Extracellular matrix protein-1 secretory isoform promotes ovarian cancer through increasing alternative mRNA splicing and stemness

Huijing Yin, Jingshu Wang, Hui Li, Yinjue Yu, Xiaoling Wang, Lili Lu, Cuiting Lv, Bin Chang, Wei Jin, Wenwen Guo, Chunxia Ren () and Gong Yang ()
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Huijing Yin: Fudan University Shanghai Cancer Center
Jingshu Wang: Fudan University
Hui Li: Fudan University
Yinjue Yu: Fudan University
Xiaoling Wang: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine
Lili Lu: Fudan University Shanghai Cancer Center
Cuiting Lv: Fudan University
Bin Chang: Fudan University
Wei Jin: The People’s Hospital of Guangxi Zhuang Autonomous Region
Wenwen Guo: Fudan University
Chunxia Ren: Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine
Gong Yang: Fudan University Shanghai Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24315-1

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