Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Cell biology Oncology

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

  • Text
  • PDF
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

×

Figure 2

Elevated urine prohibitin at diagnosis is a specific biomarker of relapse in favorable-histology Wilms’ tumor.

Options: View larger image (or click on image) Download as PowerPoint
Elevated urine prohibitin at diagnosis is a specific biomarker of relaps...
(A) ELISA comparing known prohibitin levels (ng/mL) with measured absorbance via ELISA. (B) Diagnostic urine prohibitin levels (ng/mL) in patients with Wilms’ tumor who have favorable histology and relapsed (red, n = 49) are compared with those who were cured (blue, n = 50) and normal controls (black, n = 40). Exploratory simple logistic regression models determined that 998 ng/mL was the optimal cutoff point for urine prohibitin. Using Fisher’s exact test for distribution differences in dichotomized PHB among the 3 patient groups (relapsed, cured, control) revealed a statistically increased number of relapsed Wilms’ tumor with this cutoff threshold. OR of relapse for patients with diagnostic urine prohibitin greater than 998 ng/mL = 153 (95% CI, 19.6–1,000). (C) A receiver-operating characteristic curve demonstrates the prognostic power of diagnostic urine prohibitin to predict relapse in favorable-histology Wilms’ tumor at different sensitivity and specificity with an AUC of 0.78 (95% CI, 0.68–1.0). (D) Risk of relapse in patients with favorable-histology Wilms’ tumor are stratified by those with a diagnostic urine prohibitin greater than 998 ng/mL (red, n = 31) compared with those with a diagnostic urine prohibitin less than 998 ng/mL (blue, n = 68). (E) Diagnostic urine prohibitin levels in relapsed patients with favorable-histology Wilms’ tumor are stratified by site of relapse. (F) A receiver-operating characteristic curve demonstrates the prognostic power of diagnostic urine prohibitin to predict abdominal relapse in favorable-histology Wilms’ tumor at different sensitivity and specificity with an AUC of 0.96 (95% CI, 0.91–1.0).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts