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Background: Histologic tumor necrosis (TN) is a well-established independent prognostic indicator in patients treated surgically for clear cell renal cell carcinoma (ccRCC). However, the precise mechanisms by which TN alters disease progression remain unknown. The DEAD-box protein DDX41, a member of a large family of helicases, has been characterized as a pattern recognition receptor against an array of double-stranded (ds)DNA produced from bacteria, dsDNA viruses, and nearby cells that have released dsDNA fragments through necrosis. We hypothesized that DDX41 expression may be upregulated in ccRCC with TN, leading to worse prognosis., Methods: Relationship between the presence of TN and DDX41 expression were examined using The Cancer Genome Atlas data sets or using ccRCC samples in our institution. Further, the molecular functions of DDX41 were investigated with human ccRCC cells., Results: The presence of TN was significantly associated with the upregulation of mRNA and protein expression of DDX41 in the 2different patient cohorts with ccRCC. In addition, the mRNA and protein expression levels of DDX41 revealed a worse prognosis. In vitro analyses with ccRCC cells revealed that DDX41 expression promotes tumor-promoting activity. Furthermore, VHL loss, 1of the most common features in ccRCC, was shown to play an extremely important role in increasing the expression of the CXCL family in DDX41-expressing ccRCC, leading to the acquisition of a worse malignant phenotype., Conclusions: DDX41 expression is associated with TN in ccRCC and leads to a worse prognosis in cooperation with VHL loss., Competing Interests: Conflict of interest All authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background/aim: Sunitinib continues to be administered as a first-line therapeutic agent in metastatic renal cell carcinoma (mRCC). This study aimed to examine the role of CD44 in sunitinib resistance and as a predictive marker in mRCC., Materials and Methods: We analyzed the effect of CD44 knockdown on sunitinib resistance in RCC cell lines using WST-1 assays. CD44 expression in mRCC patients treated with first-line sunitinib was determined by immunohistochemistry. We validated the findings of this study by in silico analysis., Results: CD44 knockdown increased sensitivity to sunitinib. Immunohistochemical analysis revealed that 19 (34.5%) of 55 mRCC cases were positive for CD44. CD44-positive cases were associated with poor progression-free survival (PFS) after first-line sunitinib treatment. In the JAVELIN 101 study, high CD44 expression was significantly associated with poor PFS after sunitinib but not after avelumab + axitinib therapy., Conclusion: CD44 is involved in sunitinib resistance and may be a promising marker for sunitinib treatment in mRCC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Sunitinib continues to be administered as a first-line therapeutic agent in metastatic renal cell carcinoma (mRCC). This study examined the potential role of p53 in sunitinib resistance and as a predictive marker in mRCC., Materials and Methods: We analysed the effects of p53 knockout on sunitinib resistance. p53 expression in 53 mRCC patients receiving first-line sunitinib was determined immunohistochemically. We performed in silico analysis to examine the predictive value of p53 in mRCC., Results: WST-1 assays showed that p53 knockout decreased sensitivity to sunitinib. Sunitinib and nutlin-3 together suppressed cell growth. Immunohistochemistry revealed 11 p53-positive cases among 53 patients with mRCC. Kaplan-Meier analysis showed that p53-positive cases tended to be associated with poor progression-free survival (PFS) after first-line sunitinib treatment. In the JAVELIN 101 study, TP53 mutation was significantly associated with poor PFS after sunitinib treatment., Conclusion: p53 may be involved in sunitinib resistance and represent a valuable marker for sunitinib treatment in mRCC., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: BUB1 mitotic checkpoint serine/threonine kinase B encoded by BUB1B gene is a member of the spindle assembly checkpoint family. Several reports have demonstrated that overexpression of BUB1B is associated with cancer progression and prognosis., Objective: This study aims to clarify the expression and function of BUB1B in renal cell carcinoma (RCC)., Methods: The expression of BUB1B was determined using immunohistochemistry and bioinformatics analysis in RCC. The effects of BUB1B knockdown on cell growth and invasion were evaluated. We analyzed the interaction between BUB1B, cancer stem cell markers, p53, and PD-L1 in RCC., Results: In 121 cases of RCC, immunohistochemistry showed that 30 (25%) of the RCC cases were positive for BUB1B. High BUB1B expression was significantly correlated with high nuclear grade, T stage, and M stage. A Kaplan-Meier analysis showed that the high expression of BUB1B was associated with poor overall survival after nephrectomy. High BUB1B expression was associated with CD44, p53, and PD-L1 in RCC. Knockdown of BUB1B suppressed cell growth and invasion in RCC cell lines. Knockdown of BUB1B also suppressed the expression of CD44 and increased the expression of phospho-p53 (Ser15). In silico analysis showed that BUB1B was associated with inflamed CD8+, exhausted T-cell signature, IFN-γ signature, and the response to nivolumab., Conclusion: These results suggest that BUB1B plays an oncogenic role and may be a promising predictive biomarker for survival in RCC., (© 2021 S. Karger AG, Basel.)

Introduction: Microtubule-associated protein tau (MAPT) overexpression has been linked to poor prognosis in several cancers. MAPT-AS1 is a long noncoding RNA existing at the antisense strand of the MAPT promoter region. The clinical significance of MAPT and MAPT-AS-1 in clear cell renal cell carcinoma (ccRCC) is unknown. This study aimed to assess the expression and function of MAPT and MAPT-AS1 in ccRCC., Methods: The expression of MAPT was determined using immunohistochemistry in ccRCC. The effects of MAPT knockdown on cell growth and invasion were evaluated and the interaction between MAPT and microtubule-associated protein tau antisense (MAPT-AS1) were analyzed. The expression of MAPT-AS1 was determined using quantitative reverse transcription polymerase chain reaction in ccRCC tissues. We investigated the effect of MAPT-AS1 knockdown on cell growth and invasion. We analyzed the regulation of MAPT and MAPT-AS1., Results: Immunohistochemistry in 135 ccRCC cases showed that 61% of the cases were positive for MAPT. Kaplan-Meier analysis showed that the low expression of MAPT was associated with poor overall survival after nephrectomy. Knockdown of MAPT enhanced cell growth and invasion. quantitative reverse transcription polymerase chain reaction revealed a positive correlation between MAPT and MAPT-AS1. The expression of MAPT-AS1 was higher in ccRCC tissue than in nonneoplastic kidney tissue. Kaplan-Meier analysis showed that the low expression of MAPT-AS1 was associated with poor overall survival after nephrectomy by in silico analysis. MAPT-AS1 knockdown promoted cell growth and invasion activity. P53 knockout suppressed the expression of MAPT and MAPT-AS1., Conclusion: These results suggest that MAPT and MAPT-AS1 may be promising predictive biomarkers for survival and play a tumor-suppressive role in ccRCC., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: Previous studies have reported that cases with clinical T1 renal cell cancer upstaging to pathological T3 are a risk factor to predicting postoperative recurrence after partial nephrectomy. The aim of our study was to investigate the impact of the radiological morphology of the enhanced CT scan of clinical T1 renal cell cancer on predicting upstaging to pathological T3., Methods: Three hundred sixty-seven cases with clinical T1 renal cell cancer diagnosed from enhanced CT scans were enrolled in this study. Based on the findings from the enhanced CT scan, the cases were classified into 'round', the margins of which were smooth and round; 'lobular', one or more findings of smooth dent and no spiky dent were identified on the margin of the tumor; and 'irregular', one or more spiky dent were identified on the margin of the tumor. The association of postoperative upstaging with these radiological morphology and other clinical characteristics of each case was analyzed., Results: Eighteen cases (4.9%) pathologically upstaged to T3a. Two round case (0.7%), 3 lobular cases (10.0%) and 13 irregular cases (22.0%) pathologically upstaged (P < 0.001, round + lobular versus irregular). Four of 17 cases (23.5%) with hilar tumors pathologically upstaged, while 14 of 350 cases (4%) with tumors pathologically upstaged in other sites (P < 0.001). Multivariate analysis revealed that irregular case was an independent factor in predicting upstaging to pathological T3a (P < 0.001)., Conclusions: Evaluation of the radiological morphology of clinical T1 renal cell cancer based on enhanced CT scans is useful for predicting pathological upstaging., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background/aim: Targeted receptor tyrosine kinase inhibitor (TKI) is a standard treatment in advanced renal cell carcinoma (RCC). However, the role of PTEN in TKI resistance remains poorly understood. We aimed to determine the functional role of PTEN knockout and analyse the predictive significance of PTEN expression for TKI treatment in RCC., Materials and Methods: We developed PTEN knockout cells in RCC cell lines using the CRISPR-Cas9 system and analysed the effect of PTEN knockout on spheroid formation and resistance to sunitinib and sorafenib., Results: PTEN knockout promoted spheroid formation and decreased sunitinib/sorafenib sensitivity in RCC cell lines. PTEN immunohistochemistry in 74 metastatic RCCs treated with sunitinib and sorafenib revealed negative PTEN expression in 23% of samples. Kaplan-Meier analysis showed a significant association of negative PTEN expression with poor progression-free survival in metastatic RCC treated with sunitinib and sorafenib (p=0.024) or sunitinib alone (p=0.009)., Conclusion: PTEN may be a biomarker and therapeutic target in patients with metastatic RCC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Renal cell carcinoma (RCC) is one of the most common human cancers. We previously reported that claspin is a key regulator in the progression of gastric cancer, and it likely plays an important role in cancer stem cells of gastric cancer. However, the significance of claspin in RCC has not been examined. First, we analyzed the expression and distribution of claspin in 95 RCC cases by immunohistochemistry. In the nonneoplastic kidney, the staining of claspin was either weak or absent, whereas RCC tissue showed nuclear staining. In total, claspin expression was detected in 45 (47%) of 95 RCC cases. The claspin staining appeared relatively stronger in high nuclear grade RCC than in low nuclear grade RCC. Claspin-positive RCC cases were associated with higher T grade, tumor stage, nuclear grade, vein invasion, and poorer prognosis. CLSPN siRNA treatment decreased RCC cell proliferation. The levels of phosphorylated Erk and Akt were lower in CLSPN siRNA-transfected RCC cells than in control cells. In addition, claspin was coexpressed with CD44, epidermal growth factor receptor, p53, and programmed death ligand-1. These results suggest that claspin plays an important role in tumor progression in RCC and might be a prognostic marker and novel therapeutic target molecule., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: MicroRNAs are a class of small noncoding RNAs that play an important role in progression and drug resistance in cancer. Several reports have shown that miR-130b modulates cell growth and drug resistance in some cancers. However, the expression and biological role of miR-130b in renal cell carcinoma (RCC) remain poorly understood. This study aimed to examine the expression and functional role of miR-130b and to analyze the association between miR-130b and sunitinib resistance in RCC., Methods: The expression of miR-130b in 32 RCC tissues and their corresponding normal kidney tissues was determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). We performed a 4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay in RCC cell lines transfected with miR-130b inhibitor or miR-130b mimics. We evaluated the relationship between miR-130b and PTEN and also analyzed the effect of miR-130b on sunitinib resistance., Results: qRT-PCR analysis showed that the expression of miR-130b was higher in RCC tissues than in corresponding normal kidney tissues. The MTT assay revealed that miR-130b modulated cell growth. qRT-PCR revealed an inverse correlation between miR-130b and PTEN in RCC. Western blotting demonstrated that miR-130b regulated the expression of PTEN in the RCC cell line. Additionally, miR-130b was associated with sunitinib resistance through regulation of PTEN. We established the sunitinib-resistant Caki-1 (Caki-1-SR) cells and observed that the expression of miR-130b was elevated in Caki-1-SR cells compared with parental Caki-1 cells. Knockdown of miR-130b improved sunitinib resistance in Caki-1-SR cells., Conclusion: The expression of miR-130b was upregulated in RCC. miR-130b promoted cell growth and was associated with sunitinib resistance through regulating PTEN expression. Collectively, these results suggest that miR-130b may play an oncogenic role and be a promising therapeutic target., (© 2019 S. Karger AG, Basel.)

Background: The transcribed ultraconserved regions (T-UCRs) are a novel class of non-coding RNAs that are absolutely conserved across species and are involved in carcinogenesis in some cancers. However, the expression and biological role of T-UCRs in renal cell carcinoma (RCC) remain poorly understood. This study aimed to examine the expression and functional role of Uc.416 + A and analyze the association between Uc.416 + A and epithelial-to-mesenchymal transition in RCC., Methods: Expression of Uc.416 + A in 35 RCC tissues, corresponding normal kidney tissues and 13 types of normal tissue samples was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). We performed a cell growth and migration assay in RCC cell line 786-O transfected with negative control and siRNA for Uc.416 + A. We evaluated the relation between Uc.416 + A and miR-153, which has a complimentary site of Uc.416 + A., Results: qRT-PCR analysis revealed that the expression of Uc.416 + A was higher in RCC tissues than that in corresponding normal kidney tissues. Inhibition of Uc.416 + A reduced cell growth and cell migration activity. There was an inverse correlation between Uc.416 + A and miR-153. Western blot analysis showed Uc.416 + A modulated E-cadherin, vimentin and snail. The expression of Uc.416 + A was positively associated with the expression of SNAI1, VIM and inversely associated with the expression of CDH1., Conclusions: The expression of Uc.416 + A was upregulated in RCC and especially in RCC tissues with sarcomatoid change. Uc.416 + A promoted epithelial-to-mesenchymal transition through miR-153. These results suggest that Uc.416 + A may be a promising therapeutic target.

Tubulocystic renal cell carcinoma (TC-RCC) has been classified as an independent subtype according to the 2016 World Health Organization (WHO) classification. It is a rare subtype that predominantly affects men. Although few in number, radiological imaging reports have suggested that TC-RCC is characterized by multilocular cystic lesions, which are categorized as the Bosniak classification II-IV, with signature pathological characteristics comprising numerous small cysts or a tubular structure. The Bosniak classification system facilitates patient management; however, the differentiation of cystic tumors exhibiting similar imaging findings remains impossible; in fact, the differentiation of multilocular cystic RCC, adult cystic nephroma, and mixed epithelial and stromal tumor remains challenging. This review aims to discuss TC-RCC with a focus on implications of radiological findings in the differential diagnosis of TC-RCC.

Tumor growth and metastasis are determined not by cancer cells alone but also by a variety of stromal cells, various populations of which overexpress platelet-derived growth factor receptors (PDGF-Rs). In addition, activation of PI3K-AKT-mammalian target of rapamycin (mTOR) signaling is frequently observed in many cancer types as well. mTOR comprises a serine/threonine kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. In this study, we investigated the impact of molecular-targeting agents including PDGF-R and mTOR inhibitors on the tumor stroma of human kidney cancer and examined the efficacy of combination therapy with these agents against this disease. Treatment with sunitinib did not suppress tumor growth, but significantly decreased stromal reactivity, microvessel density, and pericyte coverage of tumor microvessels in an orthotopic mouse model. In contrast, treatment with everolimus decreased tumor growth and microvessel density but not stromal reactivity. However, sunitinib and everolimus in combination reduced both the growth rate and stromal reaction. These findings suggest that target molecule-based inhibition of the cancer-stromal cell interaction appears promising as an effective antitumor therapy., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Papillary renal cell carcinoma (P-RCC) typically exhibits a homogeneous, solid hypovascular mass; P-RCC with a cystic appearance is atypical. Tubulocystic RCC (TC-RCC), a newly proposed entity for renal tumors in the 2016 WHO classification, and cystic papillary RCC, may yield similar imaging findings. Therefore, we investigated the incidence of papillary RCC with cystic changes and compared its CT and pathologic features to differentiate between two entities., Methods: We retrospectively evaluated 26 consecutive patients diagnosed with P-RCC. Two radiologists consensually identified dominant masses indicative of cystic changes on CT scans and recorded their Bosniak classification. In addition, two pathologists inspected the whole area of tumors macroscopically, labeled them as solid- or cystic change-dominant tumors, determined the pathogenesis of the cystic components (necrosis or hemorrhage), and recorded their inherent cystic characteristics (with/without TC-RCC components). We defined masses with cystic changes involving more than 50% of the entire tumor as cystic change-dominant tumors., Results: Of the 26 tumors, 7 (27%) were diagnosed cystic change-dominant based on imaging and pathologic findings, of these, 2 were classified as Bosniak type III and 5 as Bosniak type IV. The pathologists confirmed that two type IV tumors demonstrated extensive necrosis and one type IV tumor revealed extensive hemorrhage. Four P-RCCs (type III and IV, 2 each) were of a mixed type harboring both solid and cystic components. Only one tumor exhibited a multilocular cystic appearance. All 7 cystic change-dominant P-RCCs were pathologically diagnosed as a pure P-RCC without TC-RCC components., Conclusion: While P-RCCs may contain cystic features, the multilocular type of cystic P-RCC is rare.

Background: Renal cell carcinoma (RCC) is one of the most common types of cancer in developed countries. Bone marrow stromal cell antigen 2 (BST2) gene, which encodes BST2 transmembrane glycoprotein, is overexpressed in several cancer types. In the present study, we analyzed the expression and function of BST2 in RCC., Materials and Methods: BST2 expression was analyzed by immunohistochemistry in 123 RCC cases. RNA interference was used to inhibit BST2 expression in a RCC cell line., Results: Immunohistochemical analysis showed that 32% of the 123 RCC cases were positive for BST2. BST2 expression was positively associated with tumour stage. Furthermore, BST2 expression was an independent predictor of survival in patients with RCC. BST2 siRNA-transfected Caki-1 cells displayed significantly reduced cell growth and invasive activity relative to negative control siRNA-transfected cells., Conclusion: These results suggest that BST2 plays an important role in the progression of RCC. Because BST2 is expressed on the cell membrane, BST2 is a good therapeutic target for RCC., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Tubulocystic carcinoma of the kidney is rare and typically indolent. Our case involved an aggressive tubulocystic carcinoma as well as the radiological confirmation of its relation to papillary renal cell carcinoma. A 46-year-old male presented with renal multiloculated cysts with a solid part. On computed tomography and magnetic resonance imaging, the solid part showed the characteristics of papillary renal cell carcinoma. Contrast enhancement of the solid part was fluffy and sparse because of the coexistence of cysts. Perirenal fat invasion resulted in exophytic cysts, and renal-hilar cystic lymph node metastasis existed. The histopathological diagnosis was tubulocystic carcinoma associated with areas of papillary renal cell carcinoma and poorly differentiated carcinoma with metastasis. Our case suggests that the solid part enhancement of tubulocystic carcinoma tends to be fluffy and sparse, and exophytic cysts and cystic lymph nodes may show radiologically aggressive findings.

Objectives: To investigate the clinical significance of micro-ribonucleic acid-155 in clear cell renal cell carcinoma, in particular focusing on the association of expression levels of micro-ribonucleic acid-155 with clinicopathological factors, cancer-specific survival and therapeutic outcomes in clear cell renal cell carcinoma patients., Methods: Quantitative reverse transcription polymerase chain reaction of micro-ribonucleic acid-155 was carried out on 137 clear cell renal cell carcinoma cases, containing 77 matched pairs of clear cell renal cell carcinoma and normal adjacent kidney tissues from the same patients., Results: Significant overexpression of micro-ribonucleic acid-155 was found in clear cell renal cell carcinoma compared with normal kidney tissue. Expression of micro-ribonucleic acid-155 was not associated with prognosis in all stage groups. However, in 43 patients with stage III and IV clear cell renal cell carcinoma, low expression levels of micro-ribonucleic acid-155 correlated with a poor prognosis. Regarding cancer-free survival of 26 patients with stage III and IV clear cell renal cell carcinoma who received curative resection and cancer-specific survival of 31 patients who received postoperative therapy with interferon-α after radical nephrectomy, low expression levels of micro-ribonucleic acid-155 correlated with poor clinical outcomes in these two groups., Conclusions: Low expression of micro-ribonucleic acid-155 represents a valuable marker of poor clinical outcomes in patients with stage III and IV clear cell renal cell carcinoma., (© 2012 The Japanese Urological Association.)