Back to Search
Start Over
Aurora Kinase A Is Overexpressed in Human Retinoblastoma and Correlates with Histopathologic High-Risk Factors: Implications for Targeted Therapy.
- Source :
-
The American journal of pathology [Am J Pathol] 2024 Sep; Vol. 194 (9), pp. 1780-1798. Date of Electronic Publication: 2024 Jun 13. - Publication Year :
- 2024
-
Abstract
- Retinoblastoma (RB) is an intraocular malignancy initiated by loss of RB1 function and/or dysregulation of MYCN oncogene. RB is primarily treated with chemotherapy; however, systemic toxicity and long-term adverse effects remain a significant challenge necessitating the identification of specific molecular targets. Aurora kinase A (AURKA), a critical cell cycle regulator, contributes to cancer pathogenesis, especially in RB1-deficient and MYCN-dysregulated tumors. The current immunohistochemistry study in patient specimens (n = 67) indicated that AURKA is overexpressed in RB, and this elevated expression correlates with one or more histopathologic high-risk factors, such as tumor involvement of the optic nerve, choroid, sclera, and/or anterior segment. More specifically, AURKA is ubiquitously expressed in most advanced-stage RB tumors that show a suboptimal response to chemotherapy. shRNA-mediated depletion/pharmacologic inhibition studies in cell lines, patient-derived cells, in vivo xenografts, and enucleated patient specimens confirmed that RB cells are highly sensitive to a lack of functional AURKA. In addition, AURKA and N-myc proto-oncogene protein (MYCN) associate with each other to regulate their levels in RB cells. Overall, these results demonstrate a previously unknown up-regulation of AURKA in RB, facilitated by its crosstalk with MYCN. The elevated levels of this kinase may indicate unfavorable prognosis in tumors refractory to chemotherapy. This study provides a rationale and confirms that therapeutic targeting of elevated AURKA in RB could be a potential treatment approach.<br />Competing Interests: Disclosure Statement None declared.<br /> (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Child, Preschool
Female
Humans
Male
Biomarkers, Tumor metabolism
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Molecular Targeted Therapy
N-Myc Proto-Oncogene Protein metabolism
N-Myc Proto-Oncogene Protein genetics
Risk Factors
Animals
Chick Embryo
Aurora Kinase A metabolism
Aurora Kinase A genetics
Proto-Oncogene Mas
Retinal Neoplasms pathology
Retinal Neoplasms metabolism
Retinal Neoplasms genetics
Retinal Neoplasms drug therapy
Retinoblastoma pathology
Retinoblastoma metabolism
Retinoblastoma genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 194
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 38879085
- Full Text :
- https://doi.org/10.1016/j.ajpath.2024.05.006