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

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.

4D-quantitative proteomics signature of asthenozoospermia and identification of extracellular matrix protein 1 as a novel biomarker for sperm motility

4D mass spectrometry quantifies 1430 differential abundant proteins in asthenozoospermic sperm samples. Further, integrative analysis identifies ECM1 as a novel biomarker related to sperm motility.

Immunohistochemical Expression of Extracellular Matrix Protein-1 in Neoplastic Thyroid Lesions

Background: Upregulated Extracellular matrix protein 1 (ECM 1) expression has been observed in several malignancies including breast, thyroid carcinoma, cutaneous melanoma and gastric carcinoma. ECM 1 expression has been evaluated in various epithelial malignancies using real time – reverse transcriptase polymerase chain reaction (RT-PCR). The purpose of current study is to evaluate the immunohistochemical expression of ECM 1 in various neoplastic lesions of thyroid. Methods: The study included 81 neoplastic thyroid tissue specimens (21 benign and 60 malignant lesions) received over a period of 5 years (2012-2017). Hematoxylin and Eosin stained sections of the tissue specimens were carefully examined under light microscope in order to establish the histopathological diagnosis. The immunohistochemical marker ECM 1 was applied on appropriate sections and the slides were evaluated accordingly. Result: The expression of ECM 1 was nil (grade 0, 47.62% cases) or weak (1+, 52.38% cases) in benign lesions while majority of malignant lesions (78.33%) showed strong homogenous and crisp staining (3+). The difference in the expression of ECM 1 between benign and malignant lesions was found to be statistically significant (p < 0.001). ECM 1 has a diagnostic accuracy of 0.82 and sensitivity of 100% in differentiating benign from malignant lesions. Conclusion: ECM 1 is uniformly upregulated in all malignant thyroid neoplasms irrespective of the histological type of malignancy. Immunohistochemical expression of ECM 1 shows comparable results to RT-PCR. ECM 1 immunohistochemistry can thus serve as an important standalone marker of malignant thyroid tissue.

miR-9-Mediated Inhibition of EFEMP1 Contributes to the Acquisition of Pro-Tumoral Properties in Normal Fibroblasts

Tumor growth and invasion occurs through a dynamic interaction between cancer and stromal cells, which support an aggressive niche. MicroRNAs are thought to act as tumor messengers to “corrupt” stromal cells. We previously demonstrated that miR-9, a known metastamiR, is released by triple negative breast cancer (TNBC) cells to enhance the transition of normal fibroblasts (NFs) into cancer-associated fibroblast (CAF)-like cells. EGF containing fibulin extracellular matrix protein 1 (EFEMP1), which encodes for the ECM glycoprotein fibulin-3, emerged as a miR-9 putative target upon miRNA’s exogenous upmodulation in NFs. Here we explored the impact of EFEMP1 downmodulation on fibroblast’s acquisition of CAF-like features, and how this phenotype influences neoplastic cells to gain chemoresistance. Indeed, upon miR-9 overexpression in NFs, EFEMP1 resulted downmodulated, both at RNA and protein levels. The luciferase reporter assay showed that miR-9 directly targets EFEMP1 and its silencing recapitulates miR-9-induced pro-tumoral phenotype in fibroblasts. In particular, EFEMP1 siRNA-transfected (si-EFEMP1) fibroblasts have an increased ability to migrate and invade. Moreover, TNBC cells conditioned with the supernatant of NFs transfected with miR-9 or si-EFEMP1 became more resistant to cisplatin. Overall, our results demonstrate that miR-9/EFEMP1 axis is crucial for the conversion of NFs to CAF-like cells under TNBC signaling.