Abstract
Paraspeckle protein 1 (PSPC1) overexpression in cancers is known to be the pro-metastatic switch of tumor progression associated with poor prognosis of cancer patients. However, the detail molecular mechanisms to facilitate cancer cell migration remain elusive. Here, we conducted integrated analysis of human phospho-kinase antibody array, transcriptome analysis with RNA-seq, and proteomic analysis of protein pulldown to study the molecular detail of PSPC1-potentiated phenotypical transformation, adhesion, and motility in human hepatocellular carcinoma (HCC) cells. We found that PSPC1 overexpression re-assembles and augments stress fiber formations to promote recruitment of focal adhesion contacts at the protruding edge to facilitate cell migration. PSPC1 activated focal adhesion-associated kinases especially FAK/Src signaling to enhance cell adhesion and motility toward extracellular matrix (ECM). Integrated transcriptome and gene set enrichment analysis indicated that PSPC1 modulated receptor tyrosine kinase IGF1R involved in the focal adhesion pathway and induction of diverse integrins expression. Knockdown IGF1R expression and treatment of IGF1R inhibitor suppressed PSPC1-induced cell motility. Interestingly, knockdown PSPC1-interacted paraspeckle components including NONO, FUS, and the lncRNA Neat1 abolished PSPC1-activated IGF1R expression. Together, PSPC1 overexpression induced focal adhesion formation and facilitated cell motility via activation of IGF1R signaling. PSPC1 overexpression in tumors could be a potential biomarker of target therapy with IGF1R inhibitor for improvement of HCC therapy.
Highlights
Interactions of cell-to-cell adhesion and cell-to-extracellular matrix (ECM) play critical roles in sustaining tissue homeostasis and microenvironment to augment cell motility toward their destinations during normal tissue ontogenesis and tumor progression, respectively
We investigate the impacts of paraspeckle component proteins and their binding scaffold lncRNA Neat1 participated in paraspeckle component 1 (PSPC1)/Insulin-like growth factor 1 receptor (IGF1R) axis-potentiated cell motility
Since elevation of cell motility is generally accompanied with phenotypical transformation including cell spreading, cytoskeleton remodeling, polarized protrusion, and focal adhesion formation [27], we found that expression of PSPC1 obviously induced cell morphology transformation in SK-Hep1 and PLC5 that exhibited augmented cell spreading phenotype compared with mock cells (Figure 1F)
Summary
Interactions of cell-to-cell adhesion and cell-to-extracellular matrix (ECM) play critical roles in sustaining tissue homeostasis and microenvironment to augment cell motility toward their destinations during normal tissue ontogenesis and tumor progression, respectively. Normal epithelial cells along with other cell types build up and maintain the organ architecture by adhering to distinct proteins of adhesion and ECM to anchor cells and to trigger downstream physiological signaling for specific organ development. Cancer cells dominantly interact with stroma cells to orchestrate the microenvironment for malignant tumor progression. Paraspeckles contain several well-characterized members of the Drosophila behavior human splicing (DBHS) family proteins including paraspeckle component 1 (PSPC1), non-POU domaincontaining octamer binding protein (NONO), and splicing factor proline- and glutamine-rich (SFPQ). DBHS proteins shared consensus sequence containing domains of RNA recognition motifs (RRM), NONA/paraspeckle (NOPS) and coiled-coil.
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