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2018 ; 7
(5
): 40
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Dysregulation of the MiR-449b target TGFBI alters the TGF? pathway to induce
cisplatin resistance in nasopharyngeal carcinoma
#MMPMID29795279
Bissey PA
; Law JH
; Bruce JP
; Shi W
; Renoult A
; Chua MLK
; Yip KW
; Liu FF
Oncogenesis
2018[May]; 7
(5
): 40
PMID29795279
show ga
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.