BACKGROUND Colorectal cancer (CRC) remains a highly fatal cancer worldwide, while metastasis is the main challenge in clinical treatment. Protein arginine methyltransferase 6 (PRMT6), a type I PRMT family member, catalyzes asymmetric methylation of arginine residues and contributes to tumor cell proliferation, invasion, metastasis and chemoresistance by both epigenetic and post-translational mechanisms. Notably, PRMT6 is overexpressed in CRC tissues and is associated with a poor survival outcome for patients. However, its targeted therapy and related mechanisms remain unclear. AIM To investigate the antitumor activity and molecular mechanisms of EPZ020411 in CRC HCT116 and CACO-2 cells. METHODS Human CRC cell lines (HCT116 and CACO-2) were treated with EPZ020411, and cell proliferation, migration and invasion were evaluated by CCK-8, EdU, colony formation, wound healing and Transwell assays. RNA sequencing was performed to screen differentially expressed genes, and the results were validated by reverse transcription-quantitative polymerase chain reaction and western blotting. To assess the functional role of transglutaminase 2 (TGM2), we generated a TGM2 over-expression model. The antitumor efficacy in vivo was evaluated using the xenograft mouse model, and tumor growth, histology and immunohistochemistry were performed. RESULTS EPZ020411 inhibited CRC cell proliferation, migration, and invasion dose-dependently. IC50 values of EPZ020411 in HCT116 and CACO-2 cells at 48 hours were 126 μmol/L and 106 μmol/L. At 24 μmol/L, colony formation decreased by 32% and 50%, migration by ~62% in both lines, and invasion by 64% and 45%, respectively. Transcriptomic analysis revealed marked downregulation of TGM2, which was confirmed at both mRNA and protein levels. Mechanistically, EPZ020411 reduced phosphorylation of JNK and p38, indicating inactivation of the mitogen-activated protein kinases (MAPK) signaling pathway. Functional rescue experiments demonstrated that TGM2 overexpression partially reversed the inhibitory effects of EPZ020411. In vivo , EPZ020411 effectively suppressed tumor growth (45.1% inhibition at 10 mg/kg) without toxicity and reduced TGM2 expression in tumor tissues. CONCLUSION EPZ020411 inhibits CRC in vitro and in vivo via TGM2/MAPK, linking PRMT6-TGM2-MAPK, and suggesting PRMT6 as a potential therapeutic target.

Various dressings have been developed for the prevention and treatment of wound infections, but the complex structures and manufacturing processes designed to achieve powerful functionalities have impeded their clinical application. Herein, a dynamic injectable photothermal/chemotherapeutic hydrogel has been facilely established through mixing gellan gum (GG), indocyanine green (ICG) and amikacin (AMI) aqueous solutions at 80°C and cooling to room temperature. The hydrogel displayed a precise structure with 1.5% of GG containing ICG content of 100 μg/mL and AMI content of 1 mg/mL, and exhibited favorable injectable, self-healing, and adhesive capabilities as well as superior swelling and moisturizing properties through GG's features. Furthermore, the GG also endowed the hydrogel with the capability to efficiently release drugs in response to the microenvironment (pH 5.0, 7.4 and 8.0) of both infected and uninfected wounds. These exceptional physicochemical properties and combined effects of chemotherapy and PTT facilitated the satisfactory in vitro biocompatibility and antibacterial capability as well as wound healing acceleration ability. Therefore, such a dynamic injectable photothermal/chemotherapeutic hydrogel paves the way toward easily clinical transformation for prevention and treatment of local wound infections.

This study delineates a hierarchical signaling axis driving gastric cancer (GC) progression through integrated transcriptomic and functional analyses. Single-cell sequencing and TCGA data identified CSF2 as a key oncogene, with elevated expression correlating with poor prognosis. Mechanistically, the transcription factor HES1 directly activates IGF2BP2 transcription, as confirmed by chromatin immunoprecipitation and dual-luciferase assays. IGF2BP2 subsequently stabilizes CSF2 mRNA via N6-methyladenosine (m6A) modification, validated through RNA immunoprecipitation and mRNA decay kinetics. Functional interrogation revealed that the HES1-IGF2BP2-CSF2 axis promotes GC cell growth, motility, and infiltrative capacity while inhibiting apoptosis. Critically, this axis orchestrates glycolytic reprogramming, evidenced by upregulated HK2/PKM2/LDHA expression, increased lactate/ATP production, and enhanced glycolytic flux. In vivo xenografts demonstrated accelerated tumor growth upon axis activation, with immunohistochemistry showing elevated Ki67 and reduced apoptosis. These results establish a novel signaling cascade wherein HES1 transcriptionally integrates IGF2BP2-mediated m6A epitranscriptomics and metabolic rewiring to fuel GC aggressiveness.

This study reports the synthesis and characterization of an injectable nano-hydrogel composite (m@NPs-HG) based on selenium nanoparticles (Se NPs) and carboxymethyl chitosan (CMCS) nanoparticles for enhanced cancer therapy. Selenium nanoparticles were stabilized using CMCS to form copper selenide nanoparticles (CSe NPs), while doxorubicin (DOX)-loaded CMCS nanoparticles (CD NPs) were encapsulated within cancer cell membranes to generate biomimetic nanoparticles (m@NPs). Subsequently, CSe NPs and m@NPs were integrated into a hydrogel via crosslinking with CuCl2, resulting in the formation of m@NPs-HG. The composite exhibited remarkable photothermal conversion capability, efficient cellular uptake, and robust reactive oxygen species (ROS) generation. In vitro experiments demonstrated significant induction of apoptosis and cytotoxicity in H22 and HepG2 cancer cells. The in vivo anti-tumor efficacy was evaluated in H22 tumor-bearing mice, revealing that m@NPs-HG combined with laser irradiation effectively suppressed tumor growth while exhibiting minimal systemic toxicity. Hemolysis and biodistribution studies further confirmed the excellent biocompatibility and targeting ability of the composite system. This study concludes that the m@NPs-HG system represents a promising theranostic platform for cancer treatment.

4012 Background: Anti-PD-1 monoclonal antibody (mAbs) plus chemotherapy has become standard first-line therapy for patients (pts) with advanced/metastatic G/GEJ cancer. In this phase Ib/II study (NCT04982276), we assessed the safety and efficacy of cadonilimab, a PD-1/CTLA-4 bispecific antibody, in combination with pulocimab, an anti-VEGFR-2 mAb, and paclitaxel in G/GEJ cancer pts who failed immunochemotherapy. Methods: This study consisted of two parts: safety run-in (arms A, B and C, n = 6 each) and expansion (a randomized, double-blind phase II study). In safety part, pts received intravenous pulocimab 10mg/kg, every 2 weeks (Q2W) + paclitaxel 80 mg/m2, days 1, 8, 15 (arm A), or cadonilimab 10mg/kg + pulocimab 10mg/kg, Q2W (arm B), or cadonilimab 10mg/kg + pulocimab 10mg/kg + paclitaxel 150 mg/m2, Q3W (arm C). In expansion part, pts were randomly assigned at 1:1 ratio to receive cadonilimab 10mg/kg + pulocimab 10mg/kg + paclitaxel 150 mg/m2, Q3W (arm 1) or placebo + pulocimab + paclitaxel (arm 2). The primary endpoint was safety and objective response rate (ORR), secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: As of 30 Oct. 2023, a total of 77 pts were enrolled. In safety part (n = 18), dose-limiting toxicity (DLT) was observed in 1/6 pts in arm B, whereas no DLT was observed in either arm A or C. In expansion part, 59 pts were randomly assigned to arm 1 (n = 29) and arm 2 (n = 30). 6 pts were excluded due to treatment interruptions caused by Covid-19 epidemic between September and December, 2022. Baseline characteristics were generally balanced between treatment arms. With median follow-up of 7.3 months (mo, range: 1.4-16.1), 53 pts had at least one post-baseline tumor evaluation. ORR was 48.0% (12/25) for arm 1 vs 35.7% (10/28) for arm 2, disease control rate (DCR) was 96.0% (24/25) vs 92.9% (26/28), mPFS was 6.8 mo (95% CI 4.1, 11.2) vs 4.9 mo (95% CI 3.2, 7.1) , median duration of response (mDoR) was not reached vs 4.0 mo (95%CI 1.58, NE), the median OS was not reached for the two arms, 9-mo OS rate was 65.5% (95% CI 33.2, 85.0) vs 34.0% (95% CI 9.5, 60.9). Grade 3-4 treatment-related adverse events (TRAEs) occurred in ≥10% pts were neutrophil count decreased (27.6% vs 33.3%), white blood cell count decreased (10.3% vs 26.7%) and blood pressure increased (13.8% vs 10.0%). No new safety signals were identified. Conclusions: The combination of cadonilimab with pulocimab and paclitaxel demonstrated manageable safety profile and encouraging efficacy as second-line therapy in pts with G/GEJ cancer progressed after immunochemotherapy. Incorporation of dual immunotherapy to VEGFR-2 targeting therapy could be a potential strategy to overcome immunotherapy resistance. Additional phase III study is warranted to confirm it. Clinical trial information: NCT04982276 .

Purpose: This study aimed to determine the relevance of first- and high-order radiomic features derived from Diffusion-Weighted Imaging (DWI) and Apparent Diffusion Coefficient (ADC) maps for predicting treatment response in patients with Undifferentiated Pleomorphic Sarcoma (UPS). Methods: This retrospective study included 33 extremity UPS patients with pre-surgical DWI/ADC and surgical resection. Manual volumetric tumor segmentation was performed on DWI/ADC maps acquired at Baseline (BL), Post-Chemotherapy (PC), and Post-Radiation Therapy (PRT). The percentage of pathology-assessed treatment effect (PATE) in surgical specimens categorized patients into responders (R; PATE ≥ 90%; 16 patients), partial-responders (PR; 89% - 31% PATE; 10 patients), and non-responders (NR; PATE ≤ 30%; 7 patients). 107 radiomic features were extracted from BL, PC, and PRT ADC maps. Statistical analyses compared R vs. PR/NR. Results: Pseudo-progression at PC and universal stability at PRT were observed in R and PR/NR based on RECIST, WHO, and volumetric assessments. At PRT, responders displayed a 35% increase in ADC mean (p = 0.0034), a 136% decrease in skewness (p = 0.0001), and a 363% increase in the 90th percentile proportion (p = 0.0009). Comparing R vs. PR/NR at BL, statistically significant differences were observed in glrlm_highgraylevelrunemphasis (p = 0.0081), glrlm_shortrunhighgraylevelemphasis (p = 0.0138), gldm_highgraylevelemphasis (p = 0.0138), glcm_sumaverage (p = 0.0164), glcm_jointaverage (p = 0.0164), and glcm_autocorrelation (p = 0.0193). At PC, firstorder_meanabsolutedeviation (p = 0.0078), firstorder_interquartilerange (p = 0.0109), firstorder_variance (p = 0.0109), and firstorder_robustmeanabsolutedeviation (p = 0.0151) provided statistically significant differences. Conclusion: Observing a high post-therapeutic ADC mean, low skewness, and high 90th percentile proportion with respect to baseline is predictive of successfully treated UPS patients presenting > 90% PATE. Highly significant higher-order radiomic results include glrlm-highgraylevelrunemphasis (BL) and first-order-mean absolute deviation (PC).

The purpose of this paper is to develop a pH/thermal sensitive nanohydrogel composite for in situ injection and to achieve an enhanced chemo-photothermal synergistic antitumor effect. Pluronic F127 was oxidized to aldehyde-terminated (AF127) as the precursor of the thermally sensitive hydrogel. A series of hydrogels (HG) with different rheological behaviors were obtained by adjusting the ratio of AF127 to carboxymethyl chitosan (CMCS) (AF45/CM15, AF75/CM15, and AF90/CM15). By changing the ratio of AF127 micelles to CMCS, we can adjust the sol-gel transition time and temperature to facilitate in situ tumor injection. Indocyanine green (ICG) encapsulated AF127 micelles and doxorubicin (DOX)-loaded CMCS nanoparticles (NP-DOX) can form nanohydrogel composite (HG/ICG/NP-DOX) through dynamic Schiff base covalent bonds and physical entanglement. The nanohydrogel composite has good fluidity for injection at low temperatures and can quickly form hydrogel at 37 ?. Bromelain was introduced into the complex to improve the penetration of nanoparticles by hydrolyzing the dense extracellular matrix (ECM) in tumor tissue. ICG can produce a photothermal effect under 808 nm laser irradiation, further enhancing the antitumor effect of NP-DOX. HG/ICG/NP-DOX can remain in the tumor area for a long time, and it still shows an obvious photothermal effect even after 120 h. HG/ICG/NP-DOX with laser irradiation possesses an excellent chemo-photothermal synergistic antitumor effect, and the tumor growth inhibition rate reached 93.9%. These nanohydrogel composites have great potential in the field of in situ tumor injection as local drug delivery systems.

目的:探究奥沙利铂(L-OHP)与吴茱萸碱(EVO)联用后对L-OHP耐药的人胃癌BGC-823/L-OHP细胞增殖与凋亡能力的改变及可能机制.方法:于体外建立对L-OHP耐药的胃癌BGC-823细胞株,CCK-8法分别计算EVO及L-OHP单独使用与联合使用时BGC-823/L-OHP细胞的增殖抑制率、IC50及逆转指数;流式细胞仪检测EVO联合L-OHP作用于BGC-823/L-OHP细胞前后细胞周期分布及凋亡的变化;采用Real-time PCR、Western blot法检测细胞中MDR1、MRP1 mRNA和蛋白的表达水平.结果:2.00 μmol/L EV O处理BGC-823/L-OHP细胞48 h后,L-OHP对BGC-823/L-OHP耐药细胞株的IC,.由(18.83±0.83)μg/ml变为(12.78±1.78)μg/ml,差异有统计学意义(P＜0.05);EVO与L-OHP联用耐药细胞滞留在G2期比例升高,滞留在G1期及S期的细胞比例降低(P＜0.05);细胞凋亡率高于单独用药组(P＜0.05);MDR1、MRP1 mRNA和蛋白表达水平低于单独用药组(P＜0.05).结论:EVO和L-OHP联用能逆转BGC-823/L-OHP对L-OHP的耐药性并改变其周期分布,促进细胞凋亡.

To compare the effects of Ivor-Lewis esophagectomy and McKeown esophagectomy on perioperative anxiety and depression in patients with esophageal cancer. Sixty-three patients with stage I-III middle and lower esophageal carcinoma from June 2021 to December 2022 were randomly divided into observation group (n = 32) treated with laparoscopic Ivor-Lewis esophagectomy and control group (n = 31) treated with laparoscopic McKeown esophagectomy. Self-Rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS) were measured on the second day of admission and the fifth day after surgery to assess the presence of depression and anxiety. The preoperative and postoperative clinical data of both groups were compared, and multivariate analysis was used to identify risk factors associated with depression and anxiety in patients with esophageal cancer. There was no significant difference in SDS and SAS standard scores between the observation group and the control group ( P > 0.05). The postoperative SDS and SAS scores in the control group were significantly higher than those before and after operation in the observation group ( P < 0.01). According to univariate analysis, patients with TNM stage III, tumor diameter greater than 3 cm, postoperative complications, radical McKeown esophagectomy, and C-reactive protein levels above 10 mg/L had a higher incidence of depression and anxiety ( P < 0.05). Multivariate logistic analysis showed that TNM stage III (depression: OR 1.683, 95 CI 1.429–1.861; Anxiety: OR 1.739, 95 CI 1.516–1.902), postoperative complications (depression: OR 2.345, 95 CI 1.435–3.891; Anxiety: OR 1.872, 95 CI 1.372–3.471), surgical approach (depression: OR 1.609, 95 CI 1.502–3.193; Anxiety: OR 1.658, 95 CI 1.469–2.059), and C-reactive protein (depression: OR 2.260, 95 CI 1.157–4.059; Anxiety: OR 0.373, 95 CI 0.253–0.976) were all independent factors for depression and anxiety in patients after esophageal cancer surgery ( P < 0.05). The Ivor-Lewis esophagectomy has the advantages of fewer complications and low inflammatory response, which can help alleviate anxiety and depression and improve patients’ quality of life and prognosis.

Background and Aims: In radical gastrectomy for proximal gastric cancer, bleeding and spleen damage are likely to occur when dealing with short gastric vessels, especially in some obese patients with short spleen-gastric ligaments at the upper pole of the spleen. The author’s team has previously used a surgical method of pre-expanding the posterior gastric space, which effectively solves this problem. This study was performed to compare the clinical efficacy of laparoscopic proximal gastrectomy with pre-expansion of the retrogastric space versus conventional laparoscopic proximal gastrectomy, and explore the value of the pre-expansion method in laparoscopic proximal gastrectomy for gastric cancer.Methods: The clinical data of 196 patients who underwent laparoscopic proximal radical gastrectomy in the Department of Oncology of the First Affiliated Hospital of Bengbu Medical College from January 2019 to December 2021 were retrospectively analyzed. Of the patients, 99 cases underwent radical proximal gastrectomy with pre-expansion of the retrogastric space（study group）, 97 cases received conventional proximal gastrectomy（control group）. The clinical variables were compared between the two groups of patients.Results: There were no significant differences in general information such as age, sex, BMI, tumor location, tumor stage, surgical method, and esophagojejunostomy method between the two groups（all P＞0.05）. All patients in both groups completed the laparoscopic surgery uneventfully, with the same range of lymph node dissection and without conversion to open surgery. Compared with the control group, the study group had a significantly shorter average operative time [（100.3±25.8） min vs.（130.7±43.2） min, P=0.000] and significantly less average intraoperative blood loss [（35.0±5.7） mL vs.（44.9±4.7） mL, P=0.000]. Splenic injury occurred in 5 cases（5.2%） in the control group during the surgery, while no intraoperative spleen injury occurred in the study group, but the difference was not statistically significant（P＞0.05）. There were no statistically significant differences between the two groups in terms of the number of lymph node dissection, postoperative drainage volume, drainage time, postoperative hospital stay, hospital costs, and incidence of surgical complications（all P＞0.05）. No serious postoperative complications occurred in both groups of patients.Conclusion: The surgical method of pre-expanding the posterior gastric space in laparoscopic proximal gastrectomy has the advantages of less intraoperative bleeding, shorter operation time, and reduced iatrogenic splenic injury. So, it is recommended for clinical use.

Abstract Purpose To analyze the clinical efficacy of total laparoscopic π-shaped esophageal jejunostomy and laparoscopic assisted Roux en-Y esophago-jejunostomy for cardiac cancer and their effects on traumatic stress. Methods We collected clinical data from 72 patients with adenocarcinoma of the esophagogastric junction who were treated in our department between June 2020 and July 2022. All patients underwent laparoscopic total gastrectomy + D2 lymphadenectomy, in whom 38 patients underwent total laparoscopic total gastrectomy with π-shaped esophageal jejunostomy and 34 patients underwent laparoscopic-assisted total gastrectomy with Roux en-Y esophago-jejunostomy. The short-term therapeutic effects, safety and effects on stress response indicators of different surgical methods were analyzed. Results There were no significant differences in baseline clinical and pathological data between the two groups (P > 0.05). The mean operation duration was 201.7 ± 80.3 minutes in the total endoscopic π-shaped esophageal jejunostomy group, which was longer than 166.9 ± 26.9 minutes in the laparoscopic-assisted Roux en-Y esophago-jejunostomy group (P < 0.05). The length of the surgical incision in the total endoscopic π-shaped esophageal jejunostomy group was significantly shorter, measuring 4.6 ± 2.1 cm, compared to the Roux-en-Y anastomosis group, which had an average length of 10.4 ± 2.1 cm (P < 0.01). In terms of intraoperative bleeding, the intraoperative bleeding volume of 130.3 ± 50.3 ml in the total endoscopic π-shaped esophageal jejunostomy group was significantly lower than that of 167.2 ± 72.8 ml in the laparoscopic-assisted Roux en-Y esophago-jejunostomy group (P < 0.05). Postoperative recovery time to exhaust was 3.8 ± 1.2 days in total endoscopic π-shaped esophageal jejunostomy group, significantly lower than 5.0 ± 2.0 days in laparoscopic-assisted Roux en-Y esophago-jejunostomy group (P = 0.003). In terms of postoperative extubation time, postoperative hospital stay, postoperative complications and the number of dissected lymph nodes, there were no significant differences between the total endoscopic π-shaped esophageal jejunostomy group and the laparoscopic-assisted Roux en-Y esophago-jejunostomy group (P > 0.05). In terms of stress indicators, there were no significant differences in stress indicators between the two groups before surgery, and the serum levels of CRP, cortisol (COR) and IL-6 in the π anastomosis group were significantly lower than those in the Roux en-Y esophago-jejunostomy group on postoperative days 3 and 5 (P < 0.05). Conclusion Total laparoscopic total gastrectomy with π-shaped esophageal jejunostomy demonstrates safety and feasibility. This surgical approach effectively reduces intraoperative bleeding, accelerates patient recovery time, minimizes postoperative pain, lowers the risk of complications, and minimally impacts the body's traumatic stress response.

Dynamic carrier-free theranostic nanodrugs are in great demand, owing to their extraordinary high drug loading, enhanced targeting therapy, and panoramic tracking of the drug behaviors. Herein, this work highlights a successful development of pH-triggered dynamic carrier-free nanodrugs for precise tumoral targeting theragnostic, which are established through self-assembly between dasatinib (DAS) and chlorambucil (CLB). The study has proved the structure, change in particle size and zeta potential, fluorescence transition, cellular uptake, cytotoxicity as well as biosafety of the carrier-free nanodrugs. The nanodrugs are characterized by Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance, X-ray diffraction, Dynamic light scattering, and Microplate reader. Cellular uptake and cytotoxicity assay are conducted for free drugs and their nanodrugs using tumor cell lines including A549, HepG2, K562, and THP1. ICR mice are applied to evaluate the biosafety of nanodrugs. The introduction of CLB into DAS nanoparticles can successfully redshift the emission wavelength from 420 to 810 nm. Moreover, the nanodrugs exhibit a dynamic fluorescence intensity conversion via tumoral intracellular gradual quenching of Aggregation-induced emission (AIE). This characteristic is beneficial to the precise monitoring of tumoral intracellular drug behaviors. Furthermore, the nanodrugs show a small-to-large size transition from 175 nm to more than 500 nm in 12 h and surficial charge reversal from −2.3 mV to more than 0.2 mV by protonation at tumoral pHs. These superior properties facilitate the improved cellular uptake and synergistic cytotoxicity on various types of tumor cells. The study shows that nanodrugs made of DAS and CLB that can self-assemble without carriers under different pH levels may be ready for testing in tumor targeting, and might someday be helpful for diagnosis and treatment in the future.

目的:探究基于成果导向的教学模式在肿瘤外科学教学中的应用.方法:将2021年1月至2022年1月在蚌埠医学院第一附属医院学习的120名临床见习学生,随机分为对照组和观察组,每组60名.对照组采用常规授课方式进行教学,观察组采用基于成果导向的教学模式.对2组学生的成绩以及对教学的满意度进行分析.结果:观察组学生的理论成绩及实践成绩均高于对照组(P＜0.01);观察组学生对课程效果、知识收获和实践的满意度均高于对照组学生(P＜0.01).结论:基于成果导向的教学模式应用在肿瘤外科学临床见习学生的教学工作中,能够提高教学质量,提升学生满意度,使学生更主动地获取知识和提高成绩,值得进一步探究和推广.

Objective To investigate the effect and its mechanism of the downregulation of protein arginine methyltransferase 6（PRMT6）gene on the proliferation of gastric cancer BGC823 cell.Methods The protein expression of PRMT6 was detected by immunohistochemical staining（IHC）in tumor and paracancer tissues of 30 patients with gastric cancer.Western blot was used to detect the expression levels of PRMT6 in normal gastric mucosa cells and various gastric cancer cell lines.After siRNA interfered with PRMT6 expression in gastric cancer cells, the transfection effect was verified by Western blot and qRT-PCR.MTT assay and colony cloning assay were used to detect the proliferation of gastric cancer cells.Western blot and qRT-PCR were used to detect the effect of downregulated PRMT6 expression on the expression of downstream cell cycle-related genes CDKN1 A,CDKN1 B,CDKN1 C and CCND1.Results Immunohistochemical results showed that the expression level of PRMT6 in gastric cancer tissues was significantly higher than that in adjacent tissues, and the difference was statistically significant（P＜0.01）.Western blot results showed that PRMT6 expression level was higher in gastric cancer cell lines BGC823.SiRNA significantly reduced the expression of PRMT6 protein and mRNA in cells.MTT and colony cloning results showed that the downregulation of PRMT6 expression significantly inhibited the proliferation of gastric cancer cells.After knockdown PRMT6 expression, qRT-PCR results showed that there was no significant difference in mRNA expression levels of CDKN1 A,CDKN1 B and CDKN1 C compared with the control group.Western blot and qRT-PCR results showed that the expression level of CCND1 downstream gene was decreased.Conclusion PRMT6 is highly expressed in gastric cancer tissues and can promote the proliferation of gastric cancer cells, which may be related to the regulation of CCND1 expression.

BACKGROUND:Protein arginine methyltransferase 6 (PRMT6) is a type I arginine methyltransferase that asymmetrically dimethylates histone H3 arginine 2 (H3R2me2a). However, the biological roles and underlying molecular mechanisms of PRMT6 in colorectal cancer (CRC) remain unclear.METHODS:PRMT6 expression in CRC tissue was examined using immunohistochemistry. The effect of PRMT6 on CRC cells was investigated in vitro and in vivo. Mass spectrometry, co-immunoprecipitation and GST pulldown assays were performed to identify interaction partners of PRMT6. RNA-seq, chromatin immunoprecipitation, Western blot and qRT-PCR assays were used to investigate the mechanism of PRMT6 in gene regulation.RESULTS:PRMT6 is significantly upregulated in CRC tissues and facilitates cell proliferation of CRC cells in vitro and in vivo. Through RNA-seq analysis, CDKN2B (p15INK4b) and CCNG1 were identified as new transcriptional targets of PRMT6. PRMT6-dependent H3R2me2a mark was predominantly deposited at the promoters of CDKN2B and CCNG1 in CRC cells. Furthermore, PRMT5 was firstly characterized as an interaction partner of PRMT6. Notably, H3R2me2a coincides with PRMT5-mediated H4R3me2s and H3R8me2s marks at the promoters of CDKN2B and CCNG1 genes, thus leading to transcriptional repression of these genes.CONCLUSIONS:PRMT6 functionally associates with PRMT5 to promote CRC progression through epigenetically repressing the expression of CDKN2B and CCNG1. These insights raise the possibility that combinational intervention of PRMT6 and PRMT5 may be a promising strategy for CRC therapy.

BackgroundThis study aims to investigate the effects of ω-3, ω-6 polyunsaturated fatty acids (PUFAs), and their middle metabolites prostaglandin (PGE)2 and PGE3 on proliferation, invasion, and angiogenesis formation of gastric cancer cells and to explore associated mechanism.MethodsRT-PCR and ELISA were used to detect the expression of cyclooxygenase (COX)-1 and COX-2 in gastric cancer cell lines. The effect of ω-3, ω-6, PGE2, and PGE3 on the proliferation, invasion, and angiogenesis of gastric cancer cells were measured by cell proliferation, invasion, and angiogenesis assay in vitro. COX-2 small interfering RNA (siRNA) was transfected into gastric cancer cells, and the expression of COX-2 protein was detected by Western blot. COX-2 gene silencing influencing proliferation, invasion, and angiogenesis potential of gastric cancer cells was detected by WST-1, transwell chamber, and angiogenesis assay, respectively.ResultsCOX-2 was only expressed in MKN74 and MKN45 cells. In gastric cancer cell lines with positive COX-2 expression, ω-6 and PGE2 could significantly enhance the proliferation, invasion, and angiogenesis of gastric cancer cells, and after transfection with COX-2 siRNA, the effects of ω-6 and PGE2 on enhancing the proliferation, invasion, and angiogenesis of gastric cancer cells were significantly attenuated; ω-3 and PEG3 could inhibit the proliferation, invasion, and angiogenesis of gastric cancer cells. In gastric cancer cell lines with negative COX-2 expression, ω-6 and PGE2 had no significant effect on the proliferation, invasion, and angiogenesis of gastric cancer; ω-3 and PGE3 could significantly inhibit the proliferation, invasion, and angiogenesis of gastric cancer.Conclusionω-6 PUFAs reinforce the metastatic potential of gastric cancer cells via COX-2/PGE2; ω-3 PUFAs inhibit the metastatic potential of gastric cancer via COX-1/PGE3 signaling axis.

目的 探究胃癌细胞中CLDN18-ARHGAP26融合突变基因引起的耐化疗药的作用,并探究人参皂苷在治疗因CLDN18-ARHGAP26融合突变基因表达引起的耐化疗药治疗过程中的抗肿瘤作用.方法 采用免疫磁珠抗体标记胃癌细胞系BGC-823的侧群(SP)细胞和非侧群(NSP)细胞,选出NSP细胞转染过表达CLDN18-ARHGAP26融合突变基因的慢病毒载体.用qPCR检测细胞中CLDN18-ARHGAP26融合突变基因和三磷酸腺苷结合转运蛋白G超家族成员2(ABCG2)mRNA水平的表达.用Western blot检测转染上皮-间质转化(EMT)相关蛋白E-Cadherin、Vimentin的表达.用CCK-8检测转染细胞对化疗药奥沙利铂的敏感性.用CCK-8检测人参皂苷对转染细胞耐药性的影响.人参皂苷处理转染细胞后Western blot检测转染细胞的钙黏蛋白E(E-Cadherin)、波形蛋白(Vimentin)的表达.结果 qPCR检测显示转染过表达CLDN18-ARHGAP26融合突变基因慢病毒载体的NSP细胞中CLDN18-ARHGAP26融合突变基因表达高于未转染组,ABCG2 mRNA表达高于未转染组(P<0.001).Western bolt显示过表达CLDN18-ARHGAP26融合突变基因的NSP细胞中E-Cadherin蛋白表达低于未转染组(P<0.05),Vimentin蛋白表达高于未转染组(P<0.01),转染细胞对奥沙利铂的敏感性低于未转染组(P<0.05).人参皂苷和奥沙利铂同时处理转染细胞,细胞存活率低于单纯奥沙利铂处理(P<0.05).人参皂苷处理转染细胞后E-Cadherin蛋白表达高于未处理组(P<0.01),Vimentin蛋白表达低于未处理组(P<0.05).结论 人参皂苷能逆转胃癌细胞中CLDN18-ARHGAP26融合突变基因表达诱导的细胞EMT转化和奥沙利铂的耐药性.

The clinical transformation of polysaccharide-based nano-prodrugs remains a long way off, due to the shackles on easy metabolic clearance, dilemma of dose-dependent toxicity and immunogenicity, and poor tumor selec-tivity. To address these challenges, the fluorinated dual-crosslinked carboxymethyl chitosan (CMCS)-based nano-prodrugs with precise structure were facilely developed through the reaction of CMCS with water-soluble stimuli-responsive synergistic small molecule prodrug (Pt(IV)-1), glutaraldehyde and heptafluorobutyric anhydride successively. The fluorination enabled the nano-prodrugs to display metabolic stability and improve tumoral cellular uptake. The pH/glutathione (GSH)-sensitive dual-crosslinked structure enabled the nano-prodrugs to show physicochemical stability at physiological pH, selective drug release and synergistic cytotoxicity at tumoral intracellular pH/GSH, and circumventing the dilemma of dose-dependent toxicity and immunogenicity induced by that crosslinked or grafted via a single drug. These superior performances promoted stability in long-term storage and circulation, normal blood routine and aminotransferase, fantastic hemocompatibility, selective tumor accumulation and precisely synergistic chemotherapy, therefore achieving significant tumor growth in-hibition while minimizing side effects. Thus, the precise fluorinated dual-crosslinked CMCS-based nano-prodrugs have great potential for selective clinical cancer treatment.

目的:探讨白细胞介素-1受体2型(interleukin-1 receptor 2,IL1R2)与原癌基因c-Fos的相互作用,及其影响结肠癌细胞增殖、侵袭和血管新生的机制.方法:采用Western blot法检测结肠癌组织及癌旁组织中IL1R2和c-Fos的表达.通过双重荧光素酶测定IL1R2和c-Fos之间的相互作用关系.通过RT-PCR法检测IL1R2不同转染组IL1R2和c-Fos的mRNA表达.通过CCK8和Transwell法检测人结肠癌细胞SW620的增殖和侵袭作用.使用ELISA法测定SW620培养上清液中VEGF、VEGFR2、HIF-1α和bFGF的表达水平.结果:结肠癌组织较癌旁组织IL1R2和c-Fos的表达升高(P＜0.05).双重荧光素酶测定结果证实了c-Fos是IL1R2的真正靶点.与对照组比较,IL1R2 mimic组IL1R2和c-Fos mRNA表达升高(P＜0.05),而IL1R2 inhibitor组IL1R2和c-Fos mRNA表达降低(P＜0.05);IL1R2 mimic组细胞增殖和侵袭升高(P＜0.05),而IL1R2 inhibitor组细胞增殖和侵袭降低(P＜0.05);IL1R2 mimic组VEGF、VEGFR2、HIF-1α和bFGF表达水平升高(P＜0.05),而IL1R2 inhibitor组VEGF、VEGFR2、HIF-1α和bFGF表达水平降低(P＜0.05).结论:IL1R2与c-Fos的相互作用可以进一步影响结肠癌细胞的增殖、侵袭和血管新生.