Gondkar, K. | bioRxiv Science

bioRxiv2018

E74 like ETS transcription factor 3 (ELF3) is a negative regulator of epithelial-mesenchymal transition in bladder carcinoma

Transcription factors are known to be commonly deregulated in various cancers. The E74 like ETS transcription factor 3 (ELF3) expression is restricted to epithelial tissue. In the present study, we evaluated the role of ELF3 in the pathogenesis of bladder carcinoma (BCa) using cell line model. The cell lines with low expression of ELF3 showed increased expression of mesenchymal markers and decreased expression of epithelial markers. Immunofluorescence and immunohistochemical analysis of ELF3 showed selective expression in low-grade BCa cell lines and tumor tissues, respectively. We demonstrated that overexpression of ELF3 in UMUC3, a mesenchymal BCa cell line resulted in reduced invasion and decreased expression of mesenchymal markers. Furthermore, using publicly available data, we found that low expression of ELF3 was associated with increased risk and poor overall survival rate in BCa. In conclusion, ELF3-modulated reversal of EMT might be a useful strategy in the treatment of bladder cancer.

cancer biology↗

bioRxiv2018

Galectin-1 promotes the invasion of bladder cancer urothelia through their matrix milieu

The progression of carcinoma of the urinary bladder involves migration of cancer epithelia through their surrounding tissue matrix microenvironment. This was experimentally confirmed when a gender- and grade-diverse set of bladder cancer cell lines were cultured in pathomimetic three-dimensional laminin-rich environments. The high-grade cells, particularly female, formed multicellular invasive morphologies in 3D. In comparison, low- and intermediate-grade counterparts showed growth-restricted phenotypes. A proteomic approach combining mass spectrometry and bioinformatics analysis identified the estrogen-driven lactose-binding lectin Galectin-1 (GAL-1) as a putative candidate that could drive this invasion. Expression of LGALS1, the gene encoding GAL-1 showed an association with tumor grade progression in bladder cell lines. Immunohisto- and cyto-chemical experiments suggested greater extracellular levels of GAL-1 in 3D cultures of high-grade bladder cells and cancer tissues. High levels of GAL-1 associated with increased proliferation- and adhesion- of bladder cancer cells when grown on laminin-rich matrices. Pharmacological inhibition and Gal-1 knockdown in high-grade female cells decreased their adhesion to, and viability on, laminin-rich substrata. Higher GAL-1 also correlated with reduced E-cadherin and increased N-cadherin levels in consonance with a mesenchymal-like phenotype that we observed in 3D culture. The inhibition of GAL-1 reversed the stellate invasive phenotype to a more growth-restricted one in high-grade cells embedded within both basement-membrane-like and stromal collagenous matrix scaffolds. Finally, inhibition of GAL-1 specifically altered cell surface sialic acids, suggesting the mechanism by which the levels of GAL-1 may underlie the aggression and poor prognosis of invasive bladder cancer, especially in women.

cancer biology↗