Abstract βIII‐Tubulin, encoded by the TUBB3 gene, is a microtubule protein. We previously reported that TUBB3 is overexpressed in renal cell carcinoma. We investigated the clinicopathological significance of TUBB3 in upper tract urothelial carcinoma (UTUC) by immunohistochemistry. In normal tissue, TUBB3 expression was weak or absent. In contrast, TUBB3 overexpression was observed in urothelial carcinoma (UC) tissues in 51 (49%) of 103 UTUC cases. TUBB3 overexpression was associated with nodular/flat morphology, high‐grade disease, high T stage, and a poor prognosis. Similar results were obtained in The Cancer Genome Atlas bladder cancer cohort. TUBB3 expression was also associated with high Ki‐67 labeling index, CD44v9, HER2, EGFR, and p53 expression in UTUC. Among representative cancer‐related molecules, TUBB3 was an independent predictor of progression‐free survival and high‐grade UC. Finally, using urine cytology samples, we analyzed TUBB3 expression by immunocytochemistry. TUBB3 expression was more frequently found in UC cells than in nonneoplastic cells. The diagnostic accuracy of urine cytology was improved when combined with TUBB3 immunostaining. The findings suggest the importance of TUBB3 in tumor progression and its potential application as a biomarker for high‐grade disease and the prognosis of UC. Moreover, combination with TUBB3 immunostaining might improve the diagnostic accuracy of urine cytology.
Abstract To propose the centrality angle (C-angle) as a novel simple nephrometry score for the evaluation of tumor complexity and prediction of perioperative outcomes in nephron-sparing surgery (NSS) for renal tumors. The analysis was based on 174 patients who underwent robot-assisted partial nephrectomy retrospectively. C-angle was defined as the angle occupied by the tumor from the center of the kidney in the coronal CT images. Other nephrometry scores were calculated and compared with C-angle. Associations between C-angle and perioperative outcomes were examined. Significant differences were found in C-angle between tumors greater and less than 4 cm, exophytic and endophytic tumors, and hilar and non-hilar tumors. C-angle was correlated with other nephrometry scores, including RENAL, PADUA, and C-index. Significant positive correlations with WIT, operation time, and EBL, and significant negative correlations with preserved eGFR. C-angle could predict perioperative complications. Patients with a C-angle > 45° had worse perioperative outcomes, including longer operative time, longer WIT, lower rate of preserved eGFR, and complications. C-angle can be used to evaluate the complexity of renal tumors and predict perioperative outcomes. C-angle can potentially be used for decision-making in the treatment of patients and to guide surgical planning of NSS.
<b><i>Introduction:</i></b> BUB1 mitotic checkpoint serine/threonine kinase B encoded by <i>BUB1B</i> 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. <b><i>Objective:</i></b> This study aims to clarify the expression and function of BUB1B in renal cell carcinoma (RCC). <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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. <b><i>Conclusion:</i></b> These results suggest that BUB1B plays an oncogenic role and may be a promising predictive biomarker for survival in RCC.
<b><i>Background:</i></b> βIII-Tubulin, encoded by the <i>TUBB3</i> gene, is a microtubule protein. Several studies have shown that overexpression of TUBB3 is linked to poor prognosis and is involved in taxane resistance in some cancers. <b><i>Objective:</i></b> The aim of this study was to analyze the expression and function of TUBB3 in clear cell renal cell carcinoma (ccRCC). <b><i>Methods:</i></b> The expression of TUBB3 was determined using immunohistochemistry in ccRCC specimens. The effects of TUBB3 knockdown on cell growth and invasion were evaluated in RCC cell lines. We analyzed the interaction between TUBB3, p53, cancer stem cell markers, and PD-L1. <b><i>Results:</i></b> In 137 cases of ccRCC, immunohistochemistry showed that 28 (20%) of the ccRCC cases were positive for TUBB3. High TUBB3 expression was significantly correlated with high nuclear grade, high T stage, and N stage. A Kaplan-Meier analysis showed that high expression of TUBB3 was associated with poor overall survival after nephrectomy. In silico analysis also showed that high TUBB3 expression was correlated with overall survival. Knockdown of TUBB3 suppressed cell growth and invasion in 786-O and Caki-1 cells. High TUBB3 expression was associated with CD44, CD133, PD-L1, and p53 in ccRCC. We generated p53 knockout cells using the CRISPR-Cas9 system. Western blotting revealed that p53 knockout upregulated the expression of TUBB3. <b><i>Conclusion:</i></b> These results suggest that TUBB3 may play an oncogenic role and could be a potential therapeutic target in ccRCC.
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.
Intelectin‐1 (ITLN1) is an adipokine with an anti‐inflammatory function that is involved in neoplastic diseases such as pleural mesothelioma and gastric and prostate cancers. However, the expression and function of ITLN1 in colorectal cancer (CRC) remain unknown. To identify novel prognostic markers or therapeutic targets for CRC, we focused on ITLN1 protein. By immunohistochemistry, 87 (59%) of 148 CRC cases showed reduced expression of ITLN1. ITLN1‐reduced CRC cases were associated with higher M grades ( P = 0.0017) than ITLN1‐retained CRC cases. Furthermore, the cases with ITLN1 retained expression tended toward a more favorable prognosis than those with reduced expression. Cell growth of the CRC cell lines transfected with ITLN1 siRNA were greater than those of the negative control cell lines transfected with siRNA. Levels of phosphorylated epidermal growth factor receptor, Erk and Akt were higher in the CRC cells transfected with ITLN1 siRNA than in control cells. Immunohistochemical analysis of human colorectal polyp specimens also revealed a sequential decrease in the expression of ITLN1 through both the conventional adenoma–carcinoma pathway and the serrated pathway. These results indicated that ITLN1 might play an important role in regulating colorectal tumorigenesis.
Upper tract urothelial carcinoma (UTUC) can be divided into renal pelvis tumor (RPT) and ureteral tumor (UT) based on the tumor origin. This study aimed to evaluate the efficacy of neoadjuvant chemotherapy with gemcitabine and cisplatin (NAC-GC) in terms of the pathological outcomes and oncological prognoses in patients with UTUC. We also compared its efficacy between RPT and UT.
Recent studies have reported that TUBB3 overexpression is involved in docetaxel (DTX) resistance in prostate cancer (PCa). The aim of this study was to clarify the role of TUBB3 in DTX and cabazitaxel (CBZ) resistance, and cross-resistance between DTX and CBZ in PCa. We analyzed the effect of TUBB3 knockdown on DTX and CBZ resistance and examined the interaction between TUBB3 and PTEN. We also investigated the role of phosphoinositide 3-kinases (PI3K) inhibitor (LY294002) in DTX and CBZ resistance. TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression. LY294002 suppressed TUBB3 expression in DTX-resistant and CBZ-resistant cell lines. LY294002 re-sensitized DTX-resistant cell lines to DTX and CBZ-resistant cell lines to CBZ. These results suggest that TUBB3 is involved in DTX resistance and CBZ resistance. A combination of LY294002/DTX and that of LY294002/CBZ could be potential strategies for PCa treatment.
