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MiR-181b regulates cisplatin chemosensitivity and metastasis by targeting TGFβR1/Smad signaling pathway in NSCLC.

Wang X, Chen X, Meng Q, Jing H, Lu H, Yang Y, Cai L, Zhao Y - Sci Rep (2015)

Bottom Line: We found that miR-181b expression levels were lower in A549/DDP cells compared with A549 cells.In addition, miR-181b could inactivate the TGFβR1/Smad signaling pathway.We also observed that decreased miR-181b expression and increased TGFβR1 expression were significantly associated with chemosensitivity to DDP and tumor metastasis in NSCLC patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medical Oncology, Harbin medical University Cancer Hospital, Harbin, Heilongjiang Province, China.

ABSTRACT
MicroRNAs (miRNAs) have been identified as important post-transcriptional regulators involved in various biological and pathological processes of cells, but their underlying mechanisms in chemosensitivity and metastasis have not been fully elucidated. The objective of this study was to identify miR-181b and its mechanism in the chemosensitivity and metastasis of NSCLC. We found that miR-181b expression levels were lower in A549/DDP cells compared with A549 cells. Functional assays showed that the overexpression of miR-181b inhibited proliferation, enhanced chemosensitivity to DDP, attenuated migration and metastatic ability in NSCLC cell lines in vitro and in vivo. TGFβR1 was subsequently identified as a novel functional target of miR-181b. TGFβR1 knockdown revealed similar effects as that of ectopic miR-181b expression, whereas overexpression of TGFβR1 rescued the function of miR-181b-mediated growth, chemosensitivity and metastasis in NSCLC cells. In addition, miR-181b could inactivate the TGFβR1/Smad signaling pathway. We also observed that decreased miR-181b expression and increased TGFβR1 expression were significantly associated with chemosensitivity to DDP and tumor metastasis in NSCLC patients. Consequently, miR-181b functions as a tumor suppressor and has an important role in proliferation, chemosensitivity to DDP and metastasis of NSCLC by targeting TGFβR1/Smad signaling pathway.

No MeSH data available.


Related in: MedlinePlus

TGFβR1 is a direct target of miR-181b.(a) Venn diagrams showed the number of genes identified as potential targets of miR-181b using three predicting search programs of TargenSCan, miRanda and miRBD. (b) Relative luciferase activity was analysed after wild-type or mutant 3′-UTR reporter plasmids were co-transfected with pGLE/miR-181b or miR-181b-NC in H1299 cells. (c) qRT-PCR and western blot detection of TGFβR1 mRNA and protein expression in A549 or A549/DDP cells transfected with miR-181b mimics or anti-miR-181b. U6 or GAPDH was used as an internal control. *P < 0.05; **P < 0.01.
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f4: TGFβR1 is a direct target of miR-181b.(a) Venn diagrams showed the number of genes identified as potential targets of miR-181b using three predicting search programs of TargenSCan, miRanda and miRBD. (b) Relative luciferase activity was analysed after wild-type or mutant 3′-UTR reporter plasmids were co-transfected with pGLE/miR-181b or miR-181b-NC in H1299 cells. (c) qRT-PCR and western blot detection of TGFβR1 mRNA and protein expression in A549 or A549/DDP cells transfected with miR-181b mimics or anti-miR-181b. U6 or GAPDH was used as an internal control. *P < 0.05; **P < 0.01.

Mentions: To elucidate the underlying mechanisms of the suppressive effects of miR-181b on cell proliferation, chemosensitivity to DDP and metastasis of NSCLC, we used several bioinformatics methods to help identify the target human genes of miR-181b. Among the targets predicted by the search programs of TargetScan, miRanda and miRDB, TGFβR1 was the gene that localized at the three main centers of the net comprised of 513 predicted genes (Fig. 4a).


MiR-181b regulates cisplatin chemosensitivity and metastasis by targeting TGFβR1/Smad signaling pathway in NSCLC.

Wang X, Chen X, Meng Q, Jing H, Lu H, Yang Y, Cai L, Zhao Y - Sci Rep (2015)

TGFβR1 is a direct target of miR-181b.(a) Venn diagrams showed the number of genes identified as potential targets of miR-181b using three predicting search programs of TargenSCan, miRanda and miRBD. (b) Relative luciferase activity was analysed after wild-type or mutant 3′-UTR reporter plasmids were co-transfected with pGLE/miR-181b or miR-181b-NC in H1299 cells. (c) qRT-PCR and western blot detection of TGFβR1 mRNA and protein expression in A549 or A549/DDP cells transfected with miR-181b mimics or anti-miR-181b. U6 or GAPDH was used as an internal control. *P < 0.05; **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664936&req=5

f4: TGFβR1 is a direct target of miR-181b.(a) Venn diagrams showed the number of genes identified as potential targets of miR-181b using three predicting search programs of TargenSCan, miRanda and miRBD. (b) Relative luciferase activity was analysed after wild-type or mutant 3′-UTR reporter plasmids were co-transfected with pGLE/miR-181b or miR-181b-NC in H1299 cells. (c) qRT-PCR and western blot detection of TGFβR1 mRNA and protein expression in A549 or A549/DDP cells transfected with miR-181b mimics or anti-miR-181b. U6 or GAPDH was used as an internal control. *P < 0.05; **P < 0.01.
Mentions: To elucidate the underlying mechanisms of the suppressive effects of miR-181b on cell proliferation, chemosensitivity to DDP and metastasis of NSCLC, we used several bioinformatics methods to help identify the target human genes of miR-181b. Among the targets predicted by the search programs of TargetScan, miRanda and miRDB, TGFβR1 was the gene that localized at the three main centers of the net comprised of 513 predicted genes (Fig. 4a).

Bottom Line: We found that miR-181b expression levels were lower in A549/DDP cells compared with A549 cells.In addition, miR-181b could inactivate the TGFβR1/Smad signaling pathway.We also observed that decreased miR-181b expression and increased TGFβR1 expression were significantly associated with chemosensitivity to DDP and tumor metastasis in NSCLC patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medical Oncology, Harbin medical University Cancer Hospital, Harbin, Heilongjiang Province, China.

ABSTRACT
MicroRNAs (miRNAs) have been identified as important post-transcriptional regulators involved in various biological and pathological processes of cells, but their underlying mechanisms in chemosensitivity and metastasis have not been fully elucidated. The objective of this study was to identify miR-181b and its mechanism in the chemosensitivity and metastasis of NSCLC. We found that miR-181b expression levels were lower in A549/DDP cells compared with A549 cells. Functional assays showed that the overexpression of miR-181b inhibited proliferation, enhanced chemosensitivity to DDP, attenuated migration and metastatic ability in NSCLC cell lines in vitro and in vivo. TGFβR1 was subsequently identified as a novel functional target of miR-181b. TGFβR1 knockdown revealed similar effects as that of ectopic miR-181b expression, whereas overexpression of TGFβR1 rescued the function of miR-181b-mediated growth, chemosensitivity and metastasis in NSCLC cells. In addition, miR-181b could inactivate the TGFβR1/Smad signaling pathway. We also observed that decreased miR-181b expression and increased TGFβR1 expression were significantly associated with chemosensitivity to DDP and tumor metastasis in NSCLC patients. Consequently, miR-181b functions as a tumor suppressor and has an important role in proliferation, chemosensitivity to DDP and metastasis of NSCLC by targeting TGFβR1/Smad signaling pathway.

No MeSH data available.


Related in: MedlinePlus