Abstract
Metastasis is the leading cause of death of patients with esophageal squamous cell carcinoma (ESCC). Although an increasing number of studies have demonstrated the involvement of G3BP2 in several human cancers, how G3BP2 interacts with long noncoding RNAs and regulates mRNA transcripts in mediating ESCC metastasis remains unclear. In this study, we uncovered that G3BP2 was upregulated in ESCC. Further analysis revealed that upregulation of G3BP2 was significantly correlated with lymph node metastasis, depth of tumor invasion and unfavorable outcomes in ESCC patients. Both in vitro and in vivo functional assays demonstrated that G3BP2 dramatically enhanced ESCC cell migration and invasion. Mechanistically, LINC01554 maintained the high G3BP2 expression in ESCC by protecting G3BP2 from degradation through ubiquitination and the interaction domains within LINC01554 and G3BP2 were identified. In addition, RNA-seq revealed that HDGF was regulated by G3BP2. G3BP2 bound to HDGF mRNA transcript to stabilize its expression. Ectopic expression of HDGF effectively abolished the G3BP2 depletion-mediated inhibitory effect on tumor cell migration. Intriguingly, introduction of compound C108 which can inhibit G3BP2 remarkedly suppressed ESCC cell metastasis in vitro and in vivo. Collectively, this study describes a newly discovered regulatory axis, LINC01554/G3BP2/HDGF, that facilitates ESCC metastasis and will provide novel therapeutic strategies for ESCC.
Highlights
Esophageal carcinoma (EC) is an exceedingly aggressive cancer with a high mortality rate and poor prognosis worldwide [1], and squamous cell carcinoma is the major pathological type of EC [2]
Upregulation of G3BP2 is correlated with unfavorable outcomes in esophageal squamous cell carcinoma (ESCC) patients To investigate the expression status of G3BP2 in ESCC, we first performed big data mining from Oncomine and TCGA databases Both databases indicated that G3BP2 was highly expressed in ESCC (Fig. 1A), which was further confirmed in the SYSUCC cohort at both the mRNA (Fig. 1B) and protein levels (Supplementary Fig. 1)
The LINC01554/G3BP2/hepatomaderived growth factor (HDGF) signaling axis facilitates ESCC cell metastasis Given that LINC01554 controlled the protein stability of G3BP2 and HDGF mRNA transcript was regulated by G3BP2, we investigated whether the LINC01554/G3BP2/HDGF regulatory signaling axis played a critical role in driving ESCC metastasis
Summary
Esophageal carcinoma (EC) is an exceedingly aggressive cancer with a high mortality rate and poor prognosis worldwide [1], and squamous cell carcinoma is the major pathological type of EC [2]. L In vitro ubiquitination assay showed that the ubiquitination level of the G3BP2 protein was dramatically increased in KYSE30 cells with truncation of the RRM domain. To validate the RNA-seq result, we detected both the RNA and protein levels of HDGF in stable G3BP2-knockdown cell lines and found that they were significantly decreased compared with those in control cells (Fig. 4C).
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