Abstract
Long noncoding RNAs (lncRNAs) play critical roles in tumour progression and metastasis. Emerging evidence indicates that the lncRNA X inactive-specific transcript (XIST) is dysregulated in several tumor types, including non-small cell lung cancer (NSCLC). However, in NSCLC and other cancers the oncogenic mechanism of XIST remains incompletely understood. Here, we confirmed that XIST is upregulated in human NSCLC specimens, and is especially overexpressed in tumors previously treated with cisplatin (cis-diamminedichloroplatinum(II); DDP). In vitro, XIST knockdown inhibited NSCLC cell growth and promoted DDP chemosensitivity by stimulating apoptosis and pyroptosis. Moreover, XIST’s oncogenic effects and ability to promote DDP chemoresistance were largely related to its binding to the TGF-β effector SMAD2, which inhibited its translocation to the nucleus and prevented the transcription of p53 and NLRP3, crucial regulators of apoptosis and pyroptosis, respectively. Using DDP-resistant NSCLC cells, mouse xenograft studies verified the oncogenic function of XIST and its ability to inhibit programmed cell death, thereby mediating DDP chemoresistance. These findings suggest that XIST expression may serve as a novel biomarker to predict DDP treatment efficacy, and may help in the design of new therapies to circumvent DDP chemoresistance in NSCLC and other tumor types.
Highlights
Lung cancer is the leading cause of cancer-related deaths in China and around the world
X inactive-specific transcript (XIST)’s oncogenic effects and ability to promote DDP chemoresistance were largely related to its binding to the TGF-β effector SMAD2, which inhibited its translocation to the nucleus and prevented the transcription of p53 and NLRP3, crucial regulators of apoptosis and pyroptosis, respectively
The analysis revealed significant upregulation of XIST in non-small cell lung cancer (NSCLC) samples (Figure 1A), and negative correlation between XIST expression and patient survival was detected in the KM plotter database (Figure 1B)
Summary
Lung cancer is the leading cause of cancer-related deaths in China and around the world. Due to the lack of early diagnostic biomarkers, lung cancer is detected in the majority of the cases in advanced stages: more than 50% of NSCLC patients are diagnosed with locally advanced (stage III) or metastatic (stage IV) disease [1]. Long noncoding RNAs (lncRNAs) constitute a large class of RNA transcripts greater than 200 nucleotides in length. They are the most abundant type of non-proteincoding RNAs and are involved in numerous physiological and pathological processes, including regulation of gene expression, genomic imprinting, chromatin organization, immune regulation, viral pathogenesis, and oncogenesis [2,3,4,5,6,7]. It was proposed that XIST may exert its biological effects on gene expression by altering the stability of heterochromatin [8,9,10]
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