BACKGROUND: Neuroblastoma (NBL) is a common pediatric solid tumor, and outcomes for patients with advanced neuroblastoma remain poor despite extremely aggressive treatment. Chemotherapy resistance at relapse contributes heavily to treatment failure. The poor survival of patients with high-risk NBL prompted this investigation into novel treatment options with the objective of gaining a better understanding of resistance mechanisms. On the basis of previous work and on data from publicly available studies, the authors hypothesized that human epidermal growth factor receptor 4 (Her4) contributes to resistance. METHODS: Her4 expression was reduced with small-hairpin RNA (shRNA) to over express intracellular HER4, and the authors tested its impact on tumor cell survival under various culture conditions. The resulting changes in gene expression after HER4 knockdown were measured by using a messenger RNA (mRNA) array. RESULTS: HER4 expression was up-regulated in tumor spheres compared with the expression in monolayer culture. With HER4 knockdown, NBL cells became less resistant to anoikis and serum starvation. Moreover, HER4 knockdown increased the chemosensitivity of NBL cells to cisplatin, doxorubicin, etoposide, and activated ifosfamide. In mRNA array analysis, HER4 knockdown predominately altered genes related to cell cycle regulation. In NBL spheres compared with monolayers, cell proliferation was decreased, and cyclin D expression was reduced. HER4 knockdown reversed cyclin D suppression. Overexpressed intracellular HER4 slowed the cell cycle and induced chemoresistance. CONCLUSIONS: The current results indicated that HER4 protects NBL cells from multiple exogenous apoptotic stimuli, including anoikis, nutrient deficiency, and cytotoxic chemotherapy. The intracellular fragment of HER4 was sufficient to confer this phenotype. HER4 functions as a cell cycle suppressor, maintaining resistance to cellular stress. The current findings indicate that HER4 overexpression may be associated with refractory disease, and HER4 may be an important therapeutic target.
BACKGROUND:Neuroblastoma (NBL) is a common pediatric solid tumor, and outcomes for patients with advanced neuroblastoma remain poor despite extremely aggressive treatment. Chemotherapy resistance at relapse contributes heavily to treatment failure. The poor survival of patients with high-risk NBL prompted this investigation into novel treatment options with the objective of gaining a better understanding of resistance mechanisms. On the basis of previous work and on data from publicly available studies, the authors hypothesized that humanepidermal growth factor receptor 4 (Her4) contributes to resistance. METHODS:Her4 expression was reduced with small-hairpin RNA (shRNA) to over express intracellular HER4, and the authors tested its impact on tumor cell survival under various culture conditions. The resulting changes in gene expression after HER4 knockdown were measured by using a messenger RNA (mRNA) array. RESULTS:HER4 expression was up-regulated in tumor spheres compared with the expression in monolayer culture. With HER4 knockdown, NBL cells became less resistant to anoikis and serum starvation. Moreover, HER4 knockdown increased the chemosensitivity of NBL cells to cisplatin, doxorubicin, etoposide, and activated ifosfamide. In mRNA array analysis, HER4 knockdown predominately altered genes related to cell cycle regulation. In NBL spheres compared with monolayers, cell proliferation was decreased, and cyclin D expression was reduced. HER4 knockdown reversed cyclin D suppression. Overexpressed intracellular HER4 slowed the cell cycle and induced chemoresistance. CONCLUSIONS: The current results indicated that HER4 protects NBL cells from multiple exogenous apoptotic stimuli, including anoikis, nutrient deficiency, and cytotoxic chemotherapy. The intracellular fragment of HER4 was sufficient to confer this phenotype. HER4 functions as a cell cycle suppressor, maintaining resistance to cellular stress. The current findings indicate that HER4 overexpression may be associated with refractory disease, and HER4 may be an important therapeutic target.
Authors: C I Sartor; H Zhou; E Kozlowska; K Guttridge; E Kawata; L Caskey; J Harrelson; N Hynes; S Ethier; B Calvo; H S Earp Journal: Mol Cell Biol Date: 2001-07 Impact factor: 4.272
Authors: Kwan-Suk Kim; Jacob T Seibert; Zewde Edea; Kody L Graves; Eui-Soo Kim; Aileen F Keating; Lance H Baumgard; Jason W Ross; Max F Rothschild Journal: J Anim Sci Date: 2018-06-04 Impact factor: 3.159
Authors: Annica Wilzén; Cecilia Krona; Baldur Sveinbjörnsson; Erik Kristiansson; Daniel Dalevi; Ingrid Øra; Katleen De Preter; Raymond L Stallings; John Maris; Rogier Versteeg; Staffan Nilsson; Per Kogner; Frida Abel Journal: Mol Cancer Date: 2013-07-08 Impact factor: 27.401
Authors: Ariadna Mendoza-Naranjo; Amal El-Naggar; Daniel H Wai; Priti Mistry; Nikola Lazic; Fernanda Rocha Rojas Ayala; Isabela Werneck da Cunha; Pablo Rodriguez-Viciana; Hongwei Cheng; Jose H Tavares Guerreiro Fregnani; Patrick Reynolds; Robert J Arceci; Andrew Nicholson; Timothy J Triche; Fernando A Soares; Adrienne M Flanagan; Yuzhuo Z Wang; Sandra J Strauss; Poul H Sorensen Journal: EMBO Mol Med Date: 2013-05-16 Impact factor: 12.137