Small interfering RNAs induce macrophage migration inhibitory factor production and proliferation in breast cancer cells via a double-stranded RNA-dependent protein kinase-dependent mechanism.

نویسندگان

  • Michelle E Armstrong
  • Michael Gantier
  • Lili Li
  • Wen Y Chung
  • Amanda McCann
  • John A Baugh
  • Seamas C Donnelly
چکیده

Small interfering RNAs (siRNAs) represent a novel tool to induce gene silencing in mammalian cells and clinical trials are currently ongoing to assess the therapeutic efficacy of siRNAs in various human diseases, including age-related macular degeneration and respiratory syncytial virus infection. However, previously reported off-target, nonspecific effects of siRNAs, including activation of type I IFNs and proinflammatory cytokines, remain an outstanding concern regarding use of these agents in vivo. Macrophage-migration inhibitory factor (MIF) is a pleiotropic cytokine with well-described roles in cell proliferation, tumorigenesis, and angiogenesis and represents a target gene for siRNA-based therapy in the treatment of breast cancer. However, in this study we describe an increase in MIF production from mammary adenocarcinoma (MCF-7) cells following transfection with MIF siRNA and various control siRNAs. This effect was shown to be dose-dependent and was attenuated in the presence of a double-stranded RNA-dependent protein kinase inhibitor, 2-aminopurine. Furthermore, treatment of MCF-7 cells with poly(I:C) also stimulated a PKR-dependent increase in MIF production from MCF-7 cells. The biological consequence of the siRNA-induced increase in MIF production from MCF-7 cells was a PKR-dependent increase in proliferation of breast cancer cells. Furthermore, in cDNAs prepared from a primary human breast cancer cohort, we demonstrated a significant correlation (Spearman rank correlation coefficient, r = 0.50, p < 0.0001, n = 63) between PKR- and MIF-mRNA expression. In conclusion, this study highlights the potential biological consequences of off-target, nonspecific effects of siRNAs and underlines the safety concerns regarding the use of siRNAs in the treatment of human diseases, such as cancer.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

مهار بیان ژن GFP به وسیله تداخل RNA (RNAi) در دودمان سلولی کارسینومای جنینی P19

 Introduction: RNA interference (RNAi) is a phenomenon of gene silencing that uses double-stranded RNA (dsRNA), specifically inhibits gene expression by degrading mRNA efficiently. The mediators of degradation are 21- to 23-nt small interfering RNAs (siRNA). The use of siRNAs as inhibitors of gene expression has been shown to be an effective way of studying gene function in mammalian cells.  Ai...

متن کامل

The Role of Tumor Protein 53 Mutations in Common Human Cancers and Targeting the Murine Double Minute 2–P53 Interaction for Cancer Therapy

The gene TP53 (also known as protein 53 or tumor protein 53), encoding transcription factor P53, is mutated or deleted in half of human cancers, demonstrating the crucial role of P53 in tumor suppression. There are reports of nearly 250 independent germ line TP53 mutations in over 100 publications. The P53 protein has the structure of a transcription factor and, is made up of several domains. T...

متن کامل

MED28 regulates MEK1-dependent cellular migration in human breast cancer cells.

MED28, a mammalian Mediator subunit, exhibits several cellular roles, including a merlin, Grb2, and cytoskeleton-associated protein (magicin), a repressor of smooth muscle cell differentiation, and an endothelial-derived gene (EG-1). Overexpression of MED28 may stimulate cell proliferation which presumably results from the transcriptional activation of the Mediator function. Additionally, sever...

متن کامل

Synthesis Pyrano [2,3-c] Pyrazole-based compounds to induce apoptosis by reducing the expression of anti-apoptotic Bcl-2 protein in human breast cancer MCF-7 cells

Aim: Bcl-2 is a potential target for tumor treatment. The inhibition of the Bcl-2 production is research target of attract in the field of anti-cancer drug development. Recently, the assessment of antitumor activity appeared to be promising for pyrazole derivatives. Therefore, this study was designed to investigate the anti-cancer effects of novel pyrazole derivatives (HN1and HN2.). Material an...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Journal of immunology

دوره 180 11  شماره 

صفحات  -

تاریخ انتشار 2008