Supplemental Figure 4 from EGF Receptor Promotes Prostate Cancer Bone Metastasis by Downregulating miR-1 and Activating TWIST1

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posted on 2023-03-30, 23:11 authored by Yung-Sheng Chang, Wei-Yu Chen, Juan Juan Yin, Heather Sheppard-Tillman, Jiaoti Huang, Yen-Nien Liu

(A) Mean TWIST1 levels in human normal (n=28), primary (n=98), and metastatic (n=13) prostate samples collected and analyzed at MSKCC. * vs. normal tissue; # vs. primary cancer tissues. * p<0.05, ** p<0.01, *** p<0.001. (B and C) GSEA analyses showing enrichment of the MSKCC (B) and TCGA (C) prostate cancer datasets with EGFR signaling downregulation-responsive genes in cancer patients expressing low levels of TWIST1. NES, normalized enrichment score; FDR, false discovery rate. (D and E) EGF-upregulated signature genes expressed as a summed z-score for samples separated on the basis of TWIST1 (D) and miR-1 (E) expressions above median (TWIST1 High and miR-1 Low) or below median (TWIST1 Low and miR-1 High) in the MSKCC dataset. (F) Immunoblotting of cell extracts from RasB1 and PC3 cells following EGF treatment. (G) Morphology of RasB1 and PC3 cells following EGF treatment.

History

ARTICLE ABSTRACT

Dysregulation of the EGFR signaling axis enhances bone metastases in many solid cancers. However, the relevant downstream effector signals in this axis are unclear. miR-1 was recently shown to function as a tumor suppressor in prostate cancer cells, where its expression correlated with reduced metastatic potential. In this study, we demonstrated a role for EGFR translocation in regulating transcription of miR-1-1, which directly targets expression of TWIST1. Consistent with these findings, we observed decreased miR-1 levels that correlated with enhanced expression of activated EGFR and TWIST1 in a cohort of human prostate cancer specimens and additional datasets. Our findings support a model in which nuclear EGFR acts as a transcriptional repressor to constrain the tumor-suppressive role of miR-1 and sustain oncogenic activation of TWIST1, thereby leading to accelerated bone metastasis. Cancer Res; 75(15); 3077–86. ©2015 AACR.