Dysregulation of the MiR-449b target TGFBI alters the TGFβ 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-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.

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

“…TGFBI protein has been detected in most normal human tissues [229]. Although TGFBI is a downstream component of TGF-β signaling pathway, its expression is regulated not only by TGF-β, but also by other factors and mechanisms, such as autophagy [230], microRNAs [231], interleukin (IL)-1β [232], IL-4 [233], tumor necrosis factor α (TNFα) [232], cancerassociated fibroblasts (CAFs) [234], and high glucose concentrations [235,236]. TGFBI mediates cell adhesion, migration, proliferation, apoptosis, and angiogenesis through interaction with several ECM molecules (e.g.…”

Feedback loop in miR‐449b‐3p/ADAM17/NF‐κB promotes metastasis in nasopharyngeal carcinoma

“…First, the microarray analysis and validation of tissue samples and cell lines revealed that miR‐449b‐3p might be involved in the carcinogenesis and progression of NPC. Bissey P A et al confirmed that the dysregulation of miR‐449b alters the TGF‐β pathway to induce cisplatin resistance by targeting TGFBI in NPC . Moreover, chemoradiotherapy‐treated patients with NPC and high miR‐449b levels showed an inferior 5‐year overall survival to those of low‐miR‐449b‐expressing patients (72.8% vs 91.8%, P = .017).…”

MiR-34c Downregulation Leads to SOX4 Overexpression and Cisplatin Resistance in Nasopharyngeal Carcinoma

“…We had previously demonstrated that miR-449b overexpression, another component of the validated prognostic DM signature [11], led to TGFBI mRNA degradation with subsequent TGFβ1 accumulation [12]. Given that TGFβ1 plays an important role in NPC progression [53,[63][64][65][66][67][68] and in the regulation of miRNAs, particularly miR-34a [52], we sought to measure TGFβ1 in these cell lines.…”

“…Another component of the four-miRNA DM signature is miR-34c, which was only compared to other described [12]. NP69 and NP460 cell lines were generated by SW Tsao's group [55,56] and served as "normal" cells throughout this study.…”

“…NP69 and NP460 cell lines were generated by SW Tsao's group [55,56] and served as "normal" cells throughout this study. Every new batch of cells underwent mycoplasma testing and STR analyses [12]. C666-1, NP69 and NP460 cells were used for gain-and loss-of-function assays; HEK 293T cells were used for lentiviral generation and luciferase assays.…”