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Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms’ tumor
Michael V. Ortiz, … , Hanno Steen, Alex Kentsis
Michael V. Ortiz, … , Hanno Steen, Alex Kentsis
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e127098. https://doi.org/10.1172/jci.insight.127098.
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Research Article Cell biology Oncology

Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms’ tumor

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Abstract

Wilms’ tumor is the most common type of childhood kidney cancer. To improve risk stratification and identify novel therapeutic targets for patients with Wilms’ tumor, we used high-resolution mass spectrometry proteomics to identify urine tumor markers associated with Wilms’ tumor relapse. We determined the urine proteomes at diagnosis of 49 patients with Wilms’ tumor, non–Wilms’ tumor renal tumors, and age-matched controls, leading to the quantitation of 6520 urine proteins. Supervised analysis revealed specific urine markers of renal rhabdoid tumors, kidney clear cell sarcomas, renal cell carcinomas as well as those detected in patients with cured and relapsed Wilms’ tumor. In particular, urine prohibitin was significantly elevated at diagnosis in patients with relapsed as compared with cured Wilms’ tumor. In a validation cohort of 139 patients, a specific urine prohibitin ELISA demonstrated that prohibitin concentrations greater than 998 ng/mL at diagnosis were significantly associated with ultimate Wilms’ tumor relapse. Immunohistochemical analysis revealed that prohibitin was highly expressed in primary Wilms’ tumor specimens and associated with disease stage. Using functional genetic experiments, we found that prohibitin was required for the growth and survival of Wilms’ tumor cells. Overexpression of prohibitin was sufficient to block intrinsic mitochondrial apoptosis and to cause resistance to diverse chemotherapy drugs, at least in part by dysregulating factors that control apoptotic cytochrome c release from mitochondrial cristae. Thus, urine prohibitin may improve therapy stratification, noninvasive monitoring of treatment response, and early disease detection. In addition, therapeutic targeting of chemotherapy resistance induced by prohibitin dysregulation may offer improved therapies for patients with Wilms’ and other relapsed or refractory tumors.

Authors

Michael V. Ortiz, Saima Ahmed, Melissa Burns, Anton G. Henssen, Travis J. Hollmann, Ian MacArthur, Shehana Gunasekera, Lyvia Gaewsky, Gary Bradwin, Jeremy Ryan, Anthony Letai, Ying He, Arlene Naranjo, Yueh-Yun Chi, Michael LaQuaglia, Todd Heaton, Paolo Cifani, Jeffrey S. Dome, Samantha Gadd, Elizabeth Perlman, Elizabeth Mullen, Hanno Steen, Alex Kentsis

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Figure 3

Prohibitin is highly expressed in primary Wilms’ tumor samples.

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Prohibitin is highly expressed in primary Wilms’ tumor samples.
(A–F) PH...
(A–F) PHB IHC staining was performed on formalin-fixed paraffin-embedded primary Wilms’ tumor samples and compared with adjacent normal kidneys. Original magnification, ×5 (A–C); ×40 (D–F). A and D include normal kidney. B and E include favorable-histology Wilms’ tumor. C and F include anaplastic histology Wilms’ tumor. (G) IHC was performed on a tissue microarray containing 59 primary Wilms’ tumor samples and graded from 0+ to 3+ in a blinded manner. Quantification of IHC from the tissue microarray is shown and stratified by initial tumor stage. (H and I) A second cohort of 38 patients with primary Wilms’ tumor was assessed (15 cured, 16 relapsed, 7 no information; 24 favorable, 14 anaplastic Wilms’ tumor). The expression of PHB was evaluated on a cell-by-cell basis using Halo imaging analysis software. A total of 24,862,509 cells were counted and scored from 0+ to 3+ based on PHB expression. In H, PHB expression in the cells of Wilms’ tumor that ultimately relapsed are compared with those that were cured. Whereas in I, PHB expression in the cells of Wilms’ tumor that had favorable histology are compared with those with anaplastic histology.

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