Toll-like receptors (TLRs) are well-known as patternrecognition receptors in the immune system for recognizing pathogen-associated and damage-associated molecular patterns [1]. TLRs play an essential role in the innat...Toll-like receptors (TLRs) are well-known as patternrecognition receptors in the immune system for recognizing pathogen-associated and damage-associated molecular patterns [1]. TLRs play an essential role in the innate and adaptive immune responses. To date, 10 functional TLRs have been identified in humans (TLR1–TLR10) and 12 in mice (TLR1–TLR9 and TLR11–TLR13)[1]. TLRs are evolutionarily conserved type I transmembrane proteins and comprise an ectodomain characterized by leucine-rich repeats mediating the recognition of ligands, a transmembrane region, and cytosolic Toll-interleukin (IL)-1 receptor domains that activate the downstream signaling pathways [1].展开更多
MicroRNA-21(miR-21) is frequently up-regulated in cancer and the majority of its reported targets are tumor suppressors.Through functional suppression,miR-21 is implicated in practically every walk of oncogenic life:t...MicroRNA-21(miR-21) is frequently up-regulated in cancer and the majority of its reported targets are tumor suppressors.Through functional suppression,miR-21 is implicated in practically every walk of oncogenic life:the promotion of cell proliferation,invasion and metastasis,genome instability and mutation,inflammation,replicative immortalization,abnormal metabolism,angiogenesis,and evading apoptosis,immune destruction,and growth suppressors.In particular,miR-21 is strongly involved in apoptosis.In this article,we reviewed the experimentally validated targets of miR-21 and found that two thirds are linked to intrinsic and/or extrinsic pathways of cellular apoptosis.This suggests that miR-21 is an oncogene which plays a key role in resisting programmed cell death in cancer cells and that targeting apoptosis is a viable therapeutic option against cancers expressing miR-21.展开更多
MicroRNAs （miRNAs）, which are small noncoding RNA molecules, play important roles in the post-transcriptional regulation process. The microRNA-21 gene （miR-21） has been reported to be highly expressed in various s...MicroRNAs （miRNAs）, which are small noncoding RNA molecules, play important roles in the post-transcriptional regulation process. The microRNA-21 gene （miR-21） has been reported to be highly expressed in various solid tumors, including breast cancer. Bone morphogenetic protein-6 （BMP-6） has been identified as an inhibitor of breast cancer epithelial-mesenchymal transition （EMT） through rescuing E-cadherin expression. We initiated experi- ments to identify the relationships between miR-21 and BMP-6 in breast cancer progression. Real-time PCR analysis showed that miR-21 expression was very high in MDA-MB-231 cells that expressed little BMP-6. A reverse correla- tion between BMP-6 and miR-21 was also determined in breast cancer tissue samples. Moreover, BMP-6 inhibited miR-21 transcription in MDA-MB-231 cells. In order to investigate how BMP-6 inhibited the miR-21 promoter （miPPR-21）, we constructed a series of miPPR-21 reporters. Luciferase assay results indicated that BMP-6 inhibited miPPR-21 activity through the E2-box and AP-l-binding sites. We also demonstrated that both δEF1 and TPA in- duced miR-21 expression. Using site-directed mutation and CHIP assay, we found that δEF1 induced miPPR-21 ac- tivity by binding to the E2-box on miPPR-21. Moreover, TPA triggered miPPR-21 activity through the AP-I binding sites. BMP-6 treatment significantly reduced the binding of these factors to miPPR-21 by decreasing the expression of δEF1 and c-Fos/c-Jun. We also demonstrated that BMP-6-induced downregulation of miR-21 modified the activ- ity of PDCD4 3＇UTR and inhibited MDA-MB-231 cell invasion. δEF1 overexpression and TPA induction blocked this inhibitory effect of BMP-6. In conclusion, BMP-6-induced inhibition of miR-21 suggests that BMP-6 may function as an anti-metastasis factor by a mechanism involving transcriptional repression of miR-21 in breast cancer.展开更多
基金supported by grants from the National Natural Science Foundation of China (81870874, 31371179, and 81300968)the Natural Science Foundation of Jiangsu Province, China (BK20170004 and 2015-JY-029)
文摘Toll-like receptors (TLRs) are well-known as patternrecognition receptors in the immune system for recognizing pathogen-associated and damage-associated molecular patterns [1]. TLRs play an essential role in the innate and adaptive immune responses. To date, 10 functional TLRs have been identified in humans (TLR1–TLR10) and 12 in mice (TLR1–TLR9 and TLR11–TLR13)[1]. TLRs are evolutionarily conserved type I transmembrane proteins and comprise an ectodomain characterized by leucine-rich repeats mediating the recognition of ligands, a transmembrane region, and cytosolic Toll-interleukin (IL)-1 receptor domains that activate the downstream signaling pathways [1].
基金supported by the Diabetes and Obesity Center funded by NCRR/NIH(P20RR024489)the Center for Environmental Genomics and Integrated Biology fundedby NIEHS/NIH(P30ES014443)+1 种基金the Scientist Development Grant from American Heart Association(0830288N)a R01 grant from National Institutes of Health(CA138688)
文摘MicroRNA-21(miR-21) is frequently up-regulated in cancer and the majority of its reported targets are tumor suppressors.Through functional suppression,miR-21 is implicated in practically every walk of oncogenic life:the promotion of cell proliferation,invasion and metastasis,genome instability and mutation,inflammation,replicative immortalization,abnormal metabolism,angiogenesis,and evading apoptosis,immune destruction,and growth suppressors.In particular,miR-21 is strongly involved in apoptosis.In this article,we reviewed the experimentally validated targets of miR-21 and found that two thirds are linked to intrinsic and/or extrinsic pathways of cellular apoptosis.This suggests that miR-21 is an oncogene which plays a key role in resisting programmed cell death in cancer cells and that targeting apoptosis is a viable therapeutic option against cancers expressing miR-21.
文摘MicroRNAs （miRNAs）, which are small noncoding RNA molecules, play important roles in the post-transcriptional regulation process. The microRNA-21 gene （miR-21） has been reported to be highly expressed in various solid tumors, including breast cancer. Bone morphogenetic protein-6 （BMP-6） has been identified as an inhibitor of breast cancer epithelial-mesenchymal transition （EMT） through rescuing E-cadherin expression. We initiated experi- ments to identify the relationships between miR-21 and BMP-6 in breast cancer progression. Real-time PCR analysis showed that miR-21 expression was very high in MDA-MB-231 cells that expressed little BMP-6. A reverse correla- tion between BMP-6 and miR-21 was also determined in breast cancer tissue samples. Moreover, BMP-6 inhibited miR-21 transcription in MDA-MB-231 cells. In order to investigate how BMP-6 inhibited the miR-21 promoter （miPPR-21）, we constructed a series of miPPR-21 reporters. Luciferase assay results indicated that BMP-6 inhibited miPPR-21 activity through the E2-box and AP-l-binding sites. We also demonstrated that both δEF1 and TPA in- duced miR-21 expression. Using site-directed mutation and CHIP assay, we found that δEF1 induced miPPR-21 ac- tivity by binding to the E2-box on miPPR-21. Moreover, TPA triggered miPPR-21 activity through the AP-I binding sites. BMP-6 treatment significantly reduced the binding of these factors to miPPR-21 by decreasing the expression of δEF1 and c-Fos/c-Jun. We also demonstrated that BMP-6-induced downregulation of miR-21 modified the activ- ity of PDCD4 3＇UTR and inhibited MDA-MB-231 cell invasion. δEF1 overexpression and TPA induction blocked this inhibitory effect of BMP-6. In conclusion, BMP-6-induced inhibition of miR-21 suggests that BMP-6 may function as an anti-metastasis factor by a mechanism involving transcriptional repression of miR-21 in breast cancer.
