TM4SF1 regulates apoptosis, cell cycle and ROS metabolism via the PPARγ-SIRT1 feedback loop in human bladder cancer cells.

Transmembrane-4-L-Six-Family-1 (TM4SF1) is a member of the L6 family and functions as a signal transducer to regulate cell development, growth and motility. Here we show that TM4SF1 is strongly upregulated in human muscle invasive bladder cancer (MIBC) tissues, corroborating the bioinformatical results of transcriptome analysis. Moreover, tissue microarray (TMA) shows significant correlations (p < 0.05) between high expression of TM4SF1 and T stage, TNM stage, lymph node metastasis status and survival rate of MIBC patients, indicating a positive association between TM4SF1 expression and poorer prognosis. Furthermore, in vitro and in vivo studies indicate that the proliferation of human bladder cancer (BCa) cells is significantly suppressed by knockdown of TM4SF1 (p < 0.05). Functionally, the reduction of TM4SF1 could induce cell cycle arrest and apoptosis possibly via the upregulation of reactive oxygen species (ROS) in BCa cells. In addition, these observations could be recovered by treatment with GW9662 (antagonist of PPARγ) and resveratrol (activator of SIRT1). Taken together, our results suggest that high expression of TM4SF1 predicts poor prognosis of MIBC.