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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, METHODS, RESULTS. Meshes: Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Glial Cell Line-Derived Neurotrophic Factor, Glycogen Synthase Kinase 3 beta, Hedgehog Proteins, Humans, Kruppel-Like Transcription Factors, Neuroblastoma, Nuclear Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-ret, Pyridines, Pyrimidines, RNA, Small Interfering, Signal Transduction, Transfection, Veratrum Alkaloids, Zinc Finger Protein GLI1, Zinc Finger Protein Gli2.
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Does smoothened-independent activation of hedgehog signaling by rearranged during transfection promote neuroblastoma cell proliferation and tumor growth? Context: Rearranged during transfection (RET) proto-oncogene encodes a receptor tyrosine kinase for glial cell line-derived neurotrophic factor (GDNF) signaling, and high RET expression is closely related to the tumorigenesis and malignancy of neuroblastoma(NB). We have investigated whether RET signals through hedgehog (HH) pathway in NB cell proliferation and tumor growth by in vitro cell culture and in vivo xenograft approaches. The key members of both GDNF/RET and HH/GLI pathways are expressed in NB cell lines to different extents. Knockdown of RET in NB cells significantly attenuates the activity of HH signaling, whereas overexpression of RET robustly enhances the output of transcriptional activation by HH. Likewise, activation of RET by GDNF induces HH signaling, whereas knockdown of RET attenuates both basal and GDNF-induced activities of HH signaling. Moreover, protein kinase B lies on the downstream of GDNF/RET signaling module to inhibit the GSK3β, resulting in activation of HH signaling. Furthermore, either knockdown of RET by shRNA or inhibition of HH pathway by cyclopamine attenuates not only basal but also GDNF-induced proliferation of SH-SY5Y cells, and knockdown of either RET or smoothened in SH-SY5Y cell xenografts significantly attenuated the tumor growth. Finally, inhibition of HH signaling by GLI1 and GLI2 inhibitor, Gant61, reduces not only basal but also RET-induced proliferation of SH-SY5Y cells and outgrowth of xenografts.
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GDNF/RET/AKT/GSK3β signaling module activates HH pathway to stimulate NB cells proliferation and tumor outgrowth. Final Decision: yes