Increasingly, evidence has revealed that aberrant microRNA (miRNA) expression is involved in breast cancer carcinogenesis and further progression, including metastasis. miRNA (miR)-27a was previously identified to be abnormally expressed and to serve pro-oncogenic functions in multiple human cancer types, including breast cancer. However, its functions and underlying mechanisms in breast cancer remain poorly understood. In the present study, it was demonstrated that miR-27a was significantly upregulated in breast cancer tissues and cell lines compared with their normal counterparts. Overexpression of miR-27a resulted in enhanced cell migration by inducing epithelial-to-mesenchymal transition, while its knockdown effectively reversed these cellular events. The present study additionally confirmed for the first time, to the best of our knowledge, that F-box and WD repeat domain containing 7 (FBXW7) is a downstream target gene of miR-27a in human breast cancer cells. FBXW7 is underexpressed in breast cancer tissues and cell lines, and is an independent positive factor for the overall survival rate of patients with breast cancer. Notably, the ectopic expression of FBXW7 may effectively suppress the epithelial-to-mesenchymal transition and migratory activity of breast cancer cells, in addition to reversing the cell migration mediated by miR-27a. Altogether, the results of the present study indicated the important function of miR-27a in regulating the metastasis of breast cancer in a FBXW7-dependent manner, and provide evidence for the potential application of miR-27a in breast cancer therapy.
Background: MicroRNA 942-5p (miR-942-5p) has been reported to promote migration and invasion in non-small cell lung cancer (NSCLC), but the underlying mechanism is not completely understood. The interplay between long noncoding RNAs (lncRNAs) and miRNAs plays a crucial role in tumor progression. Methods: In the present study, we performed bioinformatic and biochemical analyses to identify miR-942-5p-interacting lncRNAs. The function and clinical significance of the candidate lncRNA(s) in NSCLC were determined. Results: We identified LIFR-AS1 as a pivotal miR-942-5p-interacting lncRNA. Overexpression of miR-942-5p caused a reduction of LIFR-AS1 in NSCLC cells. LIFR-AS1 showed the ability to sponge miR-942-5p, leading to derepression of ZNF471. Functionally, LIFR-AS1 overexpression inhibited NSCLC cell migration and invasion, whereas LIFR-AS1 silencing yielded an opposite effect. In vivo studies confirmed that LIFR-AS1 overexpression suppressed lung metastasis of NSCLC cells. Rescue experiments demonstrated that enforced expression of miR-942-5p or depletion of ZNF471 restored the migration and invasion capacity of LIFR-AS1-overexpressing cells. Moreover, overexpression of ZNF471 restrained NSCLC cell invasion. Clinically, LIFR-AS1 downregulation was significantly correlated with TNM stage, lymph node metastasis, and reduced overall survival in NSCLC patients. Conclusions: we provide first evidence for the involvement of the LIFR-AS1/miR-942-5p/ZNF471 axis in NSCLC invasion and metastasis. LIFR-AS1 may represent a novel target for the treatment of NSCLC.
Ubiquitin-conjugating enzyme UBE2D3 is an important member of the ubiquitin-proteasome pathways. Our previous study showed that the expression of UBE2D3 was negatively related to human telomerase reverse transcriptase (hTERT) and radioresistance in human breast cancer cells. However, in esophageal carcinoma, the exact effects and mechanisms of UBE2D3 in radioresistance remain unclear. This study shows that UBE2D3 knockdown was associated with significant increases in radioresistance to X-rays, telomerase activity, telomere length, and telomere shelterins. UBE2D3 knockdown-mediated radioresistance was related to a decrease in the spontaneous and ionizing radiation-induced apoptosis, resulting from a decrease in the Bax/Bcl-2 ratio. Furthermore, UBE2D3 downregulation was associated with increased G1-S phase transition and prolonged IR-induced G2/M arrest through over expression of cyclin D1, decrease of CDC25A expression and promotion of the ATM/ATR-Chk1-CDC25C pathway. Moreover, UBE2D3 downregulation reduced spontaneous DNA double-strand breaks and accelerated the repair of DNA damage induced by IR. The current data thus demonstrate that UBE2D3 downregulation enhances radioresistance by increased telomere homeostasis and prolonged IR-induced G2/M arrest, but decreases the IR-induced apoptosis and the number of DNA damage foci. These results suggest that UBE2D3 might be a potential molecular target to improve radiotherapy effects in esophageal carcinoma.
Toll-like receptor 9 (TLR9) has been shown to have a significant role in cancer. MicroRNAs (miRNAs), a group of small non-coding RNAs that fine tune translation of multiple target mRNAs, are involved in the development and progression of human cancers. The present study was undertaken to determine the roles of TLR9 on lung cancer and whether miR-26a is involved in TLR9-mediated lung cancer growth and migration. The lung cancer models were elicited by injecting human lung cancer cells into the left ventricle. The expression of TLR9 and miR-26a in lung cancer tissues obtained from lung cancer patients was increased. TLR9 ligand CpG-oligodeoxynucleotides (CpG-ODN) caused an increase in the mean tumor weight and the size of tumor mass in nude mice, and the proliferation and migration of H460 human lung cancer cells. CpG-ODN also induced an increase in the expression of miR-26a in H460 cells. The overexpression of miR-26a increased the weight and size of the tumor mass in the nude mice, and the proliferation and migration of H460 cells. Expression of phosphoinositide 3 kinase (PI3K) and phosphorylation of protein kinase B (Akt) was increased after miR-26a overexpression in the H460 cells. PI3K inhibitor wortmannin (WM) or Akt inhibitor triciribine hydrate (TCN) eliminated the increase in the proliferation and migration induced by the overexpression of miR-26a in H460 cells. These results suggested that miR-26a is involved in the TLR9-mediated growth and migration of lung cancer through the PI3K-Akt signaling pathway.
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