Increasing evidences suggest the important role of calcium homeostasis in hallmarks of cancer, but its function and regulatory network in metastasis remain unclear. A comprehensive investigation of key regulators in cancer metastasis is urgently needed. Transcriptome sequencing (RNA-seq) of primary esophageal squamous cell carcinoma (ESCC) and matched metastatic tissues and a series of gain/loss-of-function experiments identified potassium channel tetramerization domain containing 4 (KCTD4) as a driver of cancer metastasis. KCTD4 expression was found upregulated in metastatic ESCC. High KCTD4 expression is associated with poor prognosis in patients with ESCC and contributes to cancer metastasis in vitro and in vivo. Mechanistically, KCTD4 binds to CLIC1 and disrupts its dimerization, thus increasing intracellular Ca²⁺ level to enhance NFATc1-dependent fibronectin transcription. KCTD4-induced fibronectin secretion activates fibroblasts in a paracrine manner, which in turn promotes cancer cell invasion via MMP24 signaling as positive feedback. Furthermore, a lead compound K279-0738 significantly suppresses cancer metastasis by targeting the KCTD4‒CLIC1 interaction, providing a potential therapeutic strategy. Taken together, our study not only uncovers KCTD4 as a regulator of calcium homeostasis, but also reveals KCTD4/CLIC1-Ca²⁺-NFATc1-fibronectin signaling as a novel mechanism of cancer metastasis. These findings validate KCTD4 as a potential prognostic biomarker and therapeutic target for ESCC.

【Objective】 To explore the clinical features, treatment and prognosis of paraganglioma of the urinary bladder (PUB). 【Methods】 The clinical data of 41 PUB patients treated at our hospital during Sep.2012 and Sep.2022 were collected. The clinical features, surgical records, pathological reports and follow-up records were retrospectively analyzed. Patients’ survival was estimated with Kaplan-Meier estimator. The differences among groups were compared with Log-rank test. 【Results】 Among the 41 patients, 20 were male and 21 were female, with a median age of 52 years. All patients were treated with surgery, including transurethral resection of bladder tumor (TURBT) in 16 cases, partial cystectomy (PC) in 23 cases, and radical cystectomy (RC) in 2 cases. All patients were followed up for 4.0 to 125.0 months, with a median of 59.0 months. Local recurrence occurred in 5 patients, and distant metastasis occurred in 5 patients. Survival analysis showed that the 5-year overall survival (OS) rate and 5-year relapse-free survival (RFS) rate were 95.7% and 84.8%, respectively. Further analysis showed statistically significant differences in OS and RFS among groups with different maximum tumor diameters, growth patterns, and Ki-67 expressions (P<0.05). For patients with a maximum tumor diameter ≤2.8 cm, there was no significant difference in OS and RFS among different surgical groups. 【Conclusion】 PUB is rare, and a definitive diagnosis is based on pathology. In addition, the main treatment is surgery and the prognosis is good.

Chronic obstructive pulmonary disease (COPD) is an important healthcare problem worldwide. Often, glucocorticoid (GC) resistance develops during COPD treatment. As a classic hypoglycemic drug, metformin (MET) can be used as a treatment strategy for COPD due to its anti-inflammatory and antioxidant effects, but its specific mechanism of action is not known. We aimed to clarify the role of MET on COPD and cigarette smoke extract (CSE)-induced GC resistance. Through establishment of a COPD model in rats, we found that MET could improve lung function, reduce pathological injury, as well as reduce the level of inflammation and oxidative stress in COPD, and upregulate expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), multidrug resistance protein 1 (MRP1), and histone deacetylase 2 (HDAC2). By establishing a model of GC resistance in human bronchial epithelial cells stimulated by CSE, we found that MET reduced secretion of interleukin-8, and could upregulate expression of Nrf2, HO-1, MRP1, and HDAC2. MET could also increase the inhibition of MRP1 efflux by MK571 significantly, and increase expression of HDAC2 mRNA and protein. In conclusion, MET may upregulate MRP1 expression by activating the Nrf2/HO-1 signaling pathway, and then regulate expression of HDAC2 protein to reduce GC resistance.

Enzalutamide (ENZ) is a second-generation androgen receptor (AR) antagonist used for the treatment of castration-resistant prostate cancer (CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance (ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR (ARfl) or dominantly active androgen receptor splice variant 7 (ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.

AIM: To explore the effect of Huatanjiangqi capsule medicated serum (HTJQ) on the resistance of human bronchial epithelial cells (16HBE) to glucocorticoid (GC) stimulated by cigarette smoke extract (CSE). METHODS: After 16HBE cells were treated with HTJQ, the effects of different concentrations of HTJQ on the viability of 16HBE cells were determined by CCK-8 method. 16HBE cells were pretreated with HTJQ, and then cultured with dexamethasone (DEX) and lipopolysaccharide (LPS) for 24 hours, the effect of HTJQ on glucocorticoid (GC) resistance of 16HBE cells was determined by Enzyme-linked immunosorbent assay (ELISA). The effects of HTJQ, sulforaphane (SFN) and glutathione (GSH) on the expression of NF-E2-related factors 2 (Nrf2), Heme oxygenase-1 (HO-1) and histone deacetylase 2 (HDAC2) in 16HBE cells stimulated by CSE were measured by Western blot, and the effects of HTJQ, SFN and GSH on interleukin-8 (IL-8) in 16HBE cells were measured by ELISA. RESULTS: HTJQ promoted the proliferation of 16HBE cells at 1 h, 2 h and 4 h, the results of ELISA and Western blot showed that CSE induced GC resistance and decreased the expression of Nrf2, HO-1 and HDAC2 in 16HBE cells, HTJQ significantly decreased IL-8 and improved GC sensitivity of 16HBE cells (P<0.01), and up-regulated the expression of Nrf2, HO-1 and HDAC2 (P<0.01). In addition, HTJQ significantly up-regulated the level of GSH in 16HBE cells (P<0.01). Nrf2 agonists SFN and GSH significantly improved the glucocorticoid sensitivity of 16HBE cells (P<0.01), and up-regulated the expression of Nrf2, HO-1 and HDAC2 (P<0.01). CONCLUSION: HTJQ improves the GC resistance of 16HBE cells by up-regulating the expression of Nrf2/HDAC2 protein and the level of intracellular GSH.

In the original publication the Supplementary Material and Fig. 2 are incorrect. The correct version is provided in this correction article. The text HBG2 appearing in the article should be read as HBG1.

Bacterial Proteins ; genetics ; CRISPR-Cas Systems ; genetics ; Endonucleases ; genetics ; Gene Editing ; HEK293 Cells ; Humans ; Transcriptional Activation ; genetics ; p300-CBP Transcription Factors ; genetics

Objective To evaluate the effect of exosomes from different sources on the growth, metastasis and immune microenvironment of hepatocellular carcinoma ( HCC ) in a mouse model of orthotopic transplanted hepatoma so as to provide new insight into the clinical immunotherapy of hepatocellular carcinoma. Methods The serum-derived exosomes were obtained by ultracentrifugation from Hepa1-6 cells and 3-week orthotopically tumor-bearing HCC mice. The morphology and size of exosomes were identified by transmission electron microscopy. One-week tumor-bearing HCC C57BL/6 mice were randomly divided into 3 groups ( 3 mice for each group ) , and respectively treated with tail vein injection of 120 μl PBS(control group), 120 μl Hepa1-6 cell-derived exosomes (1μg/μl, TEXcel group), and serum-derived exosomes (1μg/μl) (TEXserum group). The treatments were conduced once a week for 3 consecutive weeks. The mice were sacrificed on the 4th day after the treatments, and the liver tissue and lung tissues were dissected. The volumes of the liver cancer tissues were measured. The expression of PD-L1 protein and CD3+and FoxP3+T lymphocytes infiltration in the liver cancer tissues were respectively detected by Western Blot and immunohistochemical staining. The lung metastasis of the liver cancer was detected by hematoxylin-eosin staining. Results The diameters of the Hepa1-6 cell- and serum-derived exosomes both were about 100 nm, and were uniform vesicles with complete membrane structure. Compared with the control group, Hepa1-6 cell-derived exosomes had a certain inhibitory effect on the growth and lung metastasis of HCC, while there was no significant difference for the TEXserum group. Western Blot results showed that compared with the control group, PD-L1 protein expression was significantly up-regulated in both TEXcel group and TEXserum group. Immunohistochemical staining showed that compared with the control group, the infiltration number of Foxp3+-labeled regulatory T cells (Treg) had no significant changes in TEXcel group and the TEXserum group, and the differences were no statistically significant (all P>0.05). However, the infiltration number of CD3+-labeled T lymphocytes was significantly reduced in the two groups, and the differences were statistically significant (all P<0.05). Conclusion The Hepa1-6 cell-derived exosomes have a certain inhibitory effect on the growth and lung metastasis of HCC, and have no obvious regulation effects on the immune microenvironment of HCC. The serum-derived exosomes from orthotopically tumor-bearing HCC mice can promote the growth and lung metastasis of HCC and immunosuppress the microenvironment. The Hepa1-6 cell-derived exosomes are expected to be used for immunotherapy studies of liver cancer.

Objective To discuss the imaging appearances and causes of hepatic pseudolesions around the falciform ligament.Methods 40 patients (23 cases of A-type,17 cases of B-type) of hepatic pseudolesion around the falciform ligament examined by CT were collected.Combined with pathology of 2 cases,follow-up of 6 cases,MRI findings in 5 cases,and with the relevant literature reviewes,the density change of CT plain and enhanced scan and the causes of hepatic pseudolesion around the falciform ligament were analyzed retrospectively.Results There were low density in 25 cases,isodensity in 13 cases,high density in 2 cases in arterial phase,density lower than that of liver in 40 cases in portal phase,low or slightly low density in 27 cases and isodensity in 13 case of A-type in delayed phase.Of 40 cases,there were isointense in 2 cases of A-type in any sequence,and no sigal changes on out-phase images;there were intensity decline on out-phase images comparing to in-phase images in 3 cases of B type.Of 6 CT follow-up cases,there were no changes in 2 cases of A-type and shrinked or disappear in 4 cases of B-type;and there were more shrinked in 1 B-type case of MRI follow-up again after one month.Conclusion Hepatic pseudolesion of A-type can be resulted from focal fatty infiltration,and that of B-type can be caused by special blood-supply.They have characteristics in locations,and characteristic imaging appearances on CT and MRI images,and they can be clearly diagnosed generally.

Objective To study the role of lipase in inflammation in patients with acute pancreatitis.Methods Acute pancreatitis patients (n =200) were enrolled in the study.The patients were examined by computerized tomography and the severity of AP is determined by Blathazat Score.We assess the muhivariate-adjusted association of amylase and lipase with inflammatory markers of AP.We identified that lipase was more specifically correlated with AP progression than amylase,lactate dehydrogenase and creatitine kinase.Results We demonstrated that in AP patients,a doubling of lipase excretion was associated with 6.8％ increase of white blood cells (95％ CI,3.06％-10.5％,P ＜ 0.01),10.3％ (95％ CI,5.7％-14.9％,P ＜ 0.01) increase of neutrophil number but 14.8％ (95％ CI,2.3％-27.3％,P ＜0.05) decrease of lymphocytes in the blood,respectively.By contrast,amylase has no association with these cells.Both amylase and lipase had no relationship with triglyceride level in AP patients.Conclusions Lipase serves as an indicator for the severity and treatment of AP.