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Title: Mycobacterium bovis, BCG modulation of gene expression in bladder cancer
Keywords: Bladder cancer, BCG, ROS, GSTT2, MptpA
Issue Date: 27-Feb-2010
Citation: JUWITA NORASMARA BTE RAHMAT (2010-02-27). Mycobacterium bovis, BCG modulation of gene expression in bladder cancer. ScholarBank@NUS Repository.
Abstract: Adjuvant therapy with Mycobacterium bovis bacillus Calmette-Guerin (BCG) is the gold standard for treatment of superficial bladder cancer. Immune cells infiltrate the bladder to clear the bacteria and the immune reaction that ensues resulted in indirect tumour eradication. However, not all patients respond well and the side effects involved can result in reduced compliance to therapy. More efforts are needed to investigate the exact BCG mechanisms to improve outcome. In this study, we compared live and lyo BCG responses in vivo in mice and in human bladder cancer cell lines. In mice given weekly intravesical instillations, live BCG induced a predominantly chemokine gene expression response in the bladder compared to the cytokine response observed in lyo BCG treatment. However, they both have similar potential to recruit immune cells to the bladder. Bladder cancer cell lines that express integrin alpha5 well are able to internalize BCG and this process is cytotoxic to cells. Live BCG increased ROS while lyo BCG decreased ROS in cells that internalize them. Lyo BCG treatment induced expression of GSTT2, IL1beta and TNFalpha in MGH cells better than live BCG and it could be due to their different ROS regulatory effect. We also demonstrated that there are soluble BCG factors secreted that can increase MGH cellular ROS levels and reduce basal GSTT2 and TNFalpha gene expression. When GSTT2 expression was silenced in MGH cells, basal NO levels increased. After lyo BCG treatment, we observed further ROS decrease, NO reduction and significant TNFalpha release in GSTT2 silenced cells. We explored the role of a mycobacterium phosphatase (MptpA) in regulating EGFR signaling and found that its presence in combination with lyo or live BCG increased p38 phosphorylation but itself has no ROS or immune regulatory role. In conclusion, GSTT2 silencing may enhance BCG therapy as it can further decrease ROS level, which was previously associated with BCG cytotoxicity, and reduce NO production. Also, removing the soluble fraction from the lyo BCG mixture before instillation may improve therapy outcome.
Appears in Collections:Ph.D Theses (Open)

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