title: PAX3 in neuroblastoma: oncogenic potential, chemosensitivity and signalling pathways.
abstract: Transcription factor PAX3/Pax3 contributes to diverse cell lineages during embryonic development and is important in tumourigenesis. We found that PAX3 is re-expressed in neuroblastoma and malignant neuroblastic (N-type) neuroblastoma cells had significantly higher PAX3 protein expression than their benign substrate-adherent (S-type) counterparts. Knock-down of PAX3 expression by siRNA transfection resulted in persistent cell growth inhibition in both types of neuroblastoma cell, owing to G1 cell cycle arrest and progressive apoptosis. Inhibition of PAX3 expression significantly decreased the attachment of S-type SH-EP1 cells to extra-cellular matrix proteins, fibronectin, laminin and collagen IV. Migration and invasion of both neuroblastoma cell types were markedly reduced after PAX3 down-regulation. PAX3 knock-down significantly augmented the cytotoxic effect of chemotherapeutic agents, etoposide, vincristine and cisplatin, commonly used to treat neuroblastoma. Microarray analyses revealed that particularly signalling pathways involving cell cycle, apoptosis, cell adhesion, cytoskeletal remodelling and development were altered by PAX3 down-regulation. Changes in PAX3 downstream genes identified by microarray analyses were validated in 47 genes by quantitative PCR. These novel findings lead us to propose that PAX3 might contribute to oncogenic characteristics of neuroblastoma cells by regulating a variety of crucial signalling pathways.
authors.affiliation: Institute of Inflammation and Repair, Faculty of Medicine and Human Sciences, The University of Manchester, Manchester, UK.
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Fang
authors.forename: Qiuyu
authors.initials: Q
authors.lastname: Wang
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Li
authors.forename: Mashud
authors.initials: M
authors.lastname: Ahmed
authors.forename: Patricia
authors.initials: P
authors.lastname: Kumar
authors.forename: Shant
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism*; D009857:Oncogenes; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D034741:RNA, Small Interfering; D005047:Etoposide; D002945:Cisplatin
keywords: PAX3; RNA interference; cellular functions; microarray; neuroblastoma; signalling pathway