Significance of PI3K signalling pathway in clear cell renal cell carcinoma in relation to VHL and HIF status

Sitaram, Raviprakash T.; Landström, Maréne; Roos, Göran; Ljungberg, Börje

doi:10.1136/jclinpath-2020-206693

Cited by 13 publications

(9 citation statements)

References 117 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The binding of renin or prorenin to PRR can activate the PI3/AKT/mTOR pathway independently of the action of angiotensins [12,21]. This is a well-known oncogenic pathway, which is aberrantly active in CCRCC [40]. Furthermore, PRR is also an important component of the Wnt receptor complex and acts as an adaptor between LRP6 and the V-ATPase.…”

Section: Discussionmentioning

confidence: 99%

Clinical Implications of (Pro)renin Receptor (PRR) Expression in Renal Tumours

et al. 2021

View full text Add to dashboard Cite

(1) Background: Renal cancer is one of the most frequent malignancies in Western countries, with an unpredictable clinical outcome, partly due to its high heterogeneity and the scarcity of reliable biomarkers of tumour progression. (Pro)renin receptor (PRR) is a novel receptor of the renin–angiotensin system (RAS) that has been associated with the development and progression of some solid tumours by RAS-dependent and -independent mechanisms. (2) Methods: In this study, we analysed the immunohistochemical expression of PRR at the centre and border in a series of 83 clear-cell renal cell (CCRCCs), 19 papillary (PRCC) and 7 chromophobe (ChRCC) renal cell carcinomas, and the benign tumour renal oncocytoma (RO, n = 11). (3) Results: PRR is expressed in all the tumour subtypes, with higher mean staining intensity in ChRCCs and ROs. A high expression of PRR at the tumour centre and at the infiltrative front of CCRCC tissues is significantly associated with high grade, tumour diameter, local invasion and stage, and with high mortality risk by UCLA integrated staging system (UISS) scale. (4) Conclusions: These findings indicate that PRR is associated with the development and progression of renal tumours. Its potential as a novel biomarker for RCC diagnosis/prognosis and as a promising therapeutic target should be taken into account in the future.

show abstract

Section: Discussionmentioning

confidence: 99%

Clinical Implications of (Pro)renin Receptor (PRR) Expression in Renal Tumours

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Genetic changes, like mutations, deletions, and epigenetic alterations, play a crucial role in modifying signaling networks, tumor pathogenesis, and prognosis. Loss of von Hippel-Lindau (VHL) gene and upregulation of hypoxiainducible factors (HIF), the signature of most sporadic ccRCC, promote multiple growth factors [4].…”

Section: Discussionmentioning

confidence: 99%

“…Nonsense mutations of the VHL gene appear to be related to poorer prognosis and survival [2]. Multiple molecular targets have been developed based on blocking major signaling pathways directly or indirectly involved in ccRCC tumor progression, metastasis, angiogenesis, and survival [4].…”

Section: Introductionmentioning

confidence: 99%

VHL, BAP1, PBRM1, SETD2 Expression in Clear Cell Renal Carcinoma, Association With PD-1, PD-L1, PD-L2 mRNA Level

Спирина¹,

Yurnazov²,

Усынин³

et al. 2021

Preprint

View full text Add to dashboard Cite

Novel mechanism of ccRCC progression is essential, including PBRM1, BAP1, and SETD2 in histone-modifying and chromatin remodeling genes. The study aimed to investigate VHL, PD-1, PD-L1, PD-L2. BAP1, PBRM1, SETD2 expression in ccRCC primary cancers and metastatic tissues associated with the cancer dissemination. A total of 62 patients with RCC were enrolled in the study. Investigation of mRNA level of VHL, PD-1, PD-L1, PD-L2. PCR in real-time performed BAP1, PBRM1, SETD2 with the previous RNA isolation. Western Blotting analysis was used for detecting the p-VHL protein content in tissues. The VHL expression and p-VHL content determined the aggressive cancer behavior and elevated in disseminated tumors. The cancer dissemination was accompanied by an increase in both mRNA and VHL content. The PD-L2 prevalence in metastatic cancers is crucial in tumor progression. ccRCC progression in VHL overexpression is associated with the decrease in BAP1 gene expression. It is revealed the heterogeneity in molecular markers in primary tumors and metastases. The low mRNA level of BAP1, PBRM1, SETD2, PD-1, PD-L1, PD-L2 in metastases compared with primary tumors were found. We show a novel mechanism for VHL tumor progression and present a new instrument and factor targeting tumor-related pathologies with p-VHL/HIF altered function.

show abstract

“…Thus, VHL-defective RCC enhances mTOR pathway activation. In addition, an increase in HIFα activates the AKT-mTOR pathway, which increases the survival of tumor cells in RCC [41]. Increased mTOR creates a vicious cycle that re-increases HIFα [41,42]; inhibition of the mTOR pathway was found to reduce HIF1α in a mouse model [43].…”

Section: Other Targets: the Protein Kinase B-mechanistic Target Of Rapamycin (Akt-mtor) And Epidermal Growth Factor Receptor (Egfr) Pathwmentioning

confidence: 99%

“…In addition, an increase in HIFα activates the AKT-mTOR pathway, which increases the survival of tumor cells in RCC [41]. Increased mTOR creates a vicious cycle that re-increases HIFα [41,42]; inhibition of the mTOR pathway was found to reduce HIF1α in a mouse model [43]. Consequently, studies have been conducted to apply mTOR inhibitors in the treatment of mRCC.…”

Section: Other Targets: the Protein Kinase B-mechanistic Target Of Rapamycin (Akt-mtor) And Epidermal Growth Factor Receptor (Egfr) Pathwmentioning

confidence: 99%

Loss of Von Hippel–Lindau (VHL) Tumor Suppressor Gene Function: VHL–HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC)

Kim

Shim

Lee

et al. 2021

IJMS

View full text Add to dashboard Cite

Renal cell carcinoma (RCC) is a malignancy of the kidney originating from the tubular epithelium. Inactivation of the von Hippel–Lindau tumor-suppressor gene (VHL) is found in most clear cell renal cell carcinomas (ccRCCs). The VHL–HIF–VEGF/VEGFR pathway, which involves the von Hippel–Lindau tumor suppressor protein (VHL), hypoxia-inducible factor (HIF), vascular endothelial growth factor (VEGF), and its receptor (VEGFR), is a well-studied therapeutic target for metastatic ccRCC. Therefore, over the past decade, anti-angiogenic agents targeting VEGFR have served as the standard treatment for metastatic RCC. Recently, based on the immunomodulatory effect of anti-VEGFR therapy, anti-angiogenic agents and immune checkpoint inhibitor combination strategies have also emerged as therapeutic strategies. These advances were made possible by the improved understanding of the VHL–HIF pathway. In this review, we summarize the historical evolution of ccRCC treatments, with a focus on the involvement of the VHL–HIF pathway.

show abstract

Significance of PI3K signalling pathway in clear cell renal cell carcinoma in relation to VHL and HIF status

Cited by 13 publications

References 117 publications

Clinical Implications of (Pro)renin Receptor (PRR) Expression in Renal Tumours

Clinical Implications of (Pro)renin Receptor (PRR) Expression in Renal Tumours

VHL, BAP1, PBRM1, SETD2 Expression in Clear Cell Renal Carcinoma, Association With PD-1, PD-L1, PD-L2 mRNA Level

Loss of Von Hippel–Lindau (VHL) Tumor Suppressor Gene Function: VHL–HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC)

Contact Info

Product

Resources

About