Explore the vast range of titles available.

Background Increasing evidences indicate that circular RNAs exert critical function in regulating bladder cancer progression. However, the expressive patterns and roles of circular RNAs in bladder cancer remain less investigated. Methods circRIP2 was identified and evaluated by RNA-sequencing and qPCR; in vitro effects of circRIP2 were determined by CCK8, clone forming, wound healing and trans-well assays; while mice subcutaneous tumor model was designed for in vivo analysis. Western blot, RNA pulldown assay, miRNA capture and dual luciferase assessment were applied for mechanistic studies. Results circRIP2 was identified as a conserved and dramatically repressed circular RNA in bladder cancer. Patients that displayed higher circRIP2 expression negatively associate with the grade, stage, metastasis as well as outcome of bladder cancer. In vitro and in vivo studies suggest that circRIP2 enables to promote bladder cancer progression via inducing EMT. Regarding the mechanism, we performed RNA-sequencing analysis, RNA pulldown with biotin-labeled circRIP2-specific probe, dual luciferase reporter assay. It was found that circRIP2 enables to sponge miR-1305 to elevate Tgf-β2 in bladder cancer, and inducing EMT via Tgf-β2/smad3 pathway. Blocking Tgf-β2 in bladder cancer deprives circRIP2 induced cancer progression and EMT. Conclusions Taken together, our study provides the first evidence that circRIP2 expresses differentially in bladder cancer and negatively along with the cancer progression; effective circRIP2 activity accelerates bladder cancer progression via inducing EMT by activating miR-1305/Tgf-β2/smad3 pathway. The research implies that circRIP2 might be a potential biomarker and therapeutic target for bladder cancer patients.

Tumor-associated macrophages (TAMs) are the most abundant inflammatory infiltrates in the tumor microenvironment and contribute to lymph node (LN) metastasis. However, the precise mechanisms of TAMs-induced LN metastasis remain largely unknown. Herein, we identify a long noncoding RNA, termed Lymph Node Metastasis Associated Transcript 1 ( LNMAT1 ), which is upregulated in LN-positive bladder cancer and associated with LN metastasis and prognosis. Through gain and loss of function approaches, we find that LNMAT1 promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. Mechanistically, LNMAT1 epigenetically activates CCL2 expression by recruiting hnRNPL to CCL2 promoter, which leads to increased H3K4 tri-methylation that ensures hnRNPL binding and enhances transcription. Furthermore, LNMAT1 -induced upregulation of CCL2 recruits macrophages into the tumor, which promotes lymphatic metastasis via VEGF-C excretion. These findings provide a plausible mechanism for LNMAT1 -modulated tumor microenvironment in lymphatic metastasis and suggest that LNMAT1 may represent a potential therapeutic target for clinical intervention in LN-metastatic bladder cancer. Mechanism of lymph node (LN) metastasis induced by tumor associated macrophages (TAMs) remains unclear. Here they demonstrate that a long noncoding RNA LNMAT1 promotes LN metastasis of bladder cancer via recruitment of TAMs through epigenetic regulation of CCL2 expression.

Small ubiquitin-like modifier (SUMO) binding (termed SUMOylation) emerged as the inducer for the sorting of bioactive molecules into extracellular vesicles (EVs), triggering lymphangiogenesis and further driving tumor lymph node (LN) metastasis, but the precise mechanisms remain largely unclear. Here, we show that bladder cancer (BCa) cell-secreted EVs mediated intercellular communication with human lymphatic endothelial cells (HLECs) through transmission of the long noncoding RNA ELNAT1 and promoted lymphangiogenesis and LN metastasis in a SUMOylation-dependent manner in both cultured BCa cell lines and mouse models. Mechanistically, ELNAT1 induced UBC9 overexpression to catalyze the SUMOylation of hnRNPA1 at the lysine 113 residue, which mediated recognition of ELNAT1 by the endosomal sorting complex required for transport (ESCRT) and facilitated its packaging into EVs. EV-mediated ELNAT1 was specifically transmitted into HLECs and epigenetically activated SOX18 transcription to induce lymphangiogenesis. Importantly, blocking the SUMOylation of tumor cells by downregulating UBC9 expression markedly reduced lymphatic metastasis in EV-mediated, ELNAT1-treated BCa in vivo. Clinically, EV-mediated ELNAT1 was correlated with LN metastasis and a poor prognosis for patients with BCa. These findings highlight a molecular mechanism whereby the EV-mediated ELNAT1/UBC9/SOX18 regulatory axis promotes lymphangiogenesis and LN metastasis in BCa in a SUMOylation-dependent manner and implicate ELNAT1 as an attractive therapeutic target for LN metastatic BCa.

Background With the development of digital pathology and the renewal of deep learning algorithm, artificial intelligence (AI) is widely applied in tumor pathology. Previous researches have demonstrated that AI-based tumor pathology may help to solve the challenges faced by traditional pathology. This technology has attracted the attention of scholars in many fields and a large amount of articles have been published. This study mainly summarizes the knowledge structure of AI-based tumor pathology through bibliometric analysis, and discusses the potential research trends and foci. Methods Publications related to AI-based tumor pathology from 1999 to 2021 were selected from Web of Science Core Collection. VOSviewer and Citespace were mainly used to perform and visualize co-authorship, co-citation, and co-occurrence analysis of countries, institutions, authors, references and keywords in this field. Results A total of 2753 papers were included. The papers on AI-based tumor pathology research had been continuously increased since 1999. The United States made the largest contribution in this field, in terms of publications (1138, 41.34%), H-index (85) and total citations (35,539 times). We identified the most productive institution and author were Harvard Medical School and Madabhushi Anant, while Jemal Ahmedin was the most co-cited author. Scientific Reports was the most prominent journal and after analysis, Lecture Notes in Computer Science was the journal with highest total link strength. According to the result of references and keywords analysis, “breast cancer histopathology” “convolutional neural network” and “histopathological image” were identified as the major future research foci. Conclusions AI-based tumor pathology is in the stage of vigorous development and has a bright prospect. International transboundary cooperation among countries and institutions should be strengthened in the future. It is foreseeable that more research foci will be lied in the interpretability of deep learning-based model and the development of multi-modal fusion model.

Background Increasing evidence has revealed that circular RNAs (circRNAs) play crucial roles in cancer biology. However, the role and underlying regulatory mechanisms of circFNDC3B in bladder cancer (BC) remain unknown. Methods A cell invasion model was established by repeated transwell assays, and invasion-related circRNAs in BC were identified through an invasion model. The expression of circFNDC3B was detected in 82 BC tissues and cell lines by quantitative real-time PCR. Functional assays were performed to evaluate the effects of circFNDC3B on proliferation, migration and invasion in vitro-, and on tumorigenesis and metastasis in vivo. The relationship between circFNDC3B and miR-1178-3p was confirmed by fluorescence in situ hybridization, pull-down assay and luciferase reporter assay. Results In the present study, we identified a novel circRNA (circFNDC3B) through our established BC cell invasion model. We found that circFNDC3B was dramatically downregulated in BC tissues and correlated with pathological T stage, grade, lymphatic invasion and patients’ overall survival rate. Functionally, overexpression of circFNDC3B significantly inhibited proliferation, migration and invasion both in vitro and in vivo. Mechanistically, circFNDC3B could directly bind to miR-1178-3p, which targeted the 5′UTR of the oncogene G3BP2. Moreover, circFNDC3B acted as a miR-1178-3p sponge to suppress G3BP2, thereby inhibiting the downstream SRC/FAK signaling pathway. Conclusions CircFNDC3B may serve as a novel tumor suppressive factor and potential target for new therapies in human BC.

Background Circular RNAs (circRNAs) represent a subclass of regulatory RNAs that have been shown to have significant regulatory roles in cancer progression. However, the biological functions of circRNAs in bladder cancer (BCa) are largely unknown. Methods Cell invasion models were established, and invasion-related circRNAs were detected by qPCR. Using above method, circ- ZKSCAN1 was picked out for further study. Circ- ZKSCAN1 expression and survival analyses were performed through qPCR. The survival curves were generated by the Kaplan-Meier method, and the log-rank test was used to assess the significance. Cell proliferation, migration and invasion were examined to investigate the function of circ- ZKSCAN1 . Tumorigenesis in nude mice was assessed to determine the effect of circ- ZKSCAN1 in bladder cancer. Biotin-coupled probe pull-down assays, FISH and luciferase reporter assays were conducted to confirm the relationship between circ- ZKSCAN1 and microRNA. RNA-seq revealed different molecular changes in downstream genes. Results Here, we found that circ- ZKSCAN1 was downregulated in BCa tissues and cell lines. Circ- ZKSCAN1 levels were associated with survival, tumor grade, pathological T stage and tumor recurrence. Overexpressed circ- ZKSCAN1 inhibits cell proliferation, migration, invasion and metastasis in vitro and in vivo. Mechanistically, we demonstrated that circ- ZKSCAN1 upregulated p21 expression by sponging miR-1178-3p, which suppressed the aggressive biological behaviors in bladder cancer. Conclusions These results reveal that Circ- ZKSCAN1 acts as a tumor suppressor via a novel circ- ZKSCAN1 /miR-1178-3p/p21 axis, which have the important role in the proliferation, migration and invasion ablitities of BCa cells and provide a novel perspective on circRNAs in BCa progression.

Castration-resistant prostate cancer (CRPC) that occurs after the failure of androgen deprivation therapy is the leading cause of deaths in prostate cancer patients. Thus, there is an obvious and urgent need to fully understand the mechanism of CRPC and discover novel therapeutic targets. Long noncoding RNAs (lncRNAs) are crucial regulators in many human cancers, yet their potential roles and molecular mechanisms in CRPC are poorly understood. In this study, we discovered that an lncRNA HOXD-AS1 is highly expressed in CRPC cells and correlated closely with Gleason score, T stage, lymph nodes metastasis, and progression-free survival. Knockdown of HOXD-AS1 inhibited the proliferation and chemo-resistance of CRPC cells in vitro and in vivo. Furthermore, we identified several cell cycle, chemo-resistance, and castration-resistance-related genes, including PLK1, AURKA, CDC25C, FOXM1, and UBE2C, that were activated transcriptionally by HOXD-AS1. Further investigation revealed that HOXD-AS1 recruited WDR5 to directly regulate the expression of target genes by mediating histone H3 lysine 4 tri-methylation (H3K4me3). In conclusion, our findings indicate that HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance in prostate cancer by recruiting WDR5. This sheds a new insight into the regulation of CRPC by lncRNA and provides a potential approach for the treatment of CRPC. [Display omitted] Huang, Lin, and colleagues show that long noncoding RNA HOXD-AS1 is upregulated in castration-resistant prostate cancer (CRPC) and correlated with disease progression. HOXD-AS1 promotes proliferation, castration resistance, and chemo-resistance of prostate cancer cells via interacting with WDR5, which in turn activates the transcription of downstream genes.

As a key step of tumor lymphatic metastasis, lymphangiogenesis is regulated by VEGFC‐VEGFR3 signaling pathway mediated by immune cells, mainly macrophages, in the tumor microenvironment. However, little is known whether tumor associated neutrophils are involved in lymphangiogenesis. Here, it is found that TANs infiltration is increased in LN‐metastatic BCa and is associated with poor prognosis. Neutrophil depletion results in significant reduction in popliteal LN metastasis and lymphangiogenesis. Mechanistically, transcription factor ETV4 enhances BCa cells‐derived CXCL1/8 to recruit TANs, leading to the increase of VEGFA and MMP9 from TANs, and then facilitating lymphangiogenesis and LN metastasis of BCa. Moreover, phosphorylation of ETV4 at tyrosine 392 by tyrosine kinase PTK6 increases nuclear translocation of ETV4 and is essential for its function in BCa. Overall, the findings reveal a novel mechanism of how tumor cells regulate TANs‐induced lymphangiogenesis and LN metastasis and identify ETV4 as a therapeutic target of LN metastasis in BCa. Tumor‐associated neutrophil (TANs) infiltration is increased in lymph node (LN)‐metastatic bladder cancer and is associated with poor prognosis. Neutrophil depletion results in significant reduction in popliteal LN metastasis and lymphangiogenesis. Mechanistically, protein tyrosine kinase 6 (PTK6)‐mediated phosphorylation of ETS variant transcription factor (ETV4) enhances bladder cancer (BCa) cells‐derived chemokine C‐X‐C motif ligand (CXCL)1/8 to recruit TANs, leading to the increase of vascular endothelial growth factor A (VEGFA) and matrix metalloproteinase‐9 (MMP9), and then facilitating lymphangiogenesis and LN metastasis of bladder cancer.

Background Circular RNAs (circRNAs) have been considered to mediate occurrence and development of human cancers, generally acting as microRNA (miRNA) sponges to regulate downstream genes expression. However, the aberrant expression profile and dysfunction of circRNAs in human bladder cancer remain to be investigated. The present study aims to elucidate the potential role and molecular mechanism of circACVR2A in regulating the proliferation and metastasis of bladder cancer. Methods circACVR2A (hsa_circ_0001073) was identified by RNA-sequencing and validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. The role of circACVR2A in bladder cancer was assessed both in vitro and in vivo. Biotin-coupled probe pull down assay, biotin-coupled microRNA capture, dual-luciferase reporter assay, and fluorescence in situ hybridization were conducted to evaluate the interaction between circACVR2A and microRNAs. Results The expression of circACVR2A was lower in bladder cancer tissues and cell lines. The down-regulation of circACVR2A was positively correlated with aggressive clinicopathological characteristics, and circACVR2A served as an independent risk factor for overall survival in bladder cancer patients after cystectomy. Our in vivo and in vitro data indicated that circACVR2A suppressed the proliferation, migration and invasion of bladder cancer cells. Mechanistically, we found that circACVR2A could directly interact with miR-626 and act as a miRNA sponge to regulate EYA4 expression. Conclusions circACVR2A functions as a tumor suppressor to inhibit bladder cancer cell proliferation and metastasis through miR-626/EYA4 axis, suggesting that circACVR2A is a potential prognostic biomarker and therapeutic target for bladder cancer.

Accurate lymph node staging is important for the diagnosis and treatment of patients with bladder cancer. We aimed to develop a lymph node metastases diagnostic model (LNMDM) on whole slide images and to assess the clinical effect of an artificial intelligence-assisted (AI) workflow. In this retrospective, multicentre, diagnostic study in China, we included consecutive patients with bladder cancer who had radical cystectomy and pelvic lymph node dissection, and from whom whole slide images of lymph node sections were available, for model development. We excluded patients with non-bladder cancer and concurrent surgery, or low-quality images. Patients from two hospitals (Sun Yat-sen Memorial Hospital of Sun Yat-sen University and Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China) were assigned before a cutoff date to a training set and after the date to internal validation sets for each hospital. Patients from three other hospitals (the Third Affiliated Hospital of Sun Yat-sen University, Nanfang Hospital of Southern Medical University, and the Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, China) were included as external validation sets. A validation subset of challenging cases from the five validation sets was used to compare performance between the LNMDM and pathologists, and two other datasets (breast cancer from the CAMELYON16 dataset and prostate cancer from the Sun Yat-sen Memorial Hospital of Sun Yat-sen University) were collected for a multi-cancer test. The primary endpoint was diagnostic sensitivity in the four prespecified groups (ie, the five validation sets, a single-lymph-node test set, the multi-cancer test set, and the subset for a performance comparison between the LNMDM and pathologists). Between Jan 1, 2013 and Dec 31, 2021, 1012 patients with bladder cancer had radical cystectomy and pelvic lymph node dissection and were included (8177 images and 20 954 lymph nodes). We excluded 14 patients (165 images) with concurrent non-bladder cancer and also excluded 21 low-quality images. We included 998 patients and 7991 images (881 [88%] men; 117 [12%] women; median age 64 years [IQR 56–72]; ethnicity data not available; 268 [27%] with lymph node metastases) to develop the LNMDM. The area under the curve (AUC) for accurate diagnosis of the LNMDM ranged from 0·978 (95% CI 0·960–0·996) to 0·998 (0·996–1·000) in the five validation sets. Performance comparisons between the LNMDM and pathologists showed that the diagnostic sensitivity of the model (0·983 [95% CI 0·941–0·998]) substantially exceeded that of both junior pathologists (0·906 [0·871–0·934]) and senior pathologists (0·947 [0·919–0·968]), and that AI assistance improved sensitivity for both junior (from 0·906 without AI to 0·953 with AI) and senior (from 0·947 to 0·986) pathologists. In the multi-cancer test, the LNMDM maintained an AUC of 0·943 (95% CI 0·918–0·969) in breast cancer images and 0·922 (0·884–0·960) in prostate cancer images. In 13 patients, the LNMDM detected tumour micrometastases that had been missed by pathologists who had previously classified these patients' results as negative. Receiver operating characteristic curves showed that the LNMDM would enable pathologists to exclude 80–92% of negative slides while maintaining 100% sensitivity in clinical application. We developed an AI-based diagnostic model that did well in detecting lymph node metastases, particularly micrometastases. The LNMDM showed substantial potential for clinical applications in improving the accuracy and efficiency of pathologists' work. National Natural Science Foundation of China, the Science and Technology Planning Project of Guangdong Province, the National Key Research and Development Programme of China, and the Guangdong Provincial Clinical Research Centre for Urological Diseases.