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MUC1‐C Induces the LIN28B→LET‐7→HMGA2 Axis to Regulate Self‐renewal in NSCLC
Author(s) -
Ahmad Rehan,
Alam Maroof,
Rajabi Hasan,
Kufe Donald
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.728.1
Subject(s) - hmga2 , gene silencing , competing endogenous rna , cancer research , biology , muc1 , signal transduction , small hairpin rna , microbiology and biotechnology , microrna , chemistry , rna , cancer , genetics , gene , long non coding rna
Objective The LIN28B→let‐7 pathway contributes to regulation of the epithelial‐mesenchymal transition (EMT) and stem cell self‐renewal. The oncogenic MUC1‐C transmembrane protein is aberrantly overexpressed in lung and other human carcinomas; however, there is no known association between MUC1‐C and the LIN28B→let‐7 pathway.
Methods: Stable silencing of MUC1‐C using MUC1 shRNA. Targeting MUC1‐C function with a dominant‐negative mutant or a peptide inhibitor was used to study the link between MUC1 expression and LIN28B→let‐7 signaling.
Results: In non‐small cell lung cancer (NSCLC), silencing MUC1‐C downregulates the RNA binding protein LIN28B and coordinately increases the miRNA let‐7. Targeting MUC1‐C function with a dominant‐negative mutant or a peptide inhibitor provides confirming evidence that MUC1‐C induces LIN28B→let‐7 signaling. MUC1‐C promotes NF‐κB p65 chromatin occupancy of the LIN28B first intron and activates LIN28Btranscription which is associated with suppression of let‐7. Consistent with let‐7‐mediated inhibition of HMGA2 transcripts, targeting of MUC1‐C also decreases HMGA2 expression. HMGA2 has been linked to stemness, and functions as a competing endogenous RNA (ceRNA) of let‐7‐mediated regulation of the TGFβ co‐receptor TGFBR3. Accordingly, targeting MUC1‐C suppresses HMGA2 mRNA and protein which is associated with decreases in TGFBR3, reversal of the EMT phenotype and inhibition of self‐renewal capacity.
Conclusion These findings support a model in which MUC1‐C activates the ⇑LIN28B→⇓let‐7→⇑HMGA2 axis in NSCLC and thereby promotes EMT traits and stemness.