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.

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.Renal cell carcinoma (RCC) accounts for around 90% of all renal tumours, and its incidence has been steadily increasing by 2-4% each year (1). More than 30% of patients diagnosed with RCC have metastatic disease (2). Patients with metastatic RCC have an approximately 13 months' median survival and a 5-year survival rate under 10% (3). Sunitinib is an oral multi-target tyrosine kinase inhibitor (TKI), which has potent anti-angiogenic effects and direct anti-tumour activities due to the inhibition of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and stem cell growth factor receptor (4). Sunitinib treatment is used as a first-line therapy for metastatic RCC (5, 6) and significantly prolongs overall survival in metastatic RCC (7). Although approximately 70% of the patients show an initial response to sunitinib, eventually, sunitinib resistance and disease progression occur. Recent evidence has shown that the mechanisms of sunitinib resistance may be multifactorial (8-10); however, the mechanisms that underpin sunitinib resistance are not fully elucidated. Therefore, there is an urgent need to clarify the mechanisms of sunitinib resistance.Phosphatase and Tensin Homolog Deleted from Chromosome 10 (PTEN) is a tumour-suppressive protein (11).The PTEN gene has both recurrent point mutations and focal deletions in RCC (12,13). PTEN has been reported to antagonize the phosphoinositol-3-kinase (PI3K)/PTEN/AKT signalling pathway, which plays a crucial role in cell growth, differentiation, survival and drug resistance in RCC (14,15). The Cancer Genome Atlas data showed that bi-allelic loss of PTEN is rare and associated with poor overall survival in RCC (16,17). Although some studies have reported the prognostic significance of PTEN for TKI treatment (18,19), the role of PTEN in sunitinib and sorafenib resistance in RCC has not been fully elucidated.In this study, we aimed to analyse the effect ...

Background: βIII-Tubulin, encoded by the TUBB3 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. Objective: The aim of this study was to analyze the expression and function of TUBB3 in clear cell renal cell carcinoma (ccRCC). Methods: 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. Results: 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. Conclusion: These results suggest that TUBB3 may play an oncogenic role and could be a potential therapeutic target in ccRCC.

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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.