Predictors of response to sequential sunitinib and the impact of prior VEGF-targeted drug washout in patients with metastatic clear-cell renal cell carcinoma

414 Background: While mutations in PBRM1 (~40%) and BAP1(~10%) are associated with clinical outcomes and pathologic features in clear cell renal cell carcinoma (ccRCC), the impact of protein expression of these genes remains unknown. Herein, we quantify PBRM1/BAP1 protein expression in a large cohort of patients with localized ccRCC and associate expression with cancer-specific survival (CSS) and pathologic features. Methods: We utilized the Mayo Clinic Renal Registry and identified 1,416 patients who underwent nephrectomy to treat clinically localized ccRCC between 1/3/1990 and 4/14/2009. We used immunohistochemistry (IHC) to detect PBRM1/BAP1 expression, and a central pathologist blinded to the outcomes scored tumors as either positive or negative. Tumors with heterogeneous or equivocal staining were excluded from this analysis. We generated Cox proportional hazard regression models for associations with ccRCC-SS, and we employed Mann-Whitney U tests for associations with pathologic features. Results: Of the 1,416 samples, 1,232 (87%) were PBRM1/BAP1 positive or negative, 163 (11%) had heterogeneous staining, and 21 (1%) could not be assessed. The distribution and association of PBRM1/BAP1 phenotypes with clinical outcomes are listed in the table below. PBRM1+/BAP1+ tumors have the best CSS, and PBRM1-/BAP1- have the worst. In addition, PBRM1/BAP1 expression strongly associated with the tumor size, stage, grade, and tumor necrosis (p<0.0001). Conclusions: This study is the first and largest to quantify PRBM1/BAP1 protein expression in ccRCC tumors. We were able to quantify PBRM1/BAP1 through IHC in the vast majority of tumors (87%), and PRBM1/BAP1 expression strongly associates with both CSS and pathologic tumor characteristics. Our data confirms our previous findings of the importance of PRBM1/BAP1 in the molecular pathogenesis of ccRCC. [Table: see text]

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The impact of three-dimensional tumor volume on cancer-specific survival for patients with pT1 clear-cell renal cell carcinoma

World Journal of Urology ◽

10.1007/s00345-015-1592-6 ◽

2015 ◽

Vol 34 (1) ◽

pp. 83-88 ◽

Cited By ~ 3

Author(s):

Wan Song ◽

Byong Chang Jeong ◽

Seong Il Seo ◽

Seong Soo Jeon ◽

Hyun Moo Lee ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Tumor Volume ◽

Clear Cell ◽

Three Dimensional ◽

Cell Renal Cell Carcinoma ◽

Cancer Specific Survival ◽

The Impact

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The impact of peptidase activity on clear cell renal cell carcinoma survival

AJP Renal Physiology ◽

10.1152/ajprenal.00477.2012 ◽

2012 ◽

Vol 303 (12) ◽

pp. F1584-F1591 ◽

Cited By ~ 24

Author(s):

Gorka Larrinaga ◽

Lorena Blanco ◽

Begoña Sanz ◽

Itxaro Perez ◽

Javier Gil ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Rank Test ◽

Activity Levels ◽

Peptidase Activity ◽

Cell Renal Cell Carcinoma ◽

Dpp Iv ◽

The Impact

Several studies have proposed that protease expression and activity may have a predictive value in the survival of clear cell renal cell carcinoma (CCRCC). Most efforts on this issue have been focused on the analysis of matrix metalloproteinases (MMP) and very little on the role of other proteases, such as peptidases. The catalytic activity of 9 peptidases (APN, APB, ASP, CAP, DPP-IV, NEP/CD10, PEP, PGI, and PSA) was quantified by fluorometric methods in a series of 79 CCRCC patients, and the results obtained were analyzed for survival (Kaplan-Meier curves, log-rank test, and Cox multivariate analysis). CCRCC patients with higher activity levels of membrane-bound APN and soluble APN, DPP-IV, and CAP had significantly shorter 5-yr survival rates than those with lower levels. By contrast, higher soluble APB activity significantly correlated with longer survival. Our data suggest the involvement of peptidases in the biological aggressiveness of CCRCC and support the usefulness of measuring these proteases to assess the prognosis of patients with CCRCC.

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RNF43 is a Novel Tumor Suppressor and Prognostic Indicator in Clear Cell Renal Cell Carcinoma

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504021x16252201000833 ◽

2021 ◽

Author(s):

Dawei Zhu ◽

Lei Zhang ◽

Xiaokai Shi ◽

Shenglin Gao ◽

Chuang Yue ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tumor Suppressor ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Prognostic Indicator ◽

Cell Renal Cell Carcinoma ◽

Targeted Drug

Identifying prognostic indicators of clear cell renal cell carcinoma (ccRCC) and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis. This study investigated the clinical significance and biological role of Ring finger protein 43 ( RNF43) in ccRCC. Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses. In vitro and in vivo experiments, RNA-seq, and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms. RNF43 expression was commonly decreased in ccRCC specimens, and low expression of RNF43 indicated a higher TNM stage, SSIGN score, and WHO/ISUP grade and short survival in patients with ccRCC. Additionally, RNF43 overexpression suppressed the proliferation, migration, and targeted drug resistance of ccRCC cells, while the knockdown of RNF43 enhanced these characteristics of ccRCC. RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP. By contrast, RNF43 overexpression showed the opposite effects. Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC. Additionally, restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC. Furthermore, combining the expression of RNF43 andYAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients. In summary, our study identified a novel tumor suppressor, RNF43, which is also a prognostic indicator and potential target for ccRCC potential target for ccRCC.

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Impact of Laparoscopic Partial Nephrectomy and Open Partial Nephrectomy on Outcomes of Clear Cell Renal Cell Carcinoma

Frontiers in Surgery ◽

10.3389/fsurg.2021.681835 ◽

2021 ◽

Vol 8 ◽

Author(s):

Feng Yu ◽

Qian Xu ◽

Xian-Gen Liu

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Partial Nephrectomy ◽

Renal Cell ◽

Clear Cell ◽

Laparoscopic Partial Nephrectomy ◽

Inflammatory Factors ◽

Cell Renal Cell Carcinoma ◽

Open Partial Nephrectomy ◽

The Impact

Objective: To analyze the impact of laparoscopic partial nephrectomy (LPN) and open partial nephrectomy (OPN) on outcomes of complex clear cell renal cell carcinoma (ccRCC).Methods: A total of 132 high-complex ccRCC patients with a Radius Exophytic Nearness Anterior Location (R.E.N.A.L) score ≥7 enrolled in our hospital between January 2018 and June 2020 were matched and assigned to an LPN group (given LPN treatment) and an OPN group (given OPN treatment), with 66 cases in each group. Two weeks and 3 months after the operation, the renal indexes, inflammatory factors, basic perioperative conditions, and incidence of complications were compared.Results: Two weeks after the operation, the levels of SCr and CysC were elevated, with higher levels observed in the LPN group (all P < 0.05), and the eGFR levels were reduced, with a lower result in the LPN group. Three months after the operation, the two groups observed decreased levels of SCr and CysC, and an increased level of eGFR; moreover, the decreased SCr and CysC levels were still higher, and the increased eGFR was lower than those before the operation (P < 0.05). The levels of CRP and TNF-α in the two groups increased after the operation, with a lower outcome in the LPN group (P < 0.05). Moreover, the LPN group had less intraoperative blood loss and shorter postoperative length of hospital stay but longer blocking time compared to the OPN group (P < 0.05). Patients in the LPN group were recorded with a lower complication incidence compared with the OPN group (3.03 vs. 15.15%, P < 0.05).Conclusion: Both LPN and OPN enjoy significant efficacy in the treatment of complex ccRCC and effectively protect renal function. Moreover, LPN is a more acceptable option for complex ccRCC due to its numerous benefits in postoperative stress response, complications, recovery. which is worthy of promotion with safety and feasibility.

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MiRNA-424-5p Suppresses Proliferation, Migration, and Invasion of Clear Cell Renal Cell Carcinoma and Attenuates Expression of O-GlcNAc-Transferase

Cancers ◽

10.3390/cancers13205160 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5160

Author(s):

Thomas J. Kalantzakos ◽

Travis B. Sullivan ◽

Thales Gloria ◽

David Canes ◽

Alireza Moinzadeh ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Proliferation ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Stage I ◽

Migration And Invasion ◽

Cell Renal Cell Carcinoma ◽

Glcnac Transferase ◽

The Impact

MicroRNAs (miRNAs) are non-coding post-transcriptional regulators of gene expression that are dysregulated in clear cell renal cell carcinoma (ccRCC) and play an important role in tumor progression. Our prior work identified a subset of miRNAs in pT1 ccRCC tumors, including miR-424-5p, that are associated with an aggressive phenotype. We investigate the impact of this dysregulated miRNA and its protein target O-GlcNAc-transferase (OGT) to better understand the mechanisms behind aggressive stage I ccRCC. The ccRCC cell lines 786-O and Caki-1 were used to assess the impact of miR-424-5p and OGT. Cells were transfected with pre-miR-424-5p, a lentiviral anti-OGT shRNA, or were treated with the demethylating agent 5-Aza-2′-deoxycytidine. Cell proliferation was measured via MT cell viability assay. Cell migration and invasion were analyzed using Transwell assays. The expression of miR-424-5p was determined through qRT-PCR, while OGT protein expression was evaluated through Western blotting. The interaction between miR-424-5p and OGT was confirmed via luciferase reporter assay. The transfection of ccRCC cells with pre-miR-424-5p or anti-OGT shRNA significantly inhibited cell proliferation, migration, and OGT expression, while miR-424-5p also attenuated cell invasion. Addition of the demethylating agent significantly reduced cell proliferation, migration, invasion, and OGT expression, while significantly increasing the expression of miR-424-5p. Altogether, these findings suggest that epigenetic downregulation of miR-424-5p, which in turn augments OGT expression, contributes to the creation of aggressive forms of stage I ccRCC.

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The impact of estimated tumour purity on gene expression-based drug repositioning of Clear Cell Renal Cell Carcinoma samples

Scientific Reports ◽

10.1038/s41598-019-39891-y ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Karel K. M. Koudijs ◽

Anton G. T. Terwisscha van Scheltinga ◽

Stefan Böhringer ◽

Kirsten J. M. Schimmel ◽

Henk-Jan Guchelaar

Keyword(s):

Gene Expression ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Drug Repositioning ◽

Cell Renal Cell Carcinoma ◽

The Impact

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MicroRNAs MiR-15a and MiR-26a cooperatively regulate O-GlcNAc-transferase to control proliferation in clear cell renal cell carcinoma

Cancer Biomarkers ◽

10.3233/cbm-200553 ◽

2020 ◽

pp. 1-9

Author(s):

Thomas J. Kalantzakos ◽

Travis B. Sullivan ◽

Luke E. Sebel ◽

David Canes ◽

Eric J. Burks ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Negative Control ◽

Luciferase Assay ◽

Luciferase Reporter ◽

Cell Renal Cell Carcinoma ◽

Glcnac Transferase ◽

The Impact

BACKGROUND: MicroRNAs (miRNAs), a group of non-coding post-transcriptional regulators of gene expression, are dysregulated in clear cell renal cell carcinoma (ccRCC) and play an important role in carcinogenesis. Our prior work identified a subset of miRNAs in pT1 ccRCC tumors associated with progression to metastatic disease. OBJECTIVE: To investigate the impact of two of these dysregulated miRNA, miR-15a-5p and -26a-5p, in an effort to elucidate the mechanisms underpinning aggressive forms of stage I ccRCC. METHODS: The ccRCC cell line 786-O was transfected with pre-miRs-15a-5p and -26a-5p to rescue expression. Cell proliferation was measured via MT Cell Viability Assay. O-GlcNAc-transferase (OGT), a known protein in ccRCC proliferation, was identified by bioinformatics analysis as a target of both miRNA and validated via luciferase reporter assay to confirm binding of each miR to the 3′ untranslated region (UTR). OGT protein expression was evaluated via western blotting. RESULTS: Luciferase assay confirmed specificity of miR-15a-5p and -26a-5p for the OGT UTR. Western blot analysis for OGT showed reduced expression following co-transfection of both miRNAs compared to negative control or individual transfection. Co-transfection of these miRNAs greatly reduced proliferation when compared to negative control or the individual transfections. CONCLUSION: Our results indicate that the dysregulation of miR-15a-5p and -26a-5p contribute cooperatively to the proliferation of ccRCC through their regulation of OGT. These results give insight into the pathogenesis of aggressive early stage ccRCC and suggest potential therapeutic targets for future research.

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