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TGFβR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness.

Lyu X, Fang W, Cai L, Zheng H, Ye Y, Zhang L, Li J, Peng H, Cho WC, Wang E, Marincola FM, Yao K, Cai H, Li J, Li X - Mol. Cancer (2014)

Bottom Line: A cluster set of 4 TGFβR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFβR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo.Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-β signaling and the activation of PI3K/Akt pathway by suppressing TGFβR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process.Impressively, the knockdown of TGFβR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFβR2 is a major target of miR-93.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China. chbing2008@126.com.

ABSTRACT

Background: MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-β receptor II (TGFβR2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGFβR2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown.

Methods: We firstly evaluated the clinical signature of TGFβR2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGFβR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFβR2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFβR2 down-regulation.

Results: TGFβR2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGFβR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFβR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-β signaling and the activation of PI3K/Akt pathway by suppressing TGFβR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGFβR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFβR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFβR2 in NPC.

Conclusion: The present study reports an involvement of miR-93-mediated TGFβR2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients.

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MiR-93 and TGFβR2 were clinically associated with NPC aggressiveness. (A) The detection of miR-93 expression by qRT-PCR in an additional set of primary NPC samples. As showed in the plot diagrams, the miR-93 expression was positively correlated with T, N classification and clinical staging. Values represent mean ± SD, *p < 0.05 (B) qRT-PCR analysis of TGFβR2 mRNA expression showed a negative correlation of TGFβR2 expression with T and N classifications and clinical staging in scatter plot diagrams. Values represent mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.
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Figure 6: MiR-93 and TGFβR2 were clinically associated with NPC aggressiveness. (A) The detection of miR-93 expression by qRT-PCR in an additional set of primary NPC samples. As showed in the plot diagrams, the miR-93 expression was positively correlated with T, N classification and clinical staging. Values represent mean ± SD, *p < 0.05 (B) qRT-PCR analysis of TGFβR2 mRNA expression showed a negative correlation of TGFβR2 expression with T and N classifications and clinical staging in scatter plot diagrams. Values represent mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.

Mentions: To further support our finding, we finally investigated the clinical relevance of miR-93 and TGFβR2 in an additional set of clinical samples. The correlations of clinical TNM classification with the expression levels of miR-93 and TGFβR2 were analyzed (M classification was not analyzed due to few patients with distant metastasis). We observed that the expressions of miR-93 positively correlated with T/N classification and clinical stage respectively (Figure 6A) and TGFβR2 expression was negatively correlated with T/N classification and clinical stage respectively (Figure 6B), supporting that miR-93-mediated TGFβR2 down-regulation was closely linked to NPC aggressiveness.


TGFβR2 is a major target of miR-93 in nasopharyngeal carcinoma aggressiveness.

Lyu X, Fang W, Cai L, Zheng H, Ye Y, Zhang L, Li J, Peng H, Cho WC, Wang E, Marincola FM, Yao K, Cai H, Li J, Li X - Mol. Cancer (2014)

MiR-93 and TGFβR2 were clinically associated with NPC aggressiveness. (A) The detection of miR-93 expression by qRT-PCR in an additional set of primary NPC samples. As showed in the plot diagrams, the miR-93 expression was positively correlated with T, N classification and clinical staging. Values represent mean ± SD, *p < 0.05 (B) qRT-PCR analysis of TGFβR2 mRNA expression showed a negative correlation of TGFβR2 expression with T and N classifications and clinical staging in scatter plot diagrams. Values represent mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4016586&req=5

Figure 6: MiR-93 and TGFβR2 were clinically associated with NPC aggressiveness. (A) The detection of miR-93 expression by qRT-PCR in an additional set of primary NPC samples. As showed in the plot diagrams, the miR-93 expression was positively correlated with T, N classification and clinical staging. Values represent mean ± SD, *p < 0.05 (B) qRT-PCR analysis of TGFβR2 mRNA expression showed a negative correlation of TGFβR2 expression with T and N classifications and clinical staging in scatter plot diagrams. Values represent mean ± SD, *P < 0.05, **P < 0.01, ***P < 0.001.
Mentions: To further support our finding, we finally investigated the clinical relevance of miR-93 and TGFβR2 in an additional set of clinical samples. The correlations of clinical TNM classification with the expression levels of miR-93 and TGFβR2 were analyzed (M classification was not analyzed due to few patients with distant metastasis). We observed that the expressions of miR-93 positively correlated with T/N classification and clinical stage respectively (Figure 6A) and TGFβR2 expression was negatively correlated with T/N classification and clinical stage respectively (Figure 6B), supporting that miR-93-mediated TGFβR2 down-regulation was closely linked to NPC aggressiveness.

Bottom Line: A cluster set of 4 TGFβR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFβR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo.Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-β signaling and the activation of PI3K/Akt pathway by suppressing TGFβR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process.Impressively, the knockdown of TGFβR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFβR2 is a major target of miR-93.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Research Institute and the Provincial Key Laboratory of Functional Proteomics, Southern Medical University, Guangzhou, China. chbing2008@126.com.

ABSTRACT

Background: MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-β receptor II (TGFβR2), as an important tumor suppressor, is involved in various cancer types. However, it is in cancer that only two miRNAs of this cluster and its paralogues have been reported so far to regulate TGFβR2. MiR-93 is oncogenic, but its targetome in cancer has not been fully defined. The role of miR-93 in nasopharyngeal carcinoma (NPC) still remains largely unknown.

Methods: We firstly evaluated the clinical signature of TGFβR2 down-regulation in clinical samples, and next used a miRNA expression profiling analysis followed by multi-validations, including Luciferase reporter assay, to identify miRNAs targeting TGFβR2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGFβR2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGFβR2 down-regulation.

Results: TGFβR2 was down-regulated in more than 50% of NPC patients. It is an unfavorable prognosis factor contributing to clinical NPC aggressiveness. A cluster set of 4 TGFβR2-associated miRNAs was identified; they are all from miR-17-92 cluster and its paralogues, of which miR-93 was one of the most significant miRNAs, directly targeting TGFβR2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-β signaling and the activation of PI3K/Akt pathway by suppressing TGFβR2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGFβR2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGFβR2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGFβR2 in NPC.

Conclusion: The present study reports an involvement of miR-93-mediated TGFβR2 down-regulation in NPC aggressiveness, thus giving extended insights into molecular mechanisms underlying cancer aggressiveness. Approaches aimed at blocking miR-93 may serve as a promising therapeutic strategy for treating NPC patients.

Show MeSH
Related in: MedlinePlus