Abstract
Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXβ2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. The ATP binding cassette subfamily G member 1 (ABCG1) transduces the ECM1a-integrin αXβ2 interactive signaling to facilitate the phosphorylation of AKT/FAK/Rho/cytoskeletal molecules and to confer cancer cell cisplatin resistance through up-regulation of the CD326-mediated cell stemness. On the contrary, the non-secretory ECM1b isoform binds myosin and blocks its phosphorylation, impairing cytoskeleton-mediated signaling and tumorigenesis. Moreover, ECM1a induces the expression of the heterogeneous nuclear ribonucleoprotein L like (hnRNPLL) protein to favor the alternative mRNA splicing generating ECM1a. ECM1a, αXβ2, ABCG1 and hnRNPLL higher expression associates with poor survival, while ECM1b higher expression associates with good survival. These results highlight ECM1a, integrin αXβ2, hnRNPLL and ABCG1 as potential targets for treating cancers associated with ECM1-activated signaling.
Highlights
Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified
We show that ECM1a activates AKT/ FAK/Paxillin/Rac/cytoskeletal signaling and upregulates CD326 expression to control tumorigenesis and cisplatin resistance through Gly-Pro-Arg (GPR) motif-mediated interactions with integrin αXβ2, heterogeneous nuclear ribonucleoprotein L-like-mediated alternative mRNA splicing, and ATP binding cassette subfamily G member 1 (ABCG1)-induced upregulation of cancer cell stemness
We found that ECM1a mRNA was strongly expressed in the Hey and HeyA8 cell lines but weakly expressed in the other cancer cell lines and an immortalized fallopian tube epithelia (FTE) cell line, while it was undetectable in human ovarian surface epithelial (HOSE) cells
Summary
Extracellular matrix protein-1 (ECM1) promotes tumorigenesis in multiple organs but the mechanisms associated to ECM1 isoform subtypes have yet to be clarified. We report in this study that the secretory ECM1a isoform induces tumorigenesis through the GPR motif binding to integrin αXβ2 and the activation of AKT/FAK/Rho/cytoskeleton signaling. While ECM1a has been identified to be oncogenic in multiple cancers, ECM1b was recently reported to localized to the endoplasmic reticulum and to function as a tumor suppressor in esophageal squamous cell carcinoma (ESCC) through regulation of MTORC2/MYC/ MTORC1 signaling[9]. We show that ECM1a activates AKT/ FAK/Paxillin/Rac/cytoskeletal signaling and upregulates CD326 expression to control tumorigenesis and cisplatin resistance through Gly-Pro-Arg (GPR) motif-mediated interactions with integrin αXβ2, heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL)-mediated alternative mRNA splicing, and ATP binding cassette subfamily G member 1 (ABCG1)-induced upregulation of cancer cell stemness
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
