miR96‐ and miR182‐driven regulation of cytoskeleton results in inhibition of glioblastoma motility

Abstract

Glioblastoma multiforme (GBM) is one of the most common forms of brain tumor. As an excessively invasive tumor type, GBM cannot be fully cured due to its invasion ability into healthy brain tissues. Therefore, molecular mechanisms behind GBM migration and invasion need to be deeply investigated for the development of effective GBM treatments. Cellular motility and invasion are strictly associated with the cytoskeleton, especially with actins and tubulins. Palladin, an actin‐binding protein, tightly bundles actins during initial invadopodia and contraction fiber formations, which are essential for cellular motility. Spastin, a microtubule‐binding protein, cuts microtubules into small pieces and acts on invadopodia elongation and cellular trafficking of invadopodia‐associated proteins. Regulation of proteins such as spastin and palladin involved in dynamic reorganization of the cytoskeleton, are rapidly carried out by microRNAs at the posttranscriptional level. Therefore, determining possible regulatory miRNAs of spastin and palladin is critical to elucidate GBM motility. miR96 and miR182 down‐regulate SPAST and PALLD at both transcript and protein levels. Over‐expression of miR96 and miR182 resulted in inhibition of the motility. However, over‐expression of spastin and palladin induced the motility. Spastin and palladin rescue of miR96‐ or miR182‐transfected U251 MG cells resulted in diminished effects of the miRNAs and rescued the motility. Our results demonstrate that miR96 and miR182 over‐expressions inhibit GBM motility by regulating cytoskeleton through spastin and palladin. These findings suggest that miR96 and miR182 should be investigated in more detail for their potential use in GBM therapy.

CRISPRi screen of long non-coding RNAs identifies LINC03045 regulating glioblastoma invasion

“…Here, our RNA-seq analysis following LINC03045 KD revealed that WASF3 is a gene that was reproducibly downregulated with LINC03045 knockdown, while a correlation analysis of patient TCGA/GTEx sequencing data revealed a significant positive correlation between LINC03045 and WASF3. Additionally, the GO term for cytoskeleton organization (GO: 0007010) process was enriched for WASF3, which is consistent with prior literature that describes cytoskeletal reorganization as commonly associated with tumor invasion [46]. WASF3, a Wiskott-Aldrich syndrome protein family member, has been implicated in multiple studies as a regulator of the actin cytoskeleton and in cancer invasion, which is again consistent with our results [47].…”

Untitled

“…Here, our RNA-seq analysis following LINC03045 KD revealed that WASF3 is a gene that was reproducibly downregulated with LINC03045 knockdown, while a correlation analysis of patient TCGA/GTEx sequencing data revealed a significant positive correlation between LINC03045 and WASF3. Additionally, the GO term for cytoskeleton organization (GO: 0007010) process was enriched for WASF3, which is consistent with prior literature that describes cytoskeletal reorganization as commonly associated with tumor invasion [46]. WASF3, a Wiskott-Aldrich syndrome protein family member, has been implicated in multiple studies as a regulator of the actin cytoskeleton and in cancer invasion, which is again consistent with our results [47].…”

Untitled

“…Here, our RNA-seq analysis following LINC03045 KD revealed that WASF3 is a gene that was reproducibly downregulated with LINC03045 knockdown, while a correlation analysis of patient TCGA/GTEx sequencing data revealed a significant positive correlation between LINC03045 and WASF3. Additionally, the GO term for cytoskeleton organization (GO: 0007010) process was enriched for WASF3, which is consistent with prior literature that describes cytoskeletal reorganization as commonly associated with tumor invasion [46]. WASF3, a Wiskott-Aldrich syndrome protein family member, has been implicated in multiple studies as a regulator of the actin cytoskeleton and in cancer invasion, which is again consistent with our results [47].…”