Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas

Chandni Desai; Jon Thomason; Jordan L Kohlmeyer; Anna C Reisetter; Parmanand Ahirwar; Khadijeh Jahanseir; Mariah Leidinger; Georgina Ofori-Amanfo; Karen Fritchie; Sadanandan E Velu; Patrick Breheny; Dawn E Quelle; Munir R Tanas

doi:10.18632/oncotarget.27928

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Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas

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Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas

Chandni Desai, Jon Thomason, Jordan L Kohlmeyer, Anna C Reisetter, Parmanand Ahirwar, Khadijeh Jahanseir, Mariah Leidinger, Georgina Ofori-Amanfo, Karen Fritchie, Sadanandan E Velu, …

Oncotarget, Vol.12(8), pp.740-755

04/13/2021

DOI: 10.18632/oncotarget.27928

PMID: 33889298

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Abstract

Additional prognostic and therapeutic biomarkers effective across different histological types of sarcoma are needed. Herein we evaluate expression of TAZ and YAP, the p53-MDM2 axis, and RABL6A, a novel oncoprotein with potential ties to both pathways, in sarcomas of different histological types. Immunohistochemical staining of a tissue microarray including 163 sarcomas and correlation with clinical data showed that elevated YAP and TAZ independently predict worse overall and progression-free survival, respectively. In the absence of p53 expression, combined TAZ and YAP expression adversely affect overall, progression free, and metastasis free survival more than TAZ or YAP activation alone. RABL6A independently predicted shorter time to metastasis and was positively correlated with p53, MDM2 and YAP expression, supporting a possible functional relationship between the biomarkers. Network analysis further showed that TAZ is positively correlated with MDM2 expression. The data implicate all five proteins as clinically relevant downstream players in the Hippo pathway. Finally, a novel inhibitor of MDM2 (MA242), effectively suppressed the survival of sarcoma cell lines from different histological types regardless of p53 status. These findings suggest both independent and cooperative roles for all five biomarkers across different histological types of sarcoma in predicting patient outcomes and potentially guiding future therapeutic approaches.

p53-MDM2

RABL6A

Research Paper

sarcoma

TAZ

YAP

Details

Title: Subtitle: Prognostic and therapeutic value of the Hippo pathway, RABL6A, and p53-MDM2 axes in sarcomas
Creators: Chandni Desai - University of Iowa
Jon Thomason - University of Iowa
Jordan L Kohlmeyer - University of Iowa
Anna C Reisetter - University of Iowa
Parmanand Ahirwar - University of Alabama at Birmingham
Khadijeh Jahanseir - Mayo Clinic
Mariah Leidinger - University of Iowa
Georgina Ofori-Amanfo - University of Iowa
Karen Fritchie - Mayo Clinic
Sadanandan E Velu - University of Alabama at Birmingham
Patrick Breheny - University of Iowa
Dawn E Quelle - University of Iowa
Munir R Tanas - University of Iowa
Resource Type: Journal article
Publication Details: Oncotarget, Vol.12(8), pp.740-755
DOI: 10.18632/oncotarget.27928
PMID: 33889298
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Publisher: Impact Journals LLC
Language: English
Date published: 04/13/2021
Academic Unit: Dental Clinic Administration; Pathology; Biostatistics; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984186285202771

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