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

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.

Thy-1-Integrin Interactions in cis and Trans Mediate Distinctive Signaling

“…The binding of ECM1 to αXβ2 integrin affects the ability of this integrin to bind to Thy-1, thus altering Thy-1 function. Additionally, overexpression of ECM1 or its silencing correlates with Thy-1 expression levels ( Yin, Wang et al, 2021 ). Here, Thy-1 could account, in part, for the cancer cell stemness induced by the ECM1-αXβ2 integrin association because, on the one hand, there will be greater Thy-1 expression and, on the other, the Thy-1 integrin partner will be sequestered by the ECM1 binding; however, this is a possibility that remains to be investigated.…”

MicroRNA and Alternative mRNA Splicing Events in Cancer Drug Response/Resistance: Potent Therapeutic Targets

“…The non-secretory isoform which inhibits the phosphorylation of myosin by binding to it, blocks cytoskeletal-induced tumorigenesis. ECM1b increases the expression of hnRNPLL splicing factor, this leads to increased splicing of ECM1 thereby generating multiple isoforms such as ECM1a [ 113 ].…”

Glia Maturation Factor-γ (GMFG) Promotes Ovarian Tumorigenesis and Chemoresistance via Activation of the FAK Signaling-Associated Focal Adhesion Dynamics

“…Because ECM1 is a secreted protein closely associated with multiple malignancies [38][39][40][41]. We previously investigated the tumorigenic function of ECM1 in ovarian cancer [5], in which we rst silenced ECM1 in wild-type ovarian cancer HEY A8 cell line (HEY A8-ECM1i, subsequently abbreviated "HEY A8-Ei", where "i" refers to interfering RNA as in other labels), and then we overexpressed the subtype ECM1a in HEY A8-Ei cells (HEY A8-Ei-ECM1a, subsequently abbreviated "HEY A8-Ei-A") (Fig. 1A).…”

“…In our recent studies, we rst found that Glia maturation factor-γ (GMFG) can be a prognostic factor for several cancer types based on analysis of The Cancer Genome Atlas (TCGA) data [4]. We further revealed that, by RNA-seq analysis, GMFG was signi cantly downregulated in Extracellular matrix protein 1 (ECM1) knockdown ovarian cancer cells, but was signi cantly upregulated in ECM1a-overexpression cells, whereas ECM1a enhances the progression of ovarian cancer through activation of the Focal adhesion kinase (FAK) signaling [5]. Therefore, GMFG may contribute to ovarian tumorigenesis.…”