Abstract
Human trophoblast cell surface antigen 2 (Trop-2) is a 40-kDa transmembrane glycoprotein that was first identified as a marker of human trophoblast cells. Trop-2 acts on cell proliferation, adhesion, and migration by activating a number of intracellular signalling pathways. Elevated Trop-2 expression has been demonstrated in several types of cancer and correlated with aggressiveness and poor prognosis. Since no data are available on Trop-2 in bladder cancer (BC), the purpose of the study was to determine its levels in tissue specimens from normal individuals and patients with BC at different stages. Moreover, since according to recent evidence Trop-2 is a miR-125b target, miR-125b expression was also assessed in tissue specimens. Finally, the effect of the Trop-2/miR-125b axis on the proliferation and migration of BC cells was evaluated in vitro.The Trop-2/miR-125b axis was seen to be differentially expressed in normal urothelium, non-invasive BC and invasive BC tissue. Significant miR-125b down-regulation was associated with a significant increase in Trop-2 protein levels in BC tissue and correlated with disease severity. In vitro analysis confirmed the role of miR-125b in down-modulation of Trop-2 protein levels and showed that Trop-2/miR-125b axis affects cellular proliferation in bladder tissue.In conclusion, our findings highlight a role for the Trop-2/miR-125b axis in BC progression and suggest Trop-2 and miR-125b as diagnostic/prognostic marker candidates as well as druggable targets for innovative therapeutic approaches.
Highlights
RESULTSAs the second most common genitourinary malignancy, bladder cancer (BC) is a significant public health problem worldwide, with urothelial cell carcinoma (UC) accounting for nearly 90% of all primary BCs [1] and muscle-invasive BC (MIBC) for approximately 25 % of high mortality BCs
This study shows for the first time that trophoblast cell surface antigen 2 (Trop-2) expression increases with increasing BC severity, showing a weak expression in normal bladder and a strong expression in invasive BC
We demonstrated that Trop-2 is a miR-125b target in both cell lines, which suggests that miR-125b plays a role in modulating Trop-2 protein expression in both normal bladder and cancer cell lines
Summary
As the second most common genitourinary malignancy, bladder cancer (BC) is a significant public health problem worldwide, with urothelial cell carcinoma (UC) accounting for nearly 90% of all primary BCs [1] and muscle-invasive BC (MIBC) for approximately 25 % of high mortality BCs. Clinical presentation is heterogeneous, and despite the availability of accurate histology-based classification systems it is difficult to predict prognosis and response to therapy. BC diagnosis is based on a combination of urine cytology, cystoscopy, and bladder biopsy. Urine cytology is poorly sensitive to early, low-grade lesions, whereas cystoscopy is invasive, expensive, and only detects large lesions [2, 3]. A role as a marker of human prostate cancer stem cells has been proposed for it, in cancer initiation and progression [10,11,12]. Trop-2 is being tested as a druggable target, since an anti-Trop-2 antibody-drug conjugate is being used to treat patients with several metastatic neoplasms, including triple-negative breast cancer and non-small-cell and smallcell lung cancer [20]
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