Downregulation of DOCK1 sensitizes bladder cancer cells to cisplatin through preventing epithelial-mesenchymal transition.

During the past several decades, resistance to single or multiple anticancer agents has posed a great challenge in cancer therapy. Dedicator of cytokinesis 1 (DOCK1), the first identified member in DOCK family, plays diverse roles in cellular processes, including tumorigenesis. In this study, we explored the biological role of DOCK1 in the chemotherapeutic resistance in bladder cancer and its underlying mechanism. Our results showed that the bladder cancer cell lines UM-UC-3 and J82 with higher DOCK1 are more resistant to cisplatin, whereas B87 cells with the lowest expression of DOCK1 exhibited the highest sensitivity to cisplatin. Down-regulation of DOCK1 with small interfering RNA (siRNA) increased the cisplatin sensitivity in bladder cancer cells. Moreover, treatment with cisplatin induced epithelial-mesenchymal transition (EMT), while transfection with Twist siRNA restored the chemosensitivity to cisplatin. In addition, we found that downregulation of DOCK1 reversed EMT program in bladder cancer cells. However, cotransfection with DOCK1 siRNA could not further enhance the cisplatin sensitivity and cellular phenotypic changes in tumor cells. Taken together, these results demonstrate that downregulation of DOCK1 could increase the chemosensitivity in bladder cancer cells via preventing cisplatin-induced EMT, suggesting that DOCK1 may serve as a potential therapeutic target in bladder cancer.

Deletion of Smad3 improves cardiac allograft rejection in mice.

T cells play a critical role in acute allograft rejection. TGF-ß/Smad3 signaling is a key pathway in regulating T cell development. We report here that Smad3 is a key transcriptional factor of TGF-ß signaling that differentially regulates T cell immune responses in a mouse model of cardiac allograft rejection in which donor hearts from BALB/c mice were transplanted into Smad3 knockout (KO) and wild type (WT) mice. Results showed that the cardiac allograft survival was prolonged in Smad3 KO recipients. This allograft protection was associated with a significant inhibition of proinflammatory cytokines (IL-1ß, TNF-α, and MCP-1) and infiltration of neutrophils, CD3+ T cells, and F4/80+ macrophages. Importantly, deletion of Smad3 markedly suppressed T-bet and IFN-γ while enhancing GATA3 and IL-4 expression, resulting in a shift from the Th1 to Th2 immune responses. Furthermore, mice lacking Smad3 were also protected from the Th17-mediated cardiac injury, although the regulatory T cell (Treg) response was also suppressed. In conclusion, Smad3 is an immune regulator in T cell-mediated cardiac allograft rejection. Loss of Smad3 results in a shift from Th1 to Th2 but suppressing Th17 immune responses. Thus, modulation of TGF-ß/Smad3 signaling may be a novel therapy for acute allograft rejection.

[Effect of donor bone marrow transfusion on renal allograft function in kidney transplant patients].

OBJECTIVE: To investigate the effect of donor bone marrow transfusion on kidney function in renal allograft recipients. METHODS: From May 1999 through May 2004, 74 cadaver renal transplant patients received postoperative donor bone marrow transfusion (DBMT group), the clinical outcomes were compared with 74 non-infused renal transplant recipients (control group). Both groups received the renal allograft from the same donor and were given equivalent immunosuppressant. The immunosuppressive regimen included tacrolimus/CiclosporinA, mycophenolate mofetil, and prednisolone maintenance. Patients were followed up for 24 to 108 months (mean 69.5 months). RESULT: The serum creatinine concentrations of DBMT group at 1,2 and 3 y after operation were (105 + or - 23.9)micromol/L,(107.5 + or - 32.4) micromol/L and (115 + or - 26.6)micromol/L; those of control group were (114.7 + or - 28)micromol/L,(116.5 + or - 27.6)micromol/L and (125 + or - 32.6)micromol/L,respectively. Glomerular filtration rate (GFR) of DBMT group at 1,2 and 3 y after operation were (70.2 + or - 24.4)ml/min, (74.3 + or - 24.1)ml/min and (73.5 + or - 22.4)ml/min; those of control group were (62.4 + or - 15.8)ml/min, (63.9 + or - 18.7)ml/min and (61.9 + or - 20.3)ml/min. After 5 year-follow-up,the prevalence of proteinuria in DBMT group was 50% (37/74),that was 77% (57/74) in control group (P<0.01). Only 3/74 DBMT recipients had biopsy-proven chronic rejection, whereas 12/74 showed chronic rejection in the controls (P<0.05). CONCLUSION: In kidney transplant recipients DBMC infusions may improve the long-term graft survival.