Head and Neck Squamous Cell Carcinomas (HNSCC) are a heterogeneous collection of malignancies of the head and neck region. Transforming growth factor beta (TGF-β)-regulated long non-coding RNAs (lncRNAs) modulate several aspects of tumor development, including proliferation, invasion, epithelial-to-mesenchymal transition (EMT), metastasis, stemness, and drug resistance. However, global expression patterns and functional contributions of TGF-β-regulated lncRNAs have not been well explored in HNSCC. We identified several differentially expressed lncRNAs upon TGF-β treatment in HNSCC using whole-transcriptome sequencing. We show that TGF-β signalling induces lncRNA LASTR expression, and it promotes TGF-β signalling by enhancing TGFβR1 expression. LASTR expression is significantly up-regulated in HNSCC tissues and is associated with poor overall survival in HNSCC patients. LASTR knockdown inhibits cell proliferation, migration, invasion, and TGF-β-induced EMT in HNSCC cells. Moreover, LASTR depletion induces apoptosis and suppresses tumor growth in the xenograft mouse model. Mechanistically, LASTR suppresses miR-34a-5p biogenesis by sequestering the RNA-binding protein SART3 and also acts as a competing endogenous RNA (ceRNA) for miR-34a-5p, thereby up-regulating TGFβR1 expression. Our findings suggest that induction of LASTR by TGF-β modulates the miR-34a-5p /TGFβR1 axis to potentiate TGF-β signalling, highlighting its potential as a therapeutic target in HNSCC. • TGF-β induces LASTR expression via canonical and non-canonical signalling in HNSCC. • Overexpression of LASTR is associated with poor overall survival in HNSCC patients. • LASTR knockdown inhibits TGF-β signalling, invasion, EMT, and in vivo tumor growth. • LASTR inhibits miR-34a-5p biogenesis by sequestering SART3. • LASTR sequesters miR-34a-5p to promote TGFβR1 expression and TGF-β signalling.
Swati et al. (Sun,) studied this question.