Radiation Biology

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SU_44_2447 - Radiation-induced Calreticulin Expression Leads to MYCN Suppression and Neuronal Differentiation in Neuroblastoma Cells

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Radiation-induced Calreticulin Expression Leads to MYCN Suppression and Neuronal Differentiation in Neuroblastoma Cells
J. H. Hong1,2, A. C. L. Lee2, and Y. Y. Shih3; 1Department of Radiation Oncology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, 2Radiation Biology Research Center, Institute for Radiological Research, Chang Gung Memorial Hospital/Chang Gung University, Taoyuan, Taiwan, 3Department of Medical Imaging and Radiological Sciences, Chang Gung University, Taoyuan, Taiwan

Purpose/Objective(s): Oncogenic N-MYC (MYCN) is widely used as a biomarker in clinics for neuroblastoma (NB) patients and radiotherapy (RT) is often required in high-risk NB group Nevertheless, there has been limited information on impact of radiation on MYCN, and thus correlation between radiation and MYCN regulation remains un-explored. In this study, we unraveled ionizing radiation (IR)-inducible calreticulin (CRT) as a novel MYCN suppressor and investigated the functional roles of CRT in the response of NB to IR.

Materials/Methods: Rat pheochromocytoma cell line PC 12 and human neuroblastoma cell lines SK-N-SH and SK-SY5Y were used as our in vitro and in vivo xenograft model of NB. Transient/stable transfection of CRT and lentiviral particles containing shRNA of CRT were used to overexpress or knockdown CRT in NB cells, respectively. Luciferase reporter assay was used to quantitate the degree of suppression effect of CRT on MYCN promoter. Cell viability and survival fraction were determined by alarmblue and clonogenic assays. Neuronal differentiation was measured by neurite length and numbers under light microscopy.

Results: R was able to increase the CRT expression while decrease MYCN expression in a dose-dependent manner. We discovered that IR-induced and overexpressed CRT were both capable of suppressing MYCN in NB cells. Importantly, IR-induced CRT was correlated to MYCN-suppressed NB cell that underwent neuronal differentiation, leading to increased neurite length, neurite numbers as well as elevated differentiation marker GAP43. The differentiation of NB induced by CRT under IR also caused significantly more apoptotic death. Interestingly, the CRT-induced MYCN suppression resulted in greatly enhanced radiosensitivity in CRT-expressing NB cells than control cells. In line with these in vitro observations, depletion of CRT or IR-inducing CRT led to significantly faster or ameliorated tumor growth rate in our NB xenograft models, respectively.

Conclusion: Together, our data provided a unique mechanism of IR-induced CRT-mediated MYCN regulation and warranted further preclinical investigation towards new therapeutic strategy for NB.

Author Disclosure: J. Hong: None. A.C. Lee: None.

Ji-Hong Hong, MD, PhD

Chang Gung Memorial Hospital

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