Zhi-Bin Ke

Cisplatin-based chemotherapy remains a standard treatment for advanced bladder cancer (BCa), however, the development of chemoresistance substantially compromises its clinical efficacy and patient prognosis. In this study, we investigated the functional role of NEK8 in cisplatin resistance in BCa and elucidated its underlying molecular mechanisms. We found that NEK8 was significantly upregulated in cisplatin-resistant BCa and was associated with unfavorable prognosis. Functional studies demonstrated that NEK8 promoted cisplatin resistance and tumor progression both in vitro and in vivo. Mechanistically, NEK8 directly interacted with ALYREF and promoted its phosphorylation and subsequent nuclear translocation. Nuclear ALYREF recognized m5C-modified CDK18 mRNA and enhanced its stability, resulting in increased CDK18 expression. Elevated CDK18 facilitated DNA damage repair, ultimately driving cisplatin resistance in BCa. Collectively, we identified a NEK8-mediated mechanism in which ALYREF phosphorylation and nuclear translocation enhance CDK18 mRNA stability and DNA damage repair, thereby driving cisplatin resistance in BCa.

The resistance to radiotherapy of prostate cancer is driven by interactions within the tumor microenvironment, particularly between prostate cancer cells and tumor-associated macrophages, however the underlying mechanisms remain poorly understood. In this study, we found that STAT1 enhanced the transcription of critical glycolytic enzymes, leading to an increase in lactate secretion from prostate cancer cells. Then, the lactate was transported to macrophages via the MCT1 transporter, activating the NFκB1 pathway, which subsequently promoted macrophage polarization to the M2 phenotype and activated the transcription of MCP-1. MCP-1 was secreted from macrophages interacted with the CCR2 receptor on prostate cancer cells, thereby activating the JAK/STAT1 pathway, ultimately contributing to the progression of prostate cancer and its resistance to radiotherapy. Taken together, our findings identified a STAT1/lactate/NFκB1/MCP-1 positive feedback mechanism as a driver of prostate cancer progression and resistance to radiotherapy that functioned by interaction to macrophages, which could be potential therapeutic targets for the advanced prostate cancer.

Prostate cancer (PCa) remains a major therapeutic challenge due to aberrant androgen receptor signaling and a remodeled tumor microenvironment. Disulfidptosis, a recently identified form of cell death characterized by cytoskeletal collapse under conditions of glucose deprivation and elevated SLC7A11 expression, presents a potential novel avenue for intervention. In this study, we integrated TCGA and GEO data and employed machine learning techniques to identify disulfidptosis-related genes in prostate cancer. Functional analyses using SLC7A11-overexpressing and knockout cell lines demonstrated that SLC7A11 promotes cellular proliferation, migration, and invasion, while its overexpression under glucose-starved conditions triggers disulfidptosis, also inducible pharmacologically using the glucose uptake inhibitor BAY-876. Through CUT&Tag, ChIP-seq, and luciferase assays, we identified FOXA1 as a key transcriptional regulator of SLC7A11, driven by a super-enhancer located at chr14:37583488–37589585. CRISPR-Cas9 deletion of this super-enhancer reduced FOXA1 and SLC7A11 expression, thereby protecting cells from disulfidptosis. These findings highlight the critical role of the SE/FOXA1/SLC7A11 regulatory axis in driving both disulfidptosis and tumor progression, suggesting that targeting this pathway, particularly in glucose-deprived tumor environments, may offer promising therapeutic strategies for PCa.

The tumor environment of prostate cancer (PCa) tissues of high Gleason score has been proved to be more immune suppressive and has higher extracellular matrix (ECM) stiffness, but whether ECM mechanical stiffness is the cause of higher ability of invasiveness and immune escape of PCa with high Gleason score remains uncertain. In this study, we showed that higher polyacrylamide hydrogels (PAAG) stiffness resulted in the progression and immune escape of PCa via integrin β1/FAK/YAP axis. The translocation of YAP into cell nucleus to bind to TEAD2 promoted the transcriptional activation of USP8. NBR1 could be ubiquitinated, and then degraded, via interacting with P62/SQSTM1 and through autophagy-lysosome pathway. Increased expression of USP8 promoted the abundance of NBR1 via K63-linked de-ubiquitination and PD-L1 via K48-linked de-ubiquitination in response to high PAAG stiffness. NBR1-mediated selective autophagy accelerated the degradation of MHC-1 of PCa. The USP8 inhibitor presented a potential application value in sensitizing immunotherapy of PCa. Taken together, we identified a USP8-mediated de-ubiquitination mechanism that involves in the process of high PAAG stiffness-mediated high expression of PD-L1 and low expression of MHC-1 of PCa cells, which provided a rationale of immunotherapy sensitization of PCa via USP8 inhibition.

Objective This study aimed to compare the accuracy of adrenal vein sampling (AVS) and ⁶⁸Ga-Pentixafor positron emission tomography (PET)/computed tomography (CT) in predicting the functional outcome from adrenalectomy in patients with primary aldosteronism (PA), and to investigate the utility of ⁶⁸Ga-Pentixafor PET/CT in laparoscopic partial adrenalectomy. Methods We prospectively enrolled patients diagnosed with PA. All patients underwent ⁶⁸Ga-Pentixafor PET/CT and AVS. Patient management was discussed by a multidisciplinary team. Ninety surgically eligible patients were randomized to partial (n = 45) or total adrenalectomy (n = 45), while 97 received medical therapy. Postoperative Aldosterone Surgical Outcome (PASO) criteria served as the gold standard. Results In total, 187 patients with PA were examined using ⁶⁸Ga-pentixafor PET/CT and AVS, and 90 patients who underwent surgery were included in the analysis. The accuracy of ⁶⁸Ga-Pentixafor PET/CT in correctly predicting biomedical partial or complete success, biomedical complete success, clinical partial or complete success, and clinical complete success was 78.89%, 77.78%, 77.67%, and 67.78%, respectively. For AVS, the accuracies were 74.44%, 73.33%, 70.00%, and 54.44%, respectively. ⁶⁸Ga-pentixafor PET/CT was not significantly superior, but the differences lay within the pre-specified − 10% margin for non-inferiority. Functional outcomes did not significantly differ between the partial and total adrenalectomy groups. Multivariable logistic analysis demonstrated that the lower highest systolic blood pressure and higher SUVmax were independent factors of complete clinical success. The AUC for SUVmax in determining clinical complete success was 0.896, with an optimal cutoff value of 9.8. Subgroup analysis showed no functional outcome difference between laparoscopic partial and total adrenalectomy for patients with an SUVmax over 9.8. However, for those with an SUVmax below 9.8, laparoscopic total adrenalectomy yielded better results than laparoscopic partial adrenalectomy. Conclusion The accuracy of ⁶⁸Ga-Pentixafor PET/CT is comparable to the conventional, invasive method of AVS in forecasting the functional outcomes of adrenalectomy. SUVmax is an independent factor in determining complete clinical success and can potentially predict the functional outcome of laparoscopic adrenalectomy. It is suggested that laparoscopic partial adrenalectomy be performed on individuals who present an SUVmax value exceeding 9.8. The ability of ⁶⁸Ga-Pentixafor PET/CT to localize aldosterone-producing adenoma ultimately paves the way for the use of more focal treatment options. Trial registration ChiCTR2300070830. Registered 23 April 2023. Graphical Abstract

Purpose The optimal tool to evaluate the tumour therapeutic responses to neoadjuvant chemohormonal therapy (NCHT) in patients with high-risk non-metastatic prostate cancer (PCa) remains uncertain. We compared the role of [⁶⁸Ga]-labeled prostate-specific membrane antigen (PSMA)-11 positron emission tomography/computerized tomography ([⁶⁸Ga]Ga-PSMA-11 PET/CT), multiparametric MRI (mpMRI), and prostate-specific antigen (PSA) and assessed the practical value of the recent European Association of Urology and European Association of Nuclear Medicine (EAU/EANM) recommended criteria of PSMA PET/CT to evaluate the therapeutic responses to NCHT in patients with high-risk non-metastatic PCa. Methods This prospective study included 72 high-risk non-metastatic PCa patients receiving NCHT followed by radical prostatectomy from June 2021 to March 2022. PSA testing, [⁶⁸Ga]Ga-PSMA-11 PET/CT, and mpMRI scanning were conducted in all patients before and after NCHT. Therapeutic responses to NCHT were evaluated with PSA, RECIST 1.1, PERCIST 1.0, and EAU/EANM recommended criteria. Postoperative pathological results were considered the reference standard. A favourable pathological response was defined as pathologic complete remission (pCR) or minimal residual disease (MRD). Diagnostic accuracy was assessed by sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV), negative predictive value (NPV), and Cohen’s kappa index. Logistic regression analysis was used to determine the independent predictive value of [⁶⁸Ga]Ga-PSMA-11 PET/CT-derived parameters. Results All cases experienced a marked decrease in PSA levels after NCHT. Twenty-four (33.33%) cases experienced a favourable pathological response, including five (6.94%) cases of pCR and 19 (26.39%) cases of MRD. According to the results of [⁶⁸Ga]Ga-PSMA-11 PET/CT, EAU/EANM recommended criteria indicated that 20 (27.78%) cases had a CR, whereas PERCIST 1.0 criteria indicated that 23 (31.94%) cases had a CR. There was a strong association between EAU/EANM recommended criteria and PERCIST 1.0 criteria (Pearson’s R=0.857). The sensitivity (75.00%, 79.17% vs. 58.33%, 58.33%), specificity (95.83%, 91.67% vs. 83.33%, 68.75%), PLR (18.00, 9.50 vs. 3.50, 1.87), NLR (0.26, 0.23 vs. 0.50, 0.61), PPV (90.0%, 82.6% vs. 63.6%, 48.3%), and NPV (88.5%, 89.8% vs. 80.0%, 76.7%) of [⁶⁸Ga]Ga-PSMA-11 PET/CT (including EAU/EANM recommended criteria and PERCIST 1.0 criteria) to predict favourable pathological responses were all superior to those of mpMRI and nadir PSA. The kappa index to predict a favourable pathological response was 0.257 for PSA, 0.426 for RECIST 1.1, 0.716 for PERCIST 1.0, and 0.739 for EAU/EANM recommended criteria. Multivariate logistic analysis revealed that the post-NCHT maximum standardized uptake value (SUVmax) before radical prostatectomy was an independent predictor of a favourable pathological response to NCHT. Conclusions [⁶⁸Ga]Ga-PSMA-11 PET/CT had a better concordance with a favourable pathological response to NCHT compared with nadir PSA and mpMRI. EAU/EANM recommended criteria and PERCIST 1.0 criteria performed equally to identify pathological responders when [⁶⁸Ga]Ga-PSMA-11 PET/CT was used as a therapeutic response assessment tool.