Thrombospondin‐4 promotes bladder cancer cell migration and invasion via MMP2 production

Abstract

Bladder cancer (BC) is the second most common urological tumour in Western countries. Approximately, 80% of patients with BC will present with non‐muscle invasive bladder cancer (NMIBC), whereas a quarter will have muscle invasive disease (MIBC) at the time of BC diagnosis. However, patients with NMIBC are at risk of BC recurrence or progression into MIBC, and an MIBC prognosis is determined by the presence of progression and metastasis. Matrix metalloproteinase 2 (MMP2), a type of matrix metalloproteinase (MMP), plays a major role in tumour invasion and is well‐characterized in BC prognosis. In BC, the mechanisms regulating MMP2 expression, and, in turn, promote cancer invasion, have hardly been explored. Thrombospondin‐4 (THBS4/TSP4) is a matricellular glycoprotein that regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion and extracellular matrix modelling. Based on the results of a meta‐analysis in the Gene Expression Profiling Interactive Analysis 2 database, we observed that TSP4 expression levels were consistent with overall survival (OS) rate and BC progression, with the highest expression levels observed in the advanced stages of BC and associated with poor OS rate. In our pilot experiments, incubation with recombinant TSP4 promoted the migration and invasion in BC cells. Furthermore, MMP2 expression levels increased after recombinant TSP4 incubation. TSP4‐induced‐MMP2 expression and cell motility were regulated via the AKT signalling pathway. Our findings facilitate further investigation into TSP4 silencing‐based therapeutic strategies for BC.

Thrombospondin-2 acts as a bridge between tumor extracellular matrix and immune infiltration in pancreatic and stomach adenocarcinomas: an integrative pan-cancer analysis

“…Furthermore, MMPs not only degrade ECM but also play crucial roles in mediating tumor angiogenesis, metastasis, and invasion. Among the MMP family, MMP-2 promotes tumor growth, tissue invasion, angiogenesis, and metastasis [ 44 – 46 ], and its overexpression might be associated with tumor progression and a poor prognosis for ovarian epithelial carcinoma, oral cavity cancers, and non-small cell lung cancer patients [ 47 – 50 ]. Therefore, MMP-2 is considered a potential tumorigenesis biomarker, a key effector of ECM remodeling, and a potential target for antitumor therapy.…”

Thrombospondin-4 Is a Soluble Dermal Inflammatory Signal That Selectively Promotes Fibroblast Migration and Keratinocyte Proliferation for Skin Regeneration and Wound Healing

“…Interestingly, stimulation of keratinocytes with THBS4 yielded upregulation of their proliferation that well correlated with the hyperproliferative state of keratinocytes in psoriatic lesions that dwell in the vicinity of ECM containing abnormally high levels of THBS4. Nevertheless, THBS4 has been shown to specifically activate the migration of various cell types before, including other mesoderm-derived cells such as smooth muscle cells of different origin ( Frolova et al, 2010 ; Girard et al, 2014 ; Lv X. et al, 2016 ; Su et al, 2017 ; Andres Sastre et al, 2021 ; Chou et al, 2021 ). Interestingly, our results on skin cell-type-selective responses to THBS4 stimulation are supported by previous studies on other tissues and cell types.…”

“…Studies with THBS4 –/– mice have shown that THBS4 does not affect neuronal cell proliferation but in contrast, promotes their migration ( Girard et al, 2014 ). In two recent studies THBS4 promoted cancer progression by enhancing tumor cell migration and invasion ( Su et al, 2017 ; Chou et al, 2021 ).…”

“…TGF-β signaling targeted to THBS4 has been shown to be mediated by Smad3 ( Muppala et al, 2017 ) and p38-MAPK, which proposedly increase THBS4 expression via a positive feedback loop ( Qian et al, 2018 ). Recent studies with bladder cancer cells have shown that THBS4 is able to promote cancer progression by enhancing cell proliferation, migration and invasion by activating the AKT signaling pathway ( Chou et al, 2021 ; Shi et al, 2021 ). THBS4 was also shown to bind integrin α2 to induce phosphorylation of heat shock factor 1, which increases TGF-β1 expression and promotes its paracrine signaling cascade ( Shi et al, 2021 ).…”

Expression and prognostic value of carbonic anhydrase IX (CA-IX) in bladder urothelial carcinoma

“…Pathological staging and grading of postoperative specimens are the main key indicators for predicting prognosis, but this traditional method has certain limitations. Finding quick and convenient tumor markers is a hot point in clinical work, which can guide doctors to intervene the patients with poor prognosis in advance and reduce the recurrence and progression of tumor [ 8 ].…”