Effects of estrogen-related receptor alpha (ERRα) on proliferation and metastasis of human lung cancer A549 cells

Abstract

Estrogen-related receptor alpha (ERRα) plays an important role in the development of hormone-dependent cancers, but its roles in lung cancer remain elusive. The present study was aimed to investigate the effects of ERRα on the proliferation and metastasis of lung cancer A549 cells. The mRNA and protein levels of ERRα were detected in lung cancer A549 and MCF-7 cells and bronchial epithelial BEAS-2B cells by qRT-PCR and Western blotting, respectively. ERRα plasmid transfection and XCT-790 (an inverse agonist of ERRα) were used to up-regulate or down-regulate ERRα expression in A549 cells, respectively. The viability of A549 cells was measured by cell counting kit-8 (CCK-8) and the motility of A549 cells by wound healing assay and Transwell migration/invasion assay. The epithelial markers E-cadherin (E-Cad) and zona occludin-1 (ZO-1), the mesenchymal markers fibronectin (FN) and vimentin (Vim) and the transcription factors (Snail, Zeb1 Twist and Slug) were further detected at mRNA and protein levels by qRT-PCR and Western blotting, respectively. The results showed that ERRα promoted the growth of lung cancer A549 cells in vitro. XCT-790 significantly inhibited the migration and invasion of A549 cells. Over-expression of ERRα promoted the epithelial-to-mesenchymal transition (EMT) of A549 cells, down-regulated the epithelial makers E-Cad and ZO-1, and up-regulated the mesenchymal makers FN and Vim. Silencing of Slug, but not other transcription factors, significantly abolished the ERRα-induced EMT of A549 cells. It was suggested that ERRα promoted the migration and invasion of A549 cells by inducing EMT, and Slug was involved in the process. Targeting ERRα might be an efficient approach for lung cancer treatment.

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer

“…Invasion and metastasis are important clinicopathological factors for patients with CRC with unfavorable prognosis, and they are induced by EMT at the molecular level (26). Previous studies have reported that ERRα promotes invasion and metastasis by inducing EMT in lung cancer, and ovarian cancer cells (16,27). Therefore, we hypothesize that EMT mediated by ERRα underlies the mechanism for the association between high ERRα expression and poor prognosis in patients with CRC.…”

“…Cancer cells demonstrate high proliferating capabilities and require constant biosynthesis of macromolecules as building blocks for the generation of new cells, thereby resulting in a high-energy demand for cancer cells (14). ERRα demonstrates key regulatory roles in a variety of malignant processes, including proliferation, invasion, metastasis and chemotherapy resistance (15)(16)(17). Since ERRα serves a crucial role in cancer initiation, development and progression, it may be speculated that ERRα holds significant clinical significance for patients with cancer.…”

“…A recent study demonstrated that ERRα significantly enhanced CRC cell proliferation, colony formation and accelerated cell cycle transition from the G1 to the S phase (23). ERRα also promotes the growth of human lung cancer cells, which is not a hormone-dependent cancer (16), indicating the effect of ERRα on cell proliferation is universal in various cancer types. MicroRNAs may negatively regulate ERRα gene expression at the post-transcriptional level and by silencing ERRα expression, miR-137 reduced the proliferation of breast cancer cells and miR-125a reduced the proliferation of oral squamous cell carcinoma cells (24,25).…”

“…In CRC, EMT induces the generation of CRC stem cells, which have high metastatic potential (28). As a positive regulator of EMT in several cancer types (16,27), ERRα may increase the number of CRC stem cells from residual cancer cells in patients with CRC following curative resection, thereby contributing to recurrence. A previous study revealed that ERRα, combined with PGC1α, activates the promoter of osteopontin (OPN) gene and leads to elevated OPN expression in CRC cells (29).…”

Antimetastatic effects of cordycepin mediated by the inhibition of mitochondrial activity and estrogen-related receptor α in human ovarian carcinoma cells

“…In addition, ERRα suppression results in EMT inhibition in breast cancer cells [23]. Metastasis, proliferation, and migration of A549 lung cancer cells were increased when ERRα overexpression [24]. We speculate that cordycepin inhibits mitochondrial activity and EMT in OVCAR-3 cells may due to ERRα regulation.…”