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Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Loss of PL6 protein expression in renal clear cell carcinomas and other VHL-deficient tumours
A V Ivanova1, A Vortmeyer, S V Ivanov
1Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA. alla.ivanova@med.nyu.edu
Abstract:
Mutations in the von Hippel-Lindau tumour suppressor gene (VHL) cause the VHL hereditary cancer syndrome and occur in most sporadic clear cell renal cell cancers (CC-RCCs). The mechanisms by which VHL loss of function promotes tumour development in the kidney are not fully elucidated. Here, we analyse expression of PL6, one of the potential tumour suppressor genes from the critical 3p21.3 region involved in multiple common cancers. We classify PL6 as a Golgi-resident protein based on its perinuclear co-localization with GPP130 in all cells and tissues analysed. We show that PL6 RNA and protein expression is completely or partially lost in all analysed CC-RCCs and other VHL-deficient tumours studied, including the early precancerous lesions in VHL disease. The restoration of VHL function in vitro in the VHL-deficient CC-RCC cell lines was found to reinstate PL6 expression, thus establishing a direct link between VHL and PL6. Insensitivity of PL6 to hypoxia suggested that PL6 is regulated by VHL via a HIF-1-independent pathway. We ruled out mutations and promoter methylation as possible causes of PL6 down-regulation in CC-RCC. We hypothesize that loss of a putative PL6 secretory function due to VHL deficiency is an early and important event that may promote tumour initiation and growth.
Insights
Loss of the von Hippel-Lindau (VHL) gene function, common in kidney cancer, leads to decreased expression of the PL6 protein. This suggests PL6 loss is an early event in VHL-deficient tumor development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are implicated in VHL hereditary cancer syndrome and clear cell renal cell carcinoma (CC-RCC).
- The precise mechanisms by which VHL loss promotes kidney tumor development remain incompletely understood.
- The 3p21.3 chromosomal region contains potential tumor suppressor genes, including PL6, involved in various cancers.
Purpose of the Study:
- To investigate the role of PL6, a potential tumor suppressor gene, in VHL-deficient tumors, particularly CC-RCC.
- To determine the relationship between VHL gene function and PL6 expression.
- To elucidate the pathway regulating PL6 expression in the context of VHL deficiency.
Main Methods:
- Analysis of PL6 RNA and protein expression in CC-RCC and VHL-deficient tumors.
- Classification of PL6 subcellular localization using co-localization studies with GPP130.
- Restoration of VHL function in vitro to assess its effect on PL6 expression.
- Investigation of potential regulatory pathways, including hypoxia-inducible factors (HIF-1) and ruling out mutations or promoter methylation.
Main Results:
- PL6 was identified as a Golgi-resident protein.
- PL6 expression was lost or reduced in all analyzed CC-RCC and VHL-deficient tumors, including early lesions.
- Restoring VHL function in CC-RCC cell lines re-established PL6 expression, confirming a direct link.
- PL6 regulation by VHL occurs independently of HIF-1.
- Mutations and promoter methylation do not explain PL6 down-regulation.
Conclusions:
- Loss of PL6 expression is a consistent finding in VHL-deficient tumors, including CC-RCC.
- VHL deficiency directly impacts PL6 expression through a HIF-1-independent pathway.
- The loss of PL6's putative secretory function due to VHL deficiency is hypothesized to be an early event promoting tumor initiation and growth.
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