Impact of obesity and adiponectin signaling in patients with renal cell carcinoma: A potential mechanism for the obesity paradox.

449 Background: Obesity increases the risk of renal cell carcinoma (RCC); however, obese patients experience longer survival than non-obese patients. The mechanism of this “obesity paradox” is unknown. We examined the impact of obesity, total adiponectin (AD) level, and intratumoral AD receptors expression on RCC aggressiveness and survival, and also investigated the mechanism underlying enhanced cancer aggressiveness in RCC cells with exogenous adiponectin stimulation. Methods: A total of 129 RCC patients treated with surgery were included in the analyses. Preoperative BMI, serum total adiponectin (AD) level, total AD secretion from perinephric adipose tissue, and intratumoral AD receptors mRNA and protein expression were analyzed. Caki-2 and 786- cells were used for in vitro functional analyses. Results: Overweight and obese patients had significantly lower grade cancers than normal patients in all patients and in those without metastasis (p = 0.003, and p = 0.027, respectively). Cancer-specific survival in overweight and obese patients was significantly better than in normal patients in all patients (p = 0.035). A weak inverse correlation existed between serum AD level and BMI in RCC patients (r = −0.344). Tumor size was slightly correlated with serum AD level, and high serum AD was significantly associated with poor overall survival in patients without metastasis (p = 0.035). The AD level of perinephric adipose tissue and intratumoral AdipoR1/R2 expression in tumors did not correlate with RCC aggressiveness and survival. Exogenous AD significantly enhanced proliferation, but not invasion or migration in 786-O and Caki-2 cells. Exogenous AD significantly inhibited starvation- and metformin-induced apoptosis, and up-regulated p-AMPK and Bcl-xL in these cells. Conclusions: Low BMI and high AD level are associated with cancer aggressive and poor survival in RCC patients treated surgically. AD modulates proliferation and apoptosis, which may underlie the “obesity paradox” of RCC.

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Biological Support to Obesity Paradox in Renal Cell Carcinoma: A Review

Urologia Internationalis ◽

10.1159/000510245 ◽

2020 ◽

Vol 104 (11-12) ◽

pp. 837-848

Author(s):

Ming Li ◽

Renge Bu

Keyword(s):

Renal Cell Carcinoma ◽

Adipose Tissue ◽

Risk Factor ◽

Prognostic Factor ◽

Cell Carcinoma ◽

Renal Cell ◽

Prognostic Model ◽

Obesity Paradox ◽

Local Tumor ◽

Biological Association

Obesity is a proven risk factor and a debated prognostic factor in renal cell carcinoma (RCC). Termed as an “obesity paradox,” the topic has churned controversies, with a few arguing of no true biological association. Suggesting otherwise, a few studies revealed adiposity-induced altered molecular and transcriptomic signatures, at both the systemic and local (tumor and peritumoral adipose tissue) levels, in RCC patients, favoring the paradox. Summarizing such studies suggests of a considerable biological support to adiposity as a promising prognostic factor in RCC patients, although much needs to be clarified before adopting it as a valuable addition to the existing prognostic model.

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The impact of obesity and adiponectin signaling in patients with renal cell carcinoma: A potential mechanism for the “obesity paradox”

PLoS ONE ◽

10.1371/journal.pone.0171615 ◽

2017 ◽

Vol 12 (2) ◽

pp. e0171615 ◽

Cited By ~ 13

Author(s):

Ryuichi Ito ◽

Shintaro Narita ◽

Mingguo Huang ◽

Taketoshi Nara ◽

Kazuyuki Numakura ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Obesity Paradox ◽

Potential Mechanism ◽

The Impact

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Gender impact on renal cell carcinoma survival: A population-based analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17099 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17099-e17099

Author(s):

Firas Baidoun ◽

Inas A. Ruhban ◽

Anas M Saad ◽

Mohamed Gad ◽

Muneer J. Al-Husseini ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

P Value ◽

Lower Grade ◽

Cancer Specific Survival ◽

Cox Models ◽

Survival Difference ◽

The Us ◽

The Impact

e17099 Background: Prior evidence has suggested that females diagnosed with renal cell carcinoma (RCC) present at an earlier stage compared to males, but a survival difference between males and females has been controversial. We aimed to evaluate the impact of gender on RCC survival in the US. Methods: Data of RCC patients diagnosed between 1973 and 2015 in the US was obtained using Surveillance Epidemiology and End Results (SEER) database. We studied the overall and cancer-specific survival of patients diagnosed with RCC in the US according to gender using multivariable covariate-adjusted Cox models and Kaplan-Meier test. Results: We reviewed 155,430 RCC patients, of which 96,656 were males, and 58,774 were females. The median overall survival of female patients was 122 months and was significantly higher than male patients (98 months). Cancer-specific survival showed similar trends with females having significantly higher survival (p-value < 0.001). Adjusted for age, race, stage and grade of cancer, undergoing cancer-targeted surgery, and marital status, female sex was associated with improved overall and cancer-specific survival outcomes; HR = 0.829 (p-value < 0.001), and HR = 0.923 (p-value < 0.001), respectively. Conclusions: Females have a significantly better overall and cancer specific survival compared to males diagnosed with renal cell carcinoma. In previous studies this disparity was attributed to the lower grade and earlier stage of RCC presentation in females, but gender-based disparity persisted in this analysis after adjusting for patient baseline and tumor characteristics. This raises the question of the hormonal effects on the progression of RCC.

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The DEAD/DEAH Box Helicase, DDX11, Is Essential for the Survival of Advanced Clear Cell Renal Cell Carcinoma and Is a Determinant of PARP Inhibitor Sensitivity

Cancers ◽

10.3390/cancers13112574 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2574

Author(s):

Jee Soo Park ◽

Myung Eun Lee ◽

Won Sik Jang ◽

Koon Ho Rha ◽

Seung Hwan Lee ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Quantitative Polymerase Chain Reaction ◽

Parp Inhibitor ◽

Renal Tumors ◽

Low Grade ◽

Normal Kidney ◽

The Dead ◽

The Impact

Genes associated with the DEAD-box helicase DDX11 are significant biomarkers of aggressive renal cell carcinoma (RCC), but their molecular function is poorly understood. We analyzed the molecular pathways through which DDX11 is involved in RCC cell survival and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity. Immunohistochemistry and immunoblotting determined DDX11 expression in normal kidney tissues, benign renal tumors, and RCC tissues and cell lines. Quantitative polymerase chain reaction validated the downregulation of DDX11 in response to transfection with DDX11-specific small interfering RNA. Proliferation analysis and apoptosis assays were performed to determine the impact of DDX11 knockdown on RCC cells, and the relevant effects of sunitinib, olaparib, and sunitinib plus olaparib were evaluated. DDX11 was upregulated in high-grade, advanced RCC compared to low-grade, localized RCC, and DDX11 was not expressed in normal kidney tissues or benign renal tumors. DDX11 knockdown resulted in the inhibition of RCC cell proliferation, segregation defects, and rapid apoptosis. DDX11-deficient RCC cells exhibited significantly increased sensitivity to olaparib compared to sunitinib alone or sunitinib plus olaparib combination treatments. Moreover, DDX11 could determine PARP inhibitor sensitivity in RCC. DDX11 could serve as a novel therapeutic biomarker for RCC patients who are refractory to conventional targeted therapies and immunotherapies.

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