Conditional Ablation Of TGF-? Signaling Inhibits Tumor Progression And Invasion In An Induced Mouse Bladder Cancer Model

Bladder cancer(BCa)is the most common malignancy in urinary tract,it is the 6th common and the 9th cause of deaths of all male malignancies worldwide.In 2015,32,900 people died of BCa and the estimated new cases were 80,500 in China.Pathological studies indicate that BCa comprises two major groups: superficial carcinoma usually recurs,but rarely progresses,while muscle-invasive bladder cancer is more aggressive with worse prognosis.Despite the progress we have made in recent years,especially the insights of genome-wide landscape in BCa,our understanding of its tumorigenesis and progression is still limited.Transforming growth factor-?(TGF-?)family encodes pro-fibrotic growth factors which are involved in many physiological processes such as wound healing and tissue fibrosis by inducing fibroblast differentiation to myofibroblasts,it has been proved to play pivotal roles in cell migration,survival,proliferation,and differentiation.The signaling is initiated with ligand-induced oligomerization of TGF-? receptor1/2 complex(serine/threonine kinase)and phosphorylation of the cytoplasmic Smad2 and Smad3,which results in their translocation to the nucleus along with the common signaling transducer Smad4.Activated Smads will promote the transcription of multiple downstream targets by coordinating with other transcriptional factors such like AP-1,RUNX,et al.TGF-? signaling is well known for its contribution to cancer development by promoting invasiveness and metastasis and inducing the epithelial-to-mesenchymal transition(EMT).However,the opinions of whether TGF-? signaling could activate or suppress the tumor growth is still controversial,possibly due to the cancer context and research model used.As for the BCa,TGF-? signaling is indicated to participate in its tumorigenesis and promote EMT.However,there is still no in vivo data characterizing its role in the BCa.In the current study,we used the mouse model of KRT5-Cre driven conditional knockout of TGF-? 2 and N-butyl-N-4-hydroxybutyl Nitrosamine(BBN)induced BCa to demonstrate that ablation of TGF-? signaling could inhibit the progression,invasion and cancer stem cell population of BCa as well as the EMT.Treatment of TGF-? receptor1 specific inhibitor,LY364947,after the tumor transformation,also inhibited BCa tumor growth.To our knowledge,these findings provided the first in vivo evidence for the crucial role of TGF-? signaling in bladder cancer progression and unveiled the possible mechanism of TGF-? mediated tumor growth and invasion.