Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features

Cancers

Esther Rivero-Cortés¹  Juan Solivera¹  Paloma Moreno-Moreno¹  Manuel D. Gahete¹  and Raúl M. Luque¹  Mari C. Vázquez-Borrego¹  Justo P. Castaño¹  Antonio C. Fuentes-Fayos¹  María A. Gálvez-Moreno¹  Elena Dios²  Pablo Remón²  Alfonso Soto-Moreno²  Eva Venegas-Moreno²  Ainara Madrazo-Atutxa²  Leandro Kasuki³  Luiz E. Wildemberg³  Mônica R. Gadelha³  Judith M. López-Fernández⁴ 

[1] Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain;Metabolism and Nutrition Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), 41013 Sevilla, Spain;Neuroendocrinology Research Center/Endocrinology Division, Medical School and Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-590, Brazil;Service of Endocrinology and Nutrition, Hospital Universitario de Canarias, 38320 La Laguna, Santa Cruz de Tenerife, Spain;

关键词: splicing;    spliceosome;    pituitary neuroendocrine tumors;    pladienolide-b.;   

DOI  :  10.3390/cancers11101439

来源: DOAJ

【 摘 要 】

Pituitary neuroendocrine tumors (PitNETs) constitute approximately 15% of all brain tumors, and most have a sporadic origin. Recent studies suggest that altered alternative splicing and, consequently, appearance of aberrant splicing variants, is a common feature of most tumor pathologies. Moreover, spliceosome is considered an attractive therapeutic target in tumor pathologies, and the inhibition of SF3B1 (e.g., using pladienolide-B) has been shown to exert antitumor effects. Therefore, we aimed to analyze the expression levels of selected splicing-machinery components in 261 PitNETs (somatotropinomas/non-functioning PitNETS/corticotropinomas/prolactinomas) and evaluated the direct effects of pladienolide-B in cell proliferation/viability/hormone secretion in human PitNETs cell cultures and pituitary cell lines (AtT-20/GH3). Results revealed a severe dysregulation of splicing-machinery components in all the PitNET subtypes compared to normal pituitaries and a unique fingerprint of splicing-machinery components that accurately discriminate between normal and tumor tissue in each PitNET subtype. Moreover, expression of specific components was associated with key clinical parameters. Interestingly, certain components were commonly dysregulated throughout all PitNET subtypes. Finally, pladienolide-B reduced cell proliferation/viability/hormone secretion in PitNET cell cultures and cell lines. Altogether, our data demonstrate a drastic dysregulation of the splicing-machinery in PitNETs that might be associated to their tumorigenesis, paving the way to explore the use of specific splicing-machinery components as novel diagnostic/prognostic and therapeutic targets in PitNETs.

【 授权许可】

Unknown