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

Pierre-Antoine Bissey; Jacqueline H Law; Jeff P Bruce; Wei Shi; Aline Renoult; Melvin L K Chua; Kenneth W Yip; Fei-Fei Liu

doi:10.1038/s41389-018-0050-x

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

Oncogenesis. 2018 May 22;7(5):40. doi: 10.1038/s41389-018-0050-x.

Authors

Pierre-Antoine Bissey¹, Jacqueline H Law², Jeff P Bruce¹, Wei Shi¹, Aline Renoult³, Melvin L K Chua^{1

4

5

6}, Kenneth W Yip¹, Fei-Fei Liu^{7

8

9}

Affiliations

¹ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
² Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
³ LabEx DEVweCAN, Université de Lyon, F-69000, Lyon, France.
⁴ Department of Radiation Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada.
⁵ Division of Radiation Oncology, National Cancer Centre, Singapore, Singapore.
⁶ Duke-NUS Graduate School, Singapore, Singapore.
⁷ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. [email protected].
⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. [email protected].
⁹ Department of Radiation Oncology, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada. [email protected].

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-TGFβ1 for integrin receptor binding. Decreased TGFBI led to increased pro-TGFβ1 activation and TGFβ1 canonical/noncanonical pathway-induced cisplatin resistance. Thus, overexpression of miR-449b decreases TGFBI, thereby altering the balance between TGFBI and pro-TGFβ1, revealing a novel mechanism of chemoresistance in NPC.