Department of Biochemistry, AIIMS, New Delhi, India.
Department of Urology, AIIMS, New Delhi, India.
Mol Cell Biochem. 2018 Sep;446(1-2):105-114. doi: 10.1007/s11010-018-3278-z. Epub 2018 Jan 24.
Genetic abnormalities and epigenetic alterations both play vital role in initiation as well as progression of cancer. Whereas genetic mutations cannot be reversed, epigenetic alterations such as DNA methylation can be reversed by the application of DNA methyltransferase inhibitor decitabine. Epigenetic silencing of RASSF1A and involvement of hippo pathway both have been shown to involve in chemo-resistance. Purpose of this study was to observe the effect of combination treatment of decitabine with cisplatin or doxorubicin on bladder cancer cells involving hippo pathway through RASSF1A. Bladder cancer cells (HT1376 & T24) were treated with decitabine and its effect on RASSF1A expression, hippo pathway molecules (MST & YAP), and its downstream targets (CTGF, CYR61 & CTGF) was observed. Effect of decitabine pretreatment on sensitivity of bladder cancer cells towards chemotherapeutic drugs was also studied. Decitabine treatment leads to restoration of RASSF1A, activation of hippo pathway followed by decreased expression of its oncogenic downstream targets (CTGF & CYR61). Further pretreatment of decitabine enhanced cytotoxicity of cisplatin and doxorubicin to bladder cancer cells.
遗传异常和表观遗传改变在癌症的发生和进展中都起着至关重要的作用。虽然遗传突变无法逆转，但表观遗传改变，如 DNA 甲基化，可以通过应用 DNA 甲基转移酶抑制剂地西他滨来逆转。RASSF1A 的表观遗传沉默和 hippo 通路的参与都被证明与化疗耐药有关。本研究的目的是观察地西他滨联合顺铂或阿霉素治疗通过 RASSF1A 涉及 hippo 通路的膀胱癌细胞的效果。用地西他滨处理膀胱癌细胞（HT1376 和 T24），观察其对 RASSF1A 表达、 hippo 通路分子（MST 和 YAP）及其下游靶标（CTGF、CYR61 和 CTGF）的影响。还研究了地西他滨预处理对膀胱癌细胞对化疗药物敏感性的影响。地西他滨治疗导致 RASSF1A 的恢复， hippo 通路的激活，随后其致癌下游靶标的表达减少（CTGF 和 CYR61）。地西他滨的预处理进一步增强了顺铂和阿霉素对膀胱癌细胞的细胞毒性。
