Boxuan Zhou

High endothelial venules (HEVs) provide another portal for tumour metastasis. However, whether HEVs and other blood vessels exert different effects on tumour escape remains unknown. Here we show that tumour involvement in HEVs is an independent prognostic marker for patients with lymph node (LN)-positive female breast cancer. Tumour cells that spread via HEVs are less immunogenic and more capable of establishing distant metastases than those that spread through non-HEV blood vessels. Mechanistically, the expression of arachidonate 12-lipoxygenase (ALOX12) in HEVs is promoted by tumour-derived semaphorin 3 C (SEMA3C). Reciprocally, ALOX12-derived metabolite 12-hydroxyeicosatetraenoic acid (12-HETE) promotes ADAR1 p150-dsRNA phase separation in tumour cells by selectively binding to ADAR1 p150. Consequently, the immune recognition of dsRNA is reduced because of the increased adenosine-to-inosine (A-to-I) RNA editing in tumour cells. Collectively, our data indicate that a unique lymphatic anatomical structure mediates specific immune evasion of migrating tumour cells.

Papillary thyroid cancer (PTC) is a prevalent malignancy worldwide. Spleen tyrosine kinase (SYK) is a crucial enzyme that participates in various biological processes, including cancer progression. This study aims to uncover the biological function of SYK in PTC. SYK expression patterns in PTC were evaluated using quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), and western blot. Cell function assays were performed to assess the effects of SYK on PTC. Bioinformatics analysis was conducted to identify intriguing microRNA (miRNA) and circular RNA (circRNA). Dual-Luciferase Reporter or RNA immunoprecipitation assays were used to investigate the correlation among SYK, miR-377-3p, and hsa_circ_0006417. SYK was upregulated in PTC. Overexpression of SYK exhibited a positive correlation with tumor size, lymph node metastasis, and unfavorable disease-free survival. Functional assays revealed that SYK exerted tumorigenic effect on PTC cells through mTOR/4E-BP1 pathway. Mechanistically, hsa_circ_0006417 and miR-377-3p regulated SYK expression, offering modulating its tumor-promoting effects. Collectively, SYK acts as an oncogene in PTC through mTOR/4E-BP1 pathway, which is regulated by the hsa_circ_0006417/miR-377-3p axis, thereby providing a potential alternative for PTC treatment.

Ferroptosis is a newly characterized form of iron-dependent non-apoptotic cell death, which is closely associated with cancer progression. However, the functions and mechanisms in regulation of escaping from ferroptosis during hepatocellular carcinoma (HCC) progression remain unknown. In this study, we reported that the RNA binding motif single stranded interacting protein 1 (RBMS1) participated in HCC development，and functioned as a regulator of ferroptosis. Clinically, the downregulation of RBMS1 occurred in HCC tissues, and low RBMS1 expression was associated with worse HCC patients survival. Mechanistically, RBMS1 overexpression inhibited HCC cell growth by attenuating the expression of glutathione peroxidase 4 (GPX4)and further facilitated ferroptosis in vitro and in vivo. More importantly, a novel circIDE (hsa_circ_0000251) was identified to elevate RBMS1 expression via sponging miR-19b-3p in HCC cells. Collectively, our findings established circIDE/miR-19b-3p/RBMS1 axis as a regulator of ferroptosis, which could be a promising therapeutic target and prognostic factor. GRAPHICAL ABSTRACT

Background: Circular RNAs (circRNAs) are becoming vital biomarkers and therapeutic targets for malignant tumors due to their high stability and specificity in tissues. However, biological functions of circRNAs in hepatocellular carcinoma (HCC) are still not well studied. Methods: Gene Expression Omnibus (GEO) database and qRT-PCR were used to evaluate expression of circROBO1 (hsa_circ_0066568) in HCC tissues and cell lines. CCK-8, colony formation, EdU staining, flow cytometry for cell cycle analysis, and xenograft model assays were performed to detect the circROBO1 function in vitro and in vivo. RNA pull-down, RNA immunoprecipitation (RIP), and Luciferase reporter assays were used to investigate the relationship among circROBO1, miR-130a-5p, and CCNT2. More importantly, we developed nanoparticles made from poly lactic-co-glycolic acid (PLGA) and polyethylene glycol (PEG) chains as the delivery system of si-circROBO1 and then applied them to HCC in vitro and in mice. Results: circROBO1 was obviously upregulated in HCC tissues and cell lines, and elevated circROBO1 was closely correlated with worse prognosis for HCC patients. Functionally, knocking down circROBO1 significantly suppressed HCC cells growth in vitro and in mice. Mechanistically, circROBO1 acted as a competing endogenous RNA to downregulate miR-130a-5p, leading to CCNT2 expression upregulation. Furthermore, miR-130a-5p mimic or CCNT2 knockdown reversed the role of circROBO1 overexpression on HCC cells, which demonstrated that circROBO1 promoted HCC development via miR-130a-5p/CCNT2 axis. In addition, we developed nanoparticles loaded with si-circROBO1, named as PLGA-PEG (si-circROBO1) NPs, which significantly prevented the proliferation of HCC cells, and did not exhibit apparent toxicity to major organs in vivo. Conclusion: Our findings firstly demonstrate that circROBO1 overexpression promotes HCC progression by regulating miR-130a-5p/CCNT2 axis, which may serve as an effective nanotherapeutic target for HCC treatment.

Microvascular invasion (MVI) is a crucial risk factor related to the metastasis of hepatocellular carcinoma (HCC), but the underlying mechanisms remain to be revealed. Characterizing the inherent mechanisms of MVI may aid in the development of effective treatment strategies to improve the prognosis of HCC patients with metastasis. Through the Gene Expression Omnibus (GEO) database, we identified that small nuclear ribonucleoprotein polypeptide A (SNRPA) was related to MVI in HCC. SNRPA was overexpressed in MVI‐HCC and correlated with poor patient survival. Mechanistically, SNRPA promoted the epithelial‐mesenchymal transition (EMT)‐like process for HCC cells to accelerate metastasis by activating the NOTCH1/Snail pathway in vitro and in vivo . Importantly, circSEC62 upregulated SNRPA expression in HCC cells via miR‐625‐5p sponging. Taking these results together, our study identified a novel regulatory mechanism among SNRPA, miR‐625‐5p, circSEC62 and the NOTCH1/Snail pathway in HCC, which promoted metastasis of HCC and may provide effective suggestions for improving the prognosis of HCC patients with metastasis.

Phagocytosis is required for the optimal efficacy of many approved and promising therapeutic antibodies for various malignancies. However, the factors that determine the response to therapies that rely on phagocytosis remain largely elusive. Here, we demonstrate that mitochondrial fission in macrophages induced by multiple antibodies is essential for phagocytosis of live tumor cells. Tumor cells resistant to phagocytosis inhibit mitochondrial fission of macrophages by overexpressing glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which can be targeted to improve antibody efficacy. Mechanistically, increased cytosolic calcium by mitochondrial fission abrogates the phase transition of the Wiskott–Aldrich syndrome protein (WASP)–Wiskott–Aldrich syndrome interacting protein (WIP) complex and enables protein kinase C-θ (PKC-θ) to phosphorylate WIP during phagocytosis. GFPT2-mediated excessive use of glutamine by tumor cells impairs mitochondrial fission and prevents access of PKC-θ to compartmentalized WIP in macrophages. Our data suggest that mitochondrial dynamics dictate the phase transition of the phagocytic machinery and identify GFPT2 as a potential target to improve antibody therapy.

Neutrophil extracellular traps (NETs), which consist of chromatin DNA filaments coated with granule proteins, are released by neutrophils to trap microorganisms^1,2,3. Recent studies have suggested that the DNA component of NETs (NET-DNA) is associated with cancer metastasis in mouse models^4,5,6. However, the functional role and clinical importance of NET-DNA in metastasis in patients with cancer remain unclear. Here we show that NETs are abundant in the liver metastases of patients with breast and colon cancers, and that serum NETs can predict the occurrence of liver metastases in patients with early-stage breast cancer. NET-DNA acts as a chemotactic factor to attract cancer cells, rather than merely acting as a ‘trap’ for them; in several mouse models, NETs in the liver or lungs were found to attract cancer cells to form distant metastases. We identify the transmembrane protein CCDC25 as a NET-DNA receptor on cancer cells that senses extracellular DNA and subsequently activates the ILK–β-parvin pathway to enhance cell motility. NET-mediated metastasis is abrogated in CCDC25-knockout cells. Clinically, we show that the expression of CCDC25 on primary cancer cells is closely associated with a poor prognosis for patients. Overall, we describe a transmembrane DNA receptor that mediates NET-dependent metastasis, and suggest that targeting CCDC25 could be an appealing therapeutic strategy for the prevention of cancer metastasis.

Recurrent bile duct stones is the most common complication after gallstone surgery and the incidence is about 4-24%. Sphincter of Oddi laxity will lead to duodenal content flow into the bile or pancreatic duct. Patients with recurrent bile duct stones and Oddis sphincter laxity were intractable. Here we sought to present the possible and helpful surgical treatments for such patients. Prospective randomized clinical trial are needed for evaluating the outcome of surgical treatments.