Calcineurin is a serine-threonine protein phosphatase that plays a pivotal role in a wide series of crucial physiologic processes such as T-cell activation, apoptosis, skeletal myocyte differentiation, and cardiac hypertrophy. A new family of regulators of calcineurin (RCANs) has been shown to modulate calcineurin activity through direct binding of it in vivo. Calcineurindependent signals are transduced to the nucleus by nuclear factor of activated T-cells (NFAT) transcription factors that undergo nuclear translocation upon dephosphorylation and promote transcriptional activation of target genes. The recent researches have revealed that RCAN1 modulating catalytic activity of calcineurin can function as an endogenous backfeed inhibitor during the calcineurin-NFAT signalling pathway. RCANs have now been implicated in several pathological conditions including Alzheimer’s disease, down syndrome and cardiac hypertrophy. In addition, the RCAN family is a rational, functional name for RCAN gene and it is proposed in 2007. It is, therefore, necessary to review the RCAN gene, RCANs and the roles of RCANs in a wide variety of diseases especially including Alzheimer’s disease. It is suggested that regulation of RCAN expression may be a new target on neurodegeneration disease.

Background::Bladder cancer, characterized by a high potential of tumor recurrence, has high lifelong monitoring and treatment costs. To date, tumor cells with intrinsic softness have been identified to function as cancer stem cells in several cancer types. Nonetheless, the existence of soft tumor cells in bladder tumors remains elusive. Thus, our study aimed to develop a microbarrier microfluidic chip to efficiently isolate deformable tumor cells from distinct types of bladder cancer cells.Methods::The stiffness of bladder cancer cells was determined by atomic force microscopy (AFM). The modified microfluidic chip was utilized to separate soft cells, and the 3D Matrigel culture system was to maintain the softness of tumor cells. Expression patterns of integrin β8 (ITGB8), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) were determined by Western blotting. Double immunostaining was conducted to examine the interaction between F-actin and tripartite motif containing 59 (TRIM59). The stem-cell-like characteristics of soft cells were explored by colony formation assay and in vivo studies upon xenografted tumor models. Results::Using our newly designed microfluidic approach, we identified a small fraction of soft tumor cells in bladder cancer cells. More importantly, the existence of soft tumor cells was confirmed in clinical human bladder cancer specimens, in which the number of soft tumor cells was associated with tumor relapse. Furthermore, we demonstrated that the biomechanical stimuli arising from 3D Matrigel activated the F-actin/ITGB8/TRIM59/AKT/mTOR/glycolysis pathways to enhance the softness and tumorigenic capacity of tumor cells. Simultaneously, we detected a remarkable up-regulation in ITGB8, TRIM59, and phospho-AKT in clinical bladder recurrent tumors compared with their non-recurrent counterparts.Conclusions::The ITGB8/TRIM59/AKT/mTOR/glycolysis axis plays a crucial role in modulating tumor softness and stemness. Meanwhile, the soft tumor cells become more sensitive to chemotherapy after stiffening, that offers new insights for hampering tumor progression and recurrence.