最新發表論文
Long noncoding RNA Smyca coactivates TGF-β/Smad and Myc pathways to drive tumor progression

Background: Metastasis and chemoresistance are major culprits of cancer mortality, but factors contributing to these processes are incompletely understood.

Methods: Bioinformatics methods were used to identify the relations of Smyca expression to clinicopathological features of human cancers. RNA-sequencing analysis was used to reveal Smyca-regulated transcriptome. RNA pull-down and RNA immunoprecipitation were used to examine the binding of Smyca to Smad3/4 and c-Myc/Max. Chromatin immunoprecipitation and chromatin isolation by RNA purification were used to determine the binding of transcription factors and Smyca to various gene loci, respectively. Real-time RT-PCR and luciferase assay were used to examine gene expression levels and promoter activities, respectively. Xenograft mo were performed to evaluate the effects of Smyca on metastasis and chemoresistance. Nanoparticle-assisted gapmer antisense oligonucleotides delivery was used to target Smyca in vivo.

Results: We identify lncRNA Smyca for its association with poor prognosis of many cancer types. Smyca potentiates metabolic reprogramming, migration, invasion, cancer stemness, metastasis and chemoresistance. Mechanistically, Smyca enhances TGF-β/Smad signaling by acting as a scaffold for promoting Smad3/Smad4 association and further serves as a Smad target to amplify/prolong TGF-β signaling. Additionally, Smyca potentiates c-Myc-mediated transcription by enhancing the recruitment of c-Myc/Max complex to a set of target promoters and c-Myc binding to TRRAP. Through potentiating TGF-β and c-Myc pathways, Smyca synergizes the Warburg effect elicited by both pathways but evades the anti-proliferative effect of TGF-β. Targeting Smyca prevents metastasis and overcomes chemoresistance.

Conclusions: This study uncovers a lncRNA that coordinates tumor-relevant pathways to orchestra a pro-tumor program and establishes the clinical values of Smyca in cancer prognosis and therapy.

Keywords: Chemoresistance; EMT; LncRNA; Metastasis; Smad; TGF-β; c-Myc.