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Title: Dysregulation of the MiR-449b target TGFBI alters the TGF? pathway to induce cisplatin resistance in nasopharyngeal carcinoma
Authors: Bissey, P.-A
Law, J.H
Bruce, J.P
Shi, W
Renoult, A
Chua, M.L.K 
Yip, K.W
Liu, F.-F
Keywords: beta actin
caspase 3
fizzy related protein
integrin receptor
messenger RNA
microRNA 449b
phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase
protein kinase B
short hairpin RNA
Smad2 protein
transcription factor ZEB1
transforming growth factor beta
transforming growth factor beta induced
transforming growth factor beta1
unclassified drug
cancer resistance
down regulation
enzyme activation
enzyme activity
enzyme phosphorylation
human cell
in vitro study
nasopharynx carcinoma
priority journal
protein expression
protein phosphorylation
RNA sequence
Issue Date: 2018
Citation: Bissey, P.-A, Law, J.H, Bruce, J.P, Shi, W, Renoult, A, Chua, M.L.K, Yip, K.W, Liu, F.-F (2018). Dysregulation of the MiR-449b target TGFBI alters the TGF? pathway to induce cisplatin resistance in nasopharyngeal carcinoma. Oncogenesis 7 (5) : 40. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. © 2018 The Author(s).
Source Title: Oncogenesis
ISSN: 21579024
DOI: 10.1038/s41389-018-0050-x
Rights: Attribution 4.0 International
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