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Dysregulation of the MiR-449b target TGFBI alters the TGF? pathway to induce cisplatin resistance in nasopharyngeal carcinoma.

ABSTRACT: Despite the improvement in locoregional control of nasopharyngeal carcinoma (NPC), distant metastasis (DM), and chemoresistance persist as major causes of mortality. This study identified a novel role for miR-449b, an overexpressed gene in a validated four-miRNA signature for NPC DM, leading to chemoresistance via the direct targeting of transforming growth factor beta-induced (TGFBI). In vitro shRNA-mediated downregulation of TGFBI induced phosphorylation of PTEN and AKT, increasing cisplatin resistance. Conversely, the overexpression of TGFBI sensitized the NPC cells to cisplatin. In NPC patients treated with concurrent chemoradiotherapy (CRT), the overall survival (OS) was significantly inversely correlated with miR-449b, and directly correlated with both TGFBI mRNA and protein expression, as assessed by RNA sequencing and immunohistochemistry (IHC). Mechanistically, co-immunoprecipitation demonstrated that TGFBI competes with pro-TGF?1 for integrin receptor binding. Decreased TGFBI led to increased pro-TGF?1 activation and TGF?1 canonical/noncanonical pathway-induced cisplatin resistance. Thus, overexpression of miR-449b decreases TGFBI, thereby altering the balance between TGFBI and pro-TGF?1, revealing a novel mechanism of chemoresistance in NPC.

SUBMITTER: Bissey PA

PROVIDER: S-EPMC5966388 | biostudies-other | 2018 May

REPOSITORIES: biostudies-other

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Dysregulation of the MiR-449b target TGFBI alters the TGFβ pathway to induce cisplatin resistance in nasopharyngeal carcinoma.

Bissey Pierre-Antoine PA Law Jacqueline H JH Bruce Jeff P JP Shi Wei W Renoult Aline A Chua Melvin L K MLK Yip Kenneth W KW Liu Fei-Fei FF

Oncogenesis 20180522 5

Despite the improvement in locoregional control of nasopharyngeal carcinoma (NPC), distant metastasis (DM), and chemoresistance persist as major causes of mortality. This study identified a novel role for miR-449b, an overexpressed gene in a validated four-miRNA signature for NPC DM, leading to chemoresistance via the direct targeting of transforming growth factor beta-induced (TGFBI). In vitro shRNA-mediated downregulation of TGFBI induced phosphorylation of PTEN and AKT, increasing cisplatin r ...[more]

PMID: 29795279

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Project description:BACKGROUND:MiR-17-92 cluster and its paralogues have emerged as crucial regulators of many oncogenes and tumor suppressors. Transforming growth factor-? receptor II (TGF?R2), 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 TGF?R2. 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 TGF?R2 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 TGF?R2 in NPC. In vitro and in vivo studies were performed to further investigate the effects of miRNA-mediated TGF?R2 down-regulation on NPC aggressiveness. Finally, mechanism studies were conducted to explore the associated pathway and genes influenced by this miRNA-mediated TGF?R2 down-regulation. RESULTS:TGF?R2 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 TGF?R2-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 TGF?R2, promoting cell proliferation, invasion and metastasis in vitro and in vivo. Moreover, miR-93 resulted in the attenuation of Smad-dependent TGF-? signaling and the activation of PI3K/Akt pathway by suppressing TGF?R2, further promoting NPC cell uncontrolled growth, invasion, metastasis and EMT-like process. Impressively, the knockdown of TGF?R2 by siRNA displayed a consentaneous phenocopy with the effect of miR-93 in NPC cells, supporting TGF?R2 is a major target of miR-93. Our findings were also substantiated by investigation of the clinical signatures of miR-93 and TGF?R2 in NPC. CONCLUSION:The present study reports an involvement of miR-93-mediated TGF?R2 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.

Dataset Information

Dysregulation of the MiR-449b target TGFBI alters the TGF? pathway to induce cisplatin resistance in nasopharyngeal carcinoma.

Publications

Dysregulation of the MiR-449b target TGFBI alters the TGFβ pathway to induce cisplatin resistance in nasopharyngeal carcinoma.

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