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SOX10 regulates melanoma metastasis through the IRF1-ITGA3/EphA2-FAK pathway.

ABSTRACT: Melanoma heterogeneity is associated with an enhanced metastatic potential. Although an invasive state with MITFlow/AXLhigh in the melanoma subpopulation has been identified using a single-cell RNA-seq analysis, the mechanisms by which these cells acquire their invasiveness remains unclear. In the present study, we identified the gene set related to cell migration as one of the enriched gene ontologies after the knockdown of SOX10 in melanoma. We demonstrated that the knockdown of SOX10 induced melanoma migration independent of MITF reduction or AXL induction. An in silico analysis and in vitro analysis revealed that ITGA3 and EphA2 were downstream molecules for SOX10-mediated migration, and were required for adhesive and random motile abilities, respectively. In addition, the oncogenic activation of MAPK was required for increased random motility through EphA2 phosphorylation at the Ser 897 residue. We also demonstrated the significance of IRF1 in the induction of both ITGA3 and EphA2 after the knockdown of SOX10. The FAK inhibitor, defactinib, suppressed metastasis in vivo. In summary, the present study showed that the reduced expression of SOX10 induced melanoma metastasis through the IRF1-ITGA3/EphA2-FAK pathway and also suggests the potential of FAK inhibitors as candidate drugs for the treatment of melanoma metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298445 | GEO | 2025/12/03

REPOSITORIES: GEO

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Project description:It is believed that the inherent differentiation program of melanocytes during embryogenesis predisposes melanoma cells to high frequency of metastasis. Sox10, a transcription factor expressed in neural crest stem cells and a subset of progeny lineages, plays a key role in the development of melanocytes. We show that B16F10 melanoma cells transfected with siRNA specific for Sox10 display reduced migratory activity which in turn indicated that a subset of transcriptional regulatory target genes of Sox10 are likely to be involved in migration and metastasis of melanoma cells. We carried out microarray-based gene expression profiling using Sox10-specific siRNA to identify regulatory targets and found that multiple genes including melanocortin-1 receptor (Mc1R) partake in the regulation of migration. We provide evidences that a significant portion of the effect of Sox10 on migration is mediated by Mitf, a transcription factor downstream to Sox10. The involvement of Mc1R in migration was studied in detail in vivo using a murine metastasis model. Specifically, B16F10 melanoma cells treated with a specific siRNA showed reduced tendency in metastasizing to and colonizing the lung after being injected in the tail vein. These data reveal a cadre of novel regulators and mediators involved in migration and metastasis of melanoma cells that represent potential targets of therapeutic intervention. Chemically synthesized siRNA duplex (WT1-Sox10) was used to knock-down the transcription factor Sox10 in murine melanoma cell line B16F10. For the control, siRNA containing 5 nucleotide alterations (MT1-Sox10) were used. Total RNA was subsequently prepared to synthesize probes for microarray screening. A total of three pairs of replicate samples were generated each from separate transfection followed by RNA preparation. Expression values were determined and compared within each pair of WT1-Sox10 and MT1-Sox10 transfections. Genes showing over 2 fold changes in all three replicate pairs were subjected to subsequent analyses.

Project description:Objective We have previously shown that expression of the CEACAM1 long isoform (CC1-L) in metastatic colorectal cancer (CRC) cells results in significant inhibition of liver metastasis via Chemokine (C-C motif) Ligand 2 (CCL2) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. Yet, despite recent advances in identifying molecules involved in the CC1-L inhibition of metastasis, much remains to be elucidated regarding the molecular mechanisms orchestrating this pathway. Design We performed an untargeted transcript profiling and a phosphokinase screen between CC1-L-expressing and non-expressing (CT) CRC cells. Identified targets were validated in vitro and in vivo for their involvement in signaling and invasion or metastasis. We validated our conclusions in CRC patient cohorts for time to metastasis development and long-term survival. Results Untargeted transcript profiling revealed high Decorin (Dcn) expression in CC1-L-expressing cells versus CT cells. Decorin was detected at the peri-endothelial layers of large blood vessels and in liver stellate cells. In metastatic lesions, it was expressed in pericyte-like cells covering capillary endothelium. Phosphokinase differential screening revealed reduced Ephrin type-A receptor 2 (EphA2) expression and activity in CC1-L- versus CT-expressing cells. Treatment of CT cells with recombinant Dcn led to decreased migration and invasion and decreased EphA2-mediated Erk and Akt signaling. CRC patients exhibiting high CC1 and DCN expression, in combination with low EPHA2 expression, benefit from longer 10-year survival than those with high EPHA2 expression. Conclusion CC1-L expression in poorly differentiated CRC inhibits liver metastasis through increased Decorin expression and EphA2-mediated signaling. Quadriplicate samples of each mouse colon cancer cell lines (control cells versus those expressing either short or long isoform of CEACAM1) have been used for RNA extraction

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SOX10 regulates melanoma metastasis through the IRF1-ITGA3/EphA2-FAK pathway.

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