Sunitinib is a first-line targeted therapy for patients with renal cell carcinoma (RCC), but resistance represents a significant obstacle to the treatment of advanced and metastatic RCC. Metabolic reprogramming is a characteristic of RCC, and changes in metabolic processes might contribute to resistance to sunitinib. In this study, we identified methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), a mitochondrial enzyme involved in one-carbon metabolism, as a critical mediator of sunitinib resistance in RCC. MTHFD2 was elevated in sunitinib-resistant RCC cells, and loss of MTHDF2 conferred sensitivity to sunitinib. In patients, MTHFD2 was highly expressed in RCC and was associated with poor outcomes. Mechanistically, MTHFD2 stimulated UDP-N-acetylglucosamine (UDP-GlcNAc) biosynthesis and promoted cMYC O-GlcNAcylation by driving the folate cycle. O-GlcNAcylation enhanced cMYC stability and promoted MTHFD2 and cyclin D1 transcription. Targeting MTHFD2 or cyclin D1 sensitized tumor cells to sunitinib in vitro and in vivo. Consistently, development of a peptide drug capable of efficiently degrading MTHFD2 enabled reversal of sunitinib resistance in RCC. These findings identify a noncanonical metabolic function of MTHFD2 in cell signaling and response to therapy and reveal the interplay between one-carbon metabolism and sunitinib resistance in RCC. Targeting MTHFD2 could be an effective approach to overcome sunitinib resistance. Significance: MTHFD2 regulates cMYC O-GlcNAcylation to promote sunitinib resistance in renal cell carcinoma, highlighting the important role of one-carbon metabolism in sunitinib resistance and proposing therapeutic strategies to improve patient outcomes.

Vasculogenic mimicry (VM), the novel approach for tumor cells to obtain blood supply, was reported to be involved in antiangiogenic resistance and poor prognosis in renal cell carcinoma (RCC). However, the molecular mechanisms underlying VM formed by RCC cells are still not clearly depicted. In the present study, we found that OS-RC-2 acquired the VM forming ability accompanied with the increased expressions of Vimentin and AXL and decreased expression of E-Cadherin by CoCl₂ treatment. Downregulation of Vimentin by siRNA severely impaired the capability of OS-RC-2 and 786-O to form VM structures induced by cell hypoxia in vitro. Moreover, knockdown of Vimentin inhibited cell migration and invasion, which could be prompted by hypoxia induction in RCC cells. In our clear cell RCC tissues, we found that VM was positively correlated with Vimentin overexpression and both predicted poor prognosis. In conclusion, Vimentin plays an important role in hypoxia induced VM formation of RCC cells and targeted Vimentin might be beneficial for RCC therapy.

Background: To determine the role of Midkine (MDK) in non-invasive detection of bladder cancer (Bca) and the relationship with Ki67. Methods: Sixty-five Bca patients and 55 non-Bca patients or healthy volunteers were enrolled and voided urine samples were prospectively obtained on the first day of enrollment. Tissue samples were collected by surgery. MDK and Ki67 expressions were analyzed by immunohistochemistry and Western Blot (WB). Specificity and sensitivity of MDK mRNA testing in the detection of Bca were determined by Receiver Operating Characteristic curve (ROC). The relationship between MDK and Ki67 was also assessed. Results: MDK was overexpressed in Bca tissues than that in the non-cancer tissues. The specificity and sensitivity for MDK mRNA testing in urine in the identification of Bca was 80% and 72.3%. MDK detected 85.7% of high-grade tumors, 87.5% of muscle-invasive tumors and 79.4% of tumors larger than 3 cm in patients without gross hematuria. Microscopic hematuria may even increase the detection rate of Bca by MDK testing. Furthermore, the correlation of MDK and Ki67 was found positive. Conclusion: MDK was overexpressed in Bca tissues and positively correlated with Ki67. MDK might be a potential biomarker for the detection of Bca, especially for those without gross hematuria but with microscopic hematuria.

Background: Our study aims to investigate the mechanisms through which Fc receptor‐like A (FCRLA) promotes renal cell carcinoma (RCC) and to examine its significance in relation to tumor immune infiltration.Materials and Methods: The correlation between FCRLA and data clinically related to RCC was explored using The Cancer Genome Atlas (TCGA), then validated using Gene Expression Omnibus (GEO) gene chip data. Enrichment and protein–protein interaction (PPI) network analyses were performed for FCRLA and its co‐expressed genes. FCRLA was knocked down in RCC cell lines to evaluate its impact on biological behavior. Then the potential downstream regulators of FCRLA were determined by western blotting, and rescue experiments were performed for verification. The relevance between FCRLA and various immune cells was analyzed through GSEA, TIMER, and GEPIA tools. TIDE and ESTIMATE algorithms were used to predict the effect of FCRLA in immunotherapy.Results: Fc receptor‐like A was associated with clinical and T stages and could predict the M stage (AUC = 0.692) and 1–3‐ and 5‐year survival rates (AUC = 0.823, 0.834, and 0.862) of RCC patients. Higher expression of FCLRA predicted an unfavorable overall survival (OS) in TCGA‐RCC and GSE167573 datasets (p = 0.03, p = 0.04). FCRLA promoted the malignant biological behavior of RCC cells through the pERK1/2/‐MMP2 pathway and was associated with tumor immune microenvironment in RCC.Conclusion: Fc receptor‐like A is positively correlated with poor outcomes in RCC patients and plays an oncogenic role in RCC through the pERK1/2‐MMP2 pathway. Patients with RCC might benefit from immunotherapy targeting FCRLA.

Background and Objective: The aim of this study was to compare the efficacy and reliability of holmium (Ho:YAG) laser lithotripsy (HLL) and pneumatic lithotripsy (PL) in percutaneous nephrolithotomy (PCNL) in the treatment of patients with Grade IV kidney stones based on Guy’s Stone Score. Study Design/Materials and Methods: This retrospective study included 103 patients with Grade IV kidney stones out of 440 patients who underwent PCNL through HLL and PL in Second Affiliated Hospital of Shantou University Medical College, China, from January 2016 to December 2018. We analyzed preoperative, intraoperative, and postoperative variables of the patients to evaluate the efficacy and reliability of PCNL procedures. Results: Patients were categorized as Grade I, II, III, and IV, and the patients of each grade were 85 (19.32%), 39 (8.86%), 213 (48.41%), and 103 (23.41%), respectively. In Grade IV, the total operative time (min) for the PL and HLL groups was 137.7 ± 47.79 and 134.27 ± 53.38, respectively (p = 0.744). The variation in laboratory examination values including ΔHGB (g/L), ΔHCT, ΔPCT, and ΔCr (μmol/L) for PL and HLL groups was 19 ± 11.23/12 ± 15.42 (p = 0.012), 0.057 ± 0.034/0.038 ± 0.045 (0.009), 0.027 ± 0.034/0.026 ± 0.034 (0.702), and 3.07 ± 17.4/20.54 ± 65.93 (0.692), respectively. The postoperative hospitalization day was 8.94 ± 4.2 and 7.73 ± 2.75 (p = 0.015), respectively. As for the stone-free rate (SFR), the SFRs for PL and HLL were 48.15% (n = 39/81) and 59.09% (n = 13/22) (p = 0.363), respectively. Conclusions: HLL showed a comparable advantage of not only decreased postoperative hemoglobin and hematocrit but also fewer postoperative hospitalization days. Based on the results of our retrospective study, for those Grade IV kidney stone patients who have a risk of bleeding before PCNL operation, HLL can be a considerable treatment option. Besides, in consideration of reducing human care cost, HLL which showed fewer hospitalization days, would be more welcome by patients.