Let-7 miRNAs sensitize breast cancer stem cells to radiation-induced repression through inhibition of the cyclin D1/Akt1/Wnt1 signaling pathway

Abstract

The tumor-suppressive let-7 family of microRNAs (miRNAs) has been previously identified to induce cell apoptosis, proliferation‑inhibition and suppression of the self‑renewal capacities of cancer stem cells (CSCs). However, let‑7‑mediated sensitization of tumors to radiation treatment remains to be investigated fully in triple negative breast cancer (TNBC), of which the clinical treatment is challenging. The inhibitory effect of let‑7 miRNAs on the self‑renewal ability of CSCs from TNBC was investigated. It was identified that radiation inhibited the self‑renewal ability of TNBC stem cells by inhibiting cyclin D1 and protein kinase B (Akt1) phosphorylation. Let‑7d stimulates radiation‑induced tumor repression, exerting synergistic effects with radiotherapy on stem cell renewal. Through western blotting, immunofluorescence and a luciferase assay, it was identified that reduced cyclin D1/Akt1/wingless type MMTV integration site family member 1 (Wnt1) signaling activity accounts for the let‑7‑induced radiation sensitization. Let‑7 directly inhibits cyclin D1 expression, resulting in low phosphorylation of Akt1, which is critical for the let‑7‑induced inhibition of mammosphere numbers. The let‑7d‑induced Akt1 inhibition contributed to tumor repression, with similar results to those obtained with Akt inhibitors. Furthermore, it was identified that the inhibition of Wnt1 is critical for the functioning of let‑7d, and that addition of recombinant Wnt1 abolished the effects of let‑7d on sensitization to radiotherapy. Let‑7d is suggested to be a promising therapeutic agent in the treatment of TNBC by targeting CSCs and sensitizing tumors to radiotherapy via inhibition of cyclin D1/Akt1/Wnt1 signaling.

Angiotensin receptor blocker telmisartan inhibits cell proliferation and tumor growth of cholangiocarcinoma through cell cycle arrest

“…The let-7 family members act as tumor suppressor molecules by binding its target oncogenes, such as HMGA2 ( 51 ), Ras ( 52 ) and c-Myc ( 53 ). Moreover, Sun et al reported that in breast cancer, let-7 directly inhibits cyclin D1 expression, resulting in low phosphorylation of Akt1, which is critical for the let-7 induced inhibition of mammosphere numbers ( 54 ).…”

Meme kanseri kök hücrelerinde elajik asit ile indüklenmiş miRNA’ların ifadesi ve elajik asidin apoptoz üzerine etkisi

“…EA, Let-7 ailesi miRNA'ların ifadesini düşürerek meme kanseri kök hücre özelliklerinin korunmasına neden olabilir. Let-7 miRNA'ları siklin D1 ifadesini baskılayarak Akt1'in fosforilasyonunu azaltmaktadır (40). Bu nedenle, Let-7 radyasyon ile indüklenmiş tümör baskılanmasını arttırmaktadır (40).…”

“…Let-7 miRNA'ları siklin D1 ifadesini baskılayarak Akt1'in fosforilasyonunu azaltmaktadır (40). Bu nedenle, Let-7 radyasyon ile indüklenmiş tümör baskılanmasını arttırmaktadır (40). EA'nın Let-7 ailesine ait olgun miRNA'ların ifadelerini düşürmesi ayrıca radyoterapiye karşı direncin oluşmasında da etkili olabilir.…”

Expression of miR-590 in lung cancer and its correlation with prognosis

“…The abnormal expression of miRNAs is closely related to tumour formation, and certain key factors can promote or inhibit cell proliferation by regulating the pathways thereof ( 13 , 14 ). In addition, miRNAs are involved in regulating migration, metastasis and apoptosis of cells ( 15 – 17 ).…”