression of miRNA miR-200c hindered the EMT by increasing the expression of E-cadherin and decreasing the expression of both N-cadherin and vimentin through the direct targeting of ZEB1. These findings suggest that the saponin-rich tuber extract of CP may have considerable anti-cancer properties in lung cancer. Further studies are required to examine in detail the molecular-based mechanism involved in the EMT process of the extract along with isolation and identification of active saponin components.

Chemical and pharmacological characterization of aqueous and ethanolic extracts of Cyclamen hederifolium Ait. (Primulaceae) tuber

“…Therefore, we may not compare our results with aforementioned literature data which found low cytotoxic activity or absense of it in C. hederifolium from Turkey [9,12] . Our results are however in accordance with other studies that point out the significant antitumor effects of Cyclamen spp found on different cell lines [8,34,38,39] .…”

“…trochopteranthum against hepatocelular (HepG2) and colorectal adenocarcinoma (Caco-2) cell lines, while C. pseudibericum exhibited activity against non-small cell lung carcinoma cells (A549) [38,39] . Although strong cytotoxic effect was oberved in investigation of C. to the extracts of these plants, since the experiments were performed with isolated and purified secondary metabolites (saponins) [8] .…”

Antitumor effects of hsa‑miR661‑3p on non‑small cell lung cancer in vivo and in vitro

“…Karagur et al demonstrated that the high expression of miR-200 could reduce the expression of N-cadherin and vimentin by increasing the expression of E-cadherin and targeting ZEB1 to inhibit the ZEB1. EMT is considered to be an initiator of tumor malignancy and miR-200 was capable of impeding the EMT of NSCLC A549 cell line (30). Thus, we wondered whether the increase of aberrant expression for UbcH10 in NSCLC tissues and cells was caused by the inactivation of miRNA regulatory mechanisms.…”

Two Worlds Colliding: The Interplay Between Natural Compounds and Non-Coding Transcripts in Cancer Therapy

“…Still in NSCLC cell lines, Cyclamen pseudibericum Hildebr. extract up-regulated miR-200c which, in turn, targeted the transcriptional repressor Zinc finger E-box-binding homeobox 1 (ZEB1), resulting in decreased expression of E-cadherin, N-cadherin and vimentin, reflecting the EMT-inhibitory properties of this extract ( Karagur et al, 2018 ).…”