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bioRxiv · 10.1101/2024.11.20.624463

Mechano-sensing role of oncogenic lncRNA NEAT1 on soft vs. stiff substrates and its implications for glioblastoma progression

Ghosh, A.·Soundharya, R.·Jolly, M. K.·Majumder, A.
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Abstract

Long non-coding RNAs (lncRNAs) have gained increasing recognition as key regulators of cancer biology, overturning their earlier classification as non-functional genomic elements. Among them, NEAT1 (Nuclear-Enriched Abundant Transcript 1) has emerged as a prominent oncogenic lncRNA involved in multiple solid tumors, including liver, prostate, and gastric cancers, as well as gliomas. Although the role of NEAT1 in cancer has been extensively studied, most of these investigations have focused on biochemical factors, leaving the mechano-sensitivity of NEAT1 to mechanical alterations in the tumor microenvironment (TME) largely unexplored. As tumors progress, the TME undergoes significant mechanical changes, particularly extracellular matrix (ECM) stiffening, which modulates cellular behavior through mechano-transduction pathways. While much research has focused on how these mechanical cues influence protein-coding gene expression, their impact on lncRNAs such as NEAT1 remains understudied. This study aims to address this gap by investigating the mechano-sensitivity of NEAT1 in glioblastoma (GBM) cells cultured on polyacrylamide (PAA) gels that mimic the brains physiological stiffness (0.5 kPa) versus conventional, stiff tissue culture plastic (TCP). NEAT1 expression, quantified using qRT-PCR, revealed a significant increase on softer, brain-mimicking substrates compared to stiffer TCP. Overexpression of NEAT1 in brain-mimicking stiffness also showed higher expression levels of cancer progression markers, quantified by qRT-PCR. To further explore NEAT1s role in oncogenesis due to its mechano-sensing capabilities, siRNA-mediated downregulation of NEAT1 in GBM cells cultured on soft PAA gels was performed to reduce NEAT1 levels to those comparable to TCP. The results showed reduced cancer aggressiveness, characterized by decreased expression of invasion, stemness, and epithelial-mesenchymal transition (EMT) markers, further supported by migration and invasion assays. These findings highlight NEAT1 as a mechanosensitive regulator in response to substrate stiffness, underscoring its role in tumor progression.

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Ghosh, A., Soundharya, R., Jolly, M. K., Majumder, A.. 2024-11-21. Mechano-sensing role of oncogenic lncRNA NEAT1 on soft vs. stiff substrates and its implications for glioblastoma progression. https://doi.org/10.1101/2024.11.20.624463

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