Cancer-Associated Fibroblast-Derived miR-146a-5p Generates a Niche That Promotes Bladder Cancer Stemness and Chemoresistance.

Cancer stem-like cells (CSC) play pivotal roles in both chemoresistance and recurrence of many cancer types, including urothelial bladder cancer (UBC). In addition to intrinsic signaling pathways, extracellular cues from the tumor microenvironment (TME) are indispensable for the maintenance of CSCs. To better understand the mechanisms involved in TME-mediated generation and support of UBC CSCs, we focused on the role of cancer-associated fibroblasts (CAF) in this study. Overexpression of miR-146a-5p in CAFs promoted CAF-to-UBC cell interactions, cancer stemness, and chemoresistance to treatment with gemcitabine and cisplatin. Mechanistically, miR-146-5p upregulated SVEP1 in CAFs by enhancing the recruitment of transcriptional factor YY1. Meanwhile, by targeting the 3'UTR of mRNAs of ARID1A and PRKAA2 (also known as AMPKα2) in UBC cells, CAF-secreted miR-146a-5p promoted cancer stemness and chemoresistance. Downregulation of ARID1A resulted in the inhibition of SOCS1 and subsequent STAT3 activation, and downregulated PRKAA2 led to the activation of mTOR signaling. Elevated levels of exosomal miR-146a-5p in the serum of patients with UBC were correlated with both tumor stage and relapse risk. These findings altogether indicate that CAF-derived miR-146a-5p can promote stemness and enhance chemoresistance in UBC. Exosomal miR-146a-5p may be a biomarker of UBC recurrence and a potential therapeutic target. SIGNIFICANCE: The tumor-stromal cross-talk mediated by cancer-associated fibroblast-derived miR-146a-5p fosters cancer stem cell niche formation and cancer stemness to drive chemoresistance in urothelial bladder cancer.

Cervical lymphadenopathy as initial presentation of metastatic prostate cancer: A retrospective study of five cases and literature review.

Cervical lymphadenopathy as the initial presentation of metastatic prostate cancer is particularly uncommon, and easily misdiagnosed. In the current study, we describe five cases of metastatic prostate cancer in our hospital that presented with cervical lymphadenopathy as an initial symptom. The diagnosis was confirmed by needle biopsy of the suspicious lymph nodes and the serum prostate specific antigen (PSA) levels of all patients exceeded 100 ng/ml. The five patients were treated with hormonal therapy; four received traditional hormonal therapy, including bicalutamide and goserelin; one patient received hormonal therapy that included abiraterone and goserelin. Case 1 developed into castration-resistant prostate cancer (CRPC) after 7 months and died after 12 months. Case 2 rejected regular hormonal therapy for personal reasons and died 6 months after the initial diagnosis. Case 3 was still alive at the time of writing. Case 4 was administered with abiraterone, prednisolone and goserelin; the treatment was effective and the patient has remained symptom-free for the last 24 months. Case 5 was treated with hormonal and chemotherapy but died 8 months after diagnosis. In conclusion, any elderly male presenting with cervical lymphadenopathy should be considered the possibility of prostate cancer, especially when the needle biopsy reveals adenocarcinoma. The prognosis for patients presented with cervical lymphadenopathy as the initial presentation is usually poor. Hormone therapy based on abiraterone may yield a better response in such cases.

circCYP24A1 promotes Docetaxel resistance in prostate Cancer by Upregulating ALDH1A3.

BACKGROUND: Docetaxel (DTX) is the most widely prescribed first-line chemotherapy for advanced prostate cancer (PCa). Unfortunately, DTX resistance invariably emerges, leading to worse prognosis of PCa. Growing evidence has shown that circRNAs had complex spatiotemporal specificity during the tumor development and oncogenesis. This study was designed to investigate the biological functions and possible molecular mechanisms of circRNAs in DTX resistance of PCa. METHODS: circRNAs in established DTX-resistant DU145 cell line were identified by RNA sequencing. Biological function of circCYP24A1 was verified in vitro and in vivo. The potential role of circCYP24A1 in the development of DTX-resistant PCa was investigated via dual-luciferase reporter assays, RIP assays and RNA pull-down assays. Univariate and multivariate logistic regression analyses was used to predict DTX-chemotherapy response based on patients' clinical and biological information. RESULTS: CircCYP24A1 was identified to be upregulated in DTX-resistant DU145 cells. Upregulated circCYP24A1 was found to suppress the DTX chemosensitivity in vitro and in vivo. Furthermore, we found that circCYP24A1 promoted DTX resistance in PCa via regulating ALDH1A3 expression by sponging miR-1301-3p and activating PI3K/AKT/mTOR signaling pathway. Statistical analyses elucidated that circCYP24A1 was an independent risk factor to predict DTX response (OR = 0.165; 95% CI: 0.038-0.723; P = 0.017). CONCLUSIONS: This study demonstrated that circCYP24A played an essential role in DTX resistance in PCa, suggesting that circCYP24A1 could be a promising biomarker to predict DTX response and a potential therapeutic target in PCa patients resistant to DTX chemotherapy.

MicroRNA-582-5p regulates cell invasion in bladder cancer through targeting Forkhead Box G1.

Burgeoning evidence shows that microRNAs (miRNAs) are associated with tumorigenesis and progression. However, the alteration and function of many miRNAs in bladder cancer (BCa) are not clear. Here, we explored the regulatory effect of microRNA-582 (miR-582) on cell invasion in BCa and underlying mechanisms. The expression of miR-582 in BCa tissues and cell lines was examined by quantitative real-time PCR (qRT-PCR). The target gene of miR-582 and their binding site were predicted by bioinformatics analysis. Luciferase reporter assay and western blot analysis were performed to confirm miR-582 directly targeting Forkhead Box G1 (FOXG1). The role of miR-582-FOXG1 axis in regulating BCa invasion was evaluated in cell models. The association of miR-582 with clinicopathologic features and prognosis was analyzed. Experimental results indicated that miR-582 was downregulated in BCa tissues and cell lines. Forced miR-582 decreased cell invasion, regulating expression levels of invasion-related proteins, such as MMP2, MMP9 and ZO-1. MiR-582 directly targeted FOXG1 by binding to its 3'UTR. Overexpression of FOXG1 rescued the regulating function in BCa cells induced by miR-582. Moreover, miR-582-FOXG1 axis has obvious clinical relevance with prognosis in BCa patients. Our results indicate that miR-582-FOXG1 axis may act as a key role on cell invasion and serve as a potential prognostic predicted biomarker.

KLF2 inhibits cancer cell migration and invasion by regulating ferroptosis through GPX4 in clear cell renal cell carcinoma.

The metastatic dissemination and underlying mechanisms of clear cell renal cell carcinoma (ccRCC) remain insufficiently understood. In this study, we identified the essential role of KLF2 in suppressing the metastasis of ccRCC. Downregulation of KLF2 detected by immunohistochemistry in primary metastatic ccRCC was remarkably related to poor clinical outcomes. Overexpression of KLF2 in vitro inhibited growth, migration and invasion of RCC cells. Analysis of clinical specimens revealed that there is a close correlation between KLF2 and GPX4 in ccRCC. Mechanistically, KLF2 deficiency is sufficient to inhibit ferroptosis on account of the impairment of transcriptional repression of GPX4 and thus promotes the migration and invasion of RCC cells. Reverting KLF2 expression in vivo decreased pulmonary metastatic lesions and prolonged life span of mice, whereas GPX4 overexpression reversed these properties. Overall, our results established a novel critical pathway that drives human ccRCC invasion and metastasis, which could be a promising target regarding to the therapies of advanced ccRCC in the clinic.

Local anesthesia for percutaneous US/CT-guided bipolar radiofrequency ablation of small renal masses: A safe and feasible alternative.

PURPOSE: This study is to evaluate the safety and feasibility of local anesthesia (LA) for percutaneous ultrasound/computed tomography (US/CT)-guided bipolar radiofrequency ablation (RFA) for small renal masses (SRMs) by comparing the LA with general anesthesia. MATERIALS AND METHODS: A retrospective review was carried out between January 2018 to June 2020, 102 patients with SRMs were treated with US/CT-guided bipolar RFA. General anesthesia (GA) was performed in 42 and LA was performed in 60 patients. Demographics, tumor characteristics, peri-procedural data, pathologic and follow-up outcomes were analyzed. The factors associated with pain were also identified. RESULTS: There was no significant difference in demographics and tumor characteristics between the LA and GA group. A statistically significant difference was observed in terms of procedural time (P = 0.010) and hospital stays (P < 0.001). The maximum perceived pain in LA group comprised 60.0% (36 of 60) mild, 40.0% (24 of 60) moderate. The anxiety in LA group comprised 65.0% (39 of 60) mild, 33.3% (20 of 60) moderate, 1.7% (1 of 60) severe. On multivariate analysis, tumor diameter was a significant predictor for pain in RFA procedure (OR 1.560, 95% CI 1.233-1.974, P < 0.001). All patients were followed up for a median (range) of 12 (2-24) months. Local recurrence occurred in 8.3% (5 of 60) of the LA group and in 7.1% (3 of 42) in GA group (P = 1.000). CONCLUSION: Percutaneous bipolar RFA of SRMs using CT and ultrasound guidance under LA can be an effective and tolerable method for patients who are unfit for surgery and provide satisfactory oncologic control.

Clinico-radiological characteristic-based machine learning in reducing unnecessary prostate biopsies of PI-RADS 3 lesions with dual validation.

OBJECTIVE: To evaluate machine learning-based classifiers in detecting clinically significant prostate cancer (PCa) with Prostate Imaging Reporting and Data System (PI-RADS) score 3 lesions. METHODS: We retrospectively enrolled 346 patients with PI-RADS 3 lesions at two institutions. All patients underwent prostate multiparameter MRI (mpMRI) and transperineal MRI-ultrasonography (MRI-US)-targeted biopsy. We collected data on age, pre-biopsy serum prostate-specific antigen (PSA) level, prostate volume (PV), PSA density (PSAD), the location of suspicious PI-RADS 3 lesions, and histopathology results. Four machine learning-based classifiers-logistic regression, support vector machine, eXtreme Gradient Boosting (XGBoost), and random forest-were trained using datasets from Nanjing Drum Tower Hospital. External validation was carried out using datasets from Molinette Hospital. RESULTS: Among 287 PI-RADS 3 patients, prostate cancer was proven pathologically in 59 (20.6%), and 228 (79.4%) had benign lesions. For 380 PI-RADS 3 lesions, 81 (21.3%) were proven to be PCa and 299 (78.7%) benign. Among four classifiers, the random forest classifier had the best performance in both patient-based and lesion-based datasets, with overall accuracy of 0.713 and 0.860, sensitivity of 0.857 and 0.613, and area under curve (AUC) of 0.771 and 0.832, respectively. In external validation, our best classifiers had an AUC of 0.688 with the best sensitivity (0.870) and specificity (0.500) in the 59 PI-RADS 3 patients in Molinette Hospital dataset. CONCLUSIONS: The machine learning-based random forest classifier provided a reliable probability if a PI-RADS 3 patient was benign. KEY POINTS: • Machine learning-based classifiers could combine the clinical characteristics with accessible information on image report of PI-RADS 3 patient to generate a probability of malignancy. • This probability could assist surgeons to make diagnostic decisions with more confidence and higher efficiency.