Related Experiment Video
Updated: Mar 20, 2026
Evaluation of Abnormal Growth-related Genes of Hematopoietic Stem and Progenitor Cells by Combining CRISPR/Cas9 Technology with Cell Counting
Published on: May 2, 2025
Haploinsufficiency of the ESCRT Component HD-PTP Predisposes to Cancer
Sanaz Manteghi1, Marie-Claude Gingras1, Dmitri Kharitidi1
1Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada.
Abstract:
Endosomal sorting complexes required for transport (ESCRT) drive cell surface receptor degradation resulting in attenuation of oncogenic signaling and pointing to a tumor suppressor function. Here, we show that loss of function of an ESCRT protein (HD-PTP encoded by the PTPN23 gene, located on the tumor suppressor gene cluster 3p21.3) drives tumorigenesis in vivo. Indeed, Ptpn23(+/-) loss predisposes mice to sporadic lung adenoma, B cell lymphoma, and promotes Myc-driven lymphoma onset, dissemination, and aggressiveness. Ptpn23(+/-)-derived tumors exhibit an unaltered remaining allele and maintain 50% of HD-PTP expression. Consistent with the role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion, hemizygous Ptpn23(+/-) loss increases integrin β1-dependent B cell lymphoma survival and dissemination. Finally, we reveal frequent PTPN23 deletion and downregulation in human tumors that correlates with poor survival. Altogether, we establish HD-PTP/PTPN23 as a prominent haploinsufficient tumor suppressor gene preventing tumor progression through control of integrin trafficking.
Insights
Loss of the HD-PTP protein, encoded by the PTPN23 gene, drives tumor formation. Reduced PTPN23 function impairs tumor suppression, promoting cancer progression and poor survival in humans.
Area of Science:
- Cell Biology
- Oncology
- Molecular Biology
Background:
- Endosomal sorting complexes required for transport (ESCRT) mediate receptor degradation, attenuating oncogenic signaling.
- HD-PTP (PTPN23) is an ESCRT protein located in the tumor suppressor gene cluster 3p21.3.
Purpose of the Study:
- To investigate the role of HD-PTP/PTPN23 in tumorigenesis and its function as a tumor suppressor.
- To determine the impact of PTPN23 loss-of-function on cancer development and progression.
Main Methods:
- Utilized Ptpn23(+/-) mice to study tumorigenesis in vivo.
- Analyzed tumor development, dissemination, and aggressiveness.
- Assessed integrin trafficking and cell migration/invasion.
- Examined PTPN23 deletion and downregulation in human tumors.
Main Results:
- Ptpn23(+/-) mice developed lung adenoma and B cell lymphoma, and promoted Myc-driven lymphoma.
- Tumors maintained 50% HD-PTP expression, indicating haploinsufficiency.
- Loss of PTPN23 enhanced integrin β1-dependent lymphoma survival and dissemination.
- Human tumors frequently showed PTPN23 deletion/downregulation, correlating with poor survival.
Conclusions:
- HD-PTP/PTPN23 acts as a haploinsufficient tumor suppressor gene.
- PTPN23 controls tumor progression by regulating integrin trafficking.
- Loss of PTPN23 contributes to cancer development and poor patient outcomes.
Related Concept Videos
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:33Cancer-Critical Genes I: Proto-oncogenes
03:18Non-LTR Retrotransposons