Yu Xia

PD-L1 induces epithelial-to-mesenchymal transition via activating SREBP-1c in renal cell carcinoma

The incidence of kidney cancer has been increasing globally during the past two decades. Renal cell carcinoma (RCC) is the most aggressive subtype of kidney cancer, which usually deteriorates with epithelial–mesenchymal transition (EMT) that facilitates the migration and invasion of cancer cells. Till now, the underlying mechanism remains unclear. In this study, we demonstrated that programmed death ligand 1 (PD-L1/B7-H1/CD274) could induce EMT and enhance RCC cell cancer stemness through up-regulation of SREBP-1c. Furthermore, we found that PD-L1 is up-regulated in human RCC metastases. These results, taken together, provide evidence for a novel mechanism of PD-L1 in RCC progression, suggesting that there is a close relationship between EMT and immune escape signaling pathways in RCC.

Prognostic Value of SETD2 Expression in Patients with Metastatic Renal Cell Carcinoma Treated with Tyrosine Kinase Inhibitors

PURPOSEnMutations of SETD2 occur in 3% to 16% of clear cell renal cell carcinoma cases. Previous studies identified an association between SETD2 mutation and prognosis of patients with nonmetastatic clear cell renal cell carcinoma. In this study we explored the prognostic and predictive value of SETD2 expression in patients with metastatic renal cell carcinoma treated with targeted therapy.nnnMATERIALS AND METHODSnWe retrospectively enrolled 138 patients with metastatic renal cell carcinoma treated with sunitinib or sorafenib at a single institution from 2007 to 2014. SETD2 expression was assessed by immunohistochemistry on tissue microarrays.nnnRESULTSnAfter excluding those patients with loss of followup or unavailable tissue samples, 111 were included in the study. Low SETD2 expression was associated with reduced overall survival (p <0.001) and progression-free survival (p=0.001). After adjustment for histological type, Heng risk group and drugs used for targeted therapy, SETD2 was defined as an independent prognostic marker for overall survival (HR 2.535 [95% CI 1.429-4.497], p=0.001) and progression-free survival (HR 1.755 [95% CI 1.031-2.988], p=0.038). Its prognostic value for overall survival was more predominant in patients with clear cell renal cell carcinoma (p <0.001) or patients in the intermediate risk group of Heng risk criteria (p <0.001), while its predictive value for progression-free survival was more predominant in patients treated with sorafenib (pxa0<0.001). SETD2 could also be combined with the Heng risk model for better overall survival prediction.nnnCONCLUSIONSnSETD2 is a potential prognostic biomarker for overall survival and progression-free survival prediction in patients with metastatic renal cell carcinoma receiving targeted therapy. However, it remains to be seen whether this is generalizable to other ethnicities and prospective external validation is required.

Prognostic value of UTX expression in patients with clear cell renal cell carcinoma

PURPOSEnOur previous studies have identified an abnormal H3K27 methylation status in clear cell renal cell carcinoma (ccRCC). Ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) has been demonstrated as a histone demethylase that specifically targets di-methyl groups and tri-methyl groups on lysine 27 of histone H3 (H3K27me2/3). Herein, we explored the prognostic value of tumoral UTX expression in patient with ccRCC.nnnPATIENTS AND METHODSnWe retrospectively enrolled 290 ccRCC patients underwent nephrectomy at a single institution between 2005 and 2007. UTX expression was assessed by immunohistochemistry on tissue microarrays and its prognostic value was assessed using Kaplan-Meier method and Cox proportional hazard model. Nomograms were generated as prediction models for overall survival (OS) and disease free survival (DFS).nnnRESULTSnLow expression of UTX was associated with reduced OS (P<0.001) and DFS (P = 0.001). In multivariate cox analyses, UTX was defined as an independent prognostic factor for OS (hazard ratio = 2.732 [95% CI: 1.650-4.493], P<0.001) and DFS (hazard ratio = 1.959 [95% CI: 1.153-3.326], P<0.001) as well. After stratifying patients into different risk groups using the Mayo Clinic stage, size, grade and necrosis/Leibovich score, decreased UTX expression was associated with shorter OS in both low-risk (P = 0.002) and high-risk groups (P = 0.030), but with shorter DFS only in low-risk group (P<0.001). Overall, 2 nomograms incorporating UTX expression with other parameters performed well in predicting patients 5-year and 8-year OS and DFS (c-indices = 0.824 and 0.798, respectively).nnnCONCLUSIONSnUTX is a prognostic biomarker for patients with ccRCC both in OS and DFS prediction, especially significant in low-risk patients.

High Level of Anaphylatoxin C5a Predicts Poor Clinical Outcome in Patients with Clear Cell Renal Cell Carcinoma

Anaphylatoxin C5a, a potent pro-inflammatory peptide produced in the process of complement activation, was proved to have a vital role in tumor initiation and progession by previous investigations. However whether it could act as a prognostic marker remains unknown. Here we retrospectively enrolled 272 ccRCC patients undergoing nephrectomy in Zhongshan Hospital, Shanghai between 2005 and 2007. C5a level was assessed by immunohistochemistry and its association with clinicopathologic features and prognosis were evaluated. Our results indicated that high tumoral C5a level was associated with poor overall survival (OS) (hazard ratiou2009=u20091.753, 95% CI 1.068–2.878, Pu2009=u20090.026). In addition, tumoral C5a could significantly stratify patients’ prognosis both in advanced stage (TNM IIIu2009+u2009IV) and intermediate/high risk group (SSIGN score ≥4) (Pu2009<u20090.001 andu2009=u20090.008, respectively). Furthermore, incorporating tumoral C5a with other parameters could improve the predicting accuracy, compared with TNM and SSIGN system (c-indexu2009=u20090.789, 0.713 and 0.727, respectively). In conclusion, tumoral C5a is an independent adverse prognostic biomarker for clinical outcome of ccRCC patients after nephectomy.

Enrichment of C5a-C5aR axis predicts poor postoperative prognosis of patients with clear cell renal cell carcinoma

Anaphylatoxin C5a and its receptor C5aR on cancer cells constitute a vital axis to cancer progression. In this study, we measured C5aR level by immunohistochemistry in the same cohort of our previous C5a research, and C5a-C5aR axis status was determined by synthesizing C5a and C5aR data. C5aR was an adverse independent prognostic factor for ccRCC patients. Kaplan-Meier analyses revealed the unique position of both C5a and C5aR high population in postoperative survival, based on which patients were then shunted into C5a-C5aR enriched and non-enriched groups. Obviously, C5a-C5aR enriched patients significantly had a poorer overall survival (OS) and recurrence free survival (RFS) compared with non-enriched ones, and the independence of C5a-C5aR axis was verified by multivariable analyses (HR 2.118, P = 0.001 for OS, HR 1.715, P = 0.035 for RFS). Established nomograms based on our findings reflected much better predicting accuracy in contrast with most common used TNM and Fuhrman systems. Meanwhile, consistent with HR, C5a-C5aR axis in this study held its advantages over C5a and C5aR for OS prediction by c-index analyses, rather than RFS prediction.

Tumor infiltrating CD19+ B lymphocytes predict prognostic and therapeutic benefits in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors

ABSTRACT The objective response rate (ORR) of tyrosine kinase inhibitors (TKIs) therapy in metastatic renal cell cancer (mRCC) patients was not satisfactory. Effective indicator of mRCC patient selection for TKI therapy is urgently needed. The function of tumor infiltrating B lymphocytes (TIBs) in tumor immune elimination is still unclear. We aim to investigate the prognostic and predictive value of TIBs for TKI therapy in mRCC patients in this study. 108 eligible patients treated with TKI were enrolled in this study. TIBs was estimated by immunohistochemical staining of CD19 in the resected tumor, and its relationship with clinicopathological features, clinical outcomes and CD8+ tumor infiltrating T lymphocytes (CD8+ TILs) were evaluated. Associations between the expression level of CD19 and CD8+ TILs associated cytotoxic effectors were also assessed in public databases. Results showed TIBs positive infiltration predicted better therapeutic response to sunitinib (p = 0.006), longer overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p = 0.028) in mRCC patients. Combining TIBs and International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) model showed a better predict value of OS in TKI-treated mRCC patients than IMDC model alone. We also found a positive correlation between TIBs and CD8+ TILs (p < 0.001). Patients with both cells high infiltration showed markedly better OS compared with those infiltrated by CD8+ T cells alone (p = 0.015). To conclude, TIBs density was not only an independent prognostic factor for mRCC patients, but also a predictive marker for TKI therapy response. It may potently enhance the antitumor effect by recruiting and activating CD8+ TILs in mRCC.

Decreased expression of JMJD3 predicts poor prognosis of patients with clear cell renal cell carcinoma

Previous studies have demonstrated abnormal H3K27 methylation status during clear cell renal cell carcinoma (ccRCC) carcinogenesis, and have suggested that the histone H3K27 demethylases, jumonji domain-containing protein 3 (JMJD3) and ubiquitously-transcribed TPR gene on the X chromosome, are important regulatory factors that alter H3K27 methylation status. The present study aimed to explore the prognostic value of JMJD3 in patients with ccRCC. A total of 331 ccRCC samples were stained for JMJD3 by immunohistochemistry. Stage, Size, Grade and Necrosis (SSIGN) and University of California Los Angeles Integrated Staging System (UISS) scores were applied to stratify risks. Survival analyses were performed through the Kaplan-Meier estimator method and Cox proportional hazard model. The results revealed that JMJD3 expression in ccRCC was significantly increased compared with that in the peritumoral tissue (P<0.001) and negatively associated with a number of other clinicopathological characteristics. Kaplan-Meier estimator and multivariate analyses revealed that decreased tumoral JMJD3 expression was associated with OS (hazard ratio, 2.141; P=0.003), and DFS prediction (hazard ratio, 1.737; P=0.033). In addition, following stratification of patients into three risk levels using the SSIGN and UISS scores, decreased tumoral JMJD3 expression was associated with shorter OS (P=0.003 for SSIGN and UISS scores) and DFS (P=0.007 for SSIGN and P=0.041 for UISS score) in the intermediate risk groups. The results from the present study suggest that JMJD3 is a novel prognostic marker for patients with ccRCC and is of particular significance in patients with intermediate-risk disease.

Prognostic value of copper transporter 1 expression in patients with clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) features a Von Hippel-Lindau mutation, associated with a hypoxia-inducible factor (HIF) imbalance. Copper transporter 1 (CTR1) may also promote tumor progression through the modulation of the HIF pathway by copper. Therefore, the present study explored the prognostic effect of tumor CTR1 expression in patients with ccRCC. A total of 293 patients with ccRCC that underwent nephrectomy were retrospectively enrolled. CTR1 expression was assessed by immunohistochemistry, and its association with clinicopathological features and prognosis were evaluated. The present data indicated that high tumor CTR1 expression was independently associated with poor overall survival (OS) [hazard ratio, 2.291; 95% confidence interval (CI), 1.389–3.777; P<0.001] and disease-free survival (DFS) (hazard ratio, 2.210; 95% CI, 1.299–3.759; P=0.003) rates in patients with ccRCC. Furthermore, CTR1 expression was significantly higher for Mayo Clinic stage, size, grade and necrosis score risk groups, and could be incorporated into several existing prognostic models to improve performance. Nomograms incorporating tumor CTR1 expression with other parameters performed well in the 5- and 8-year OS and DFS rate predictions of patients (concordance index 0.805 and 0.787, respectively). In conclusion, the present study demonstrated that CTR1 expression is a potential independent biomarker for poor prognosis for the recurrence and survival prediction of patients with ccRCC following nephrectomy.

Low CCL17 expression associates with unfavorable postoperative prognosis of patients with clear cell renal cell carcinoma

BackgroundChemokine (C–C motif) ligand 17 (CCL17) is a chemokine mainly produced by myeloid dendritic cells. It is a ligand for CC chemokine receptor 4 (CCR4) and CC chemokine receptor 8 (CCR8). The aim of this study was to investigate prognostic values of CCL17 expression in patients with clear cell renal cell carcinoma (ccRCC).MethodsThe study included 286 patients with ccRCC. CCL17 expression was analyzed by immunohistochemistry on tissue microarrays. Prognostic values of CCL17 expression and patients’ clinical outcomes were evaluated.ResultsKaplan-Meier method showed that low CCL17 expression was associated with worse patient overall survival (OS) and recurrence-free survival (RFS) (OS, Pu2009=u20090.002; RFS, Pu2009=u20090.007). Low CCL17 expression was an adverse independent risk factor for OS and RFS in multivariate analyses (OS, Pu2009=u20090.006, Pu2009=u20090.011 for bootstrap; RFS, Pu2009=u20090.002, Pu2009=u20090.025 for bootstrap). We constructed two nomograms incorporating parameters derived from multivariate analyses to predict patients’ OS and RFS (OS, c-index 0.799; RFS, c-index 0.787) and they performed better than existed integrated models.ConclusionLow CCL17 expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with ccRCC after nephrectomy. Established nomograms based on this information could help predict ccRCC patients’ OS and RFS.

Prognostic value of CC-chemokine receptor seven expression in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitor

BackgroundCC-chemokine receptor seven (CCR7), a G-protein coupled receptor normally facilitating immune cells lymphatic homing, has recently been identified on several cancer cells in promoting invasion and lymphatic specific metastasis by mimicking normal leukocytes. As tyrosine kinase inhibitors for metastatic renal cell carcinoma (mRCC) mostly emphasized on vascular inhibition, whether the CCR7 expressing tumor cells with potential lymphatic invasion function could have an impact on mRCC patient’s drug response and survival, was unknown.MethodsIn this study, in a clinical aspect, we retrospectively investigated the prognostic and predictive impact of tumoral CCR7 expression in 110 mRCC patients treated with sunitinib and sorafenib, and its correlation with pre- or post-administration lymphatic involvement. Immunohistochemistry on tissue microarrays were conducted for CCR7 expression evaluation.ResultsKaplan-Meier and univariate analyses suggested high tumoral CCR7 expression as an adverse prognosticator for mRCC patients’ overall survival (OS), which was further confirmed in the multivariate analyses (Pu2009=u20090.002, Pu2009=u20090.003 for bootstrap). This molecule could be combined with Heng’s risk model for better patient OS prediction. High tumoral CCR7 expression was also an independent dismal predictor for patients’ progression free survival (PFS) (Pu2009=u20090.010, Pu2009=u20090.013 for bootstrap), and correlated with poorer best drug response. Moreover, a possible correlation of CCR7 high expression and patients’ baseline and post-administration lymph node metastasis was found.ConclusionsHigh tumoral CCR7 expression correlated with potential lymphatic involvement and poor prognosis of mRCC patients treated with tyrosine kinase inhibitors. Further external validations and basic researches were needed to confirm these results.