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LRG1 inhibits hepatic macrophage activation by enhancing TGF-β1 signaling to alleviate MAFLD in mice XU Longfei, HAN Jing, YANG Zhe, YANG Yanping, CHEN Jinhui, WU Xijun, WANG Qi, HONG Yan Journal of Southern Medical University    2023, 43 (7): 1164-1171.   DOI: 10.12122/j.issn.1673-4254.2023.07.13 Abstract （166）   HTML （17）    PDF（pc） （8437KB）（636）       Knowledge map    Save Objective To explore the effect of leucine- rich α-2-glycoprotein (LRG1) derived from hepatocytes on activation of hepatic M1 Kupffer cells. Methods A metabolic dysfunction-associated fatty liver disease (MAFLD) model was established in BALB/c mice by high-fat diet (HFD) feeding for 16 weeks. Oleic acid was used to induce steatosis in primary cultures of mouse hepatocytes. The mRNA and protein expressions of LRG1 in mouse liver tissues and hepatocytes were detected by real-time PCR and Western blotting. Primary hepatic macrophages were stimulated with the conditioned medium (CM) from steatotic hepatocyte along with LRG1 or transforming growth factor-β1 (TGF-β1), or both for 24 h, and the expression levels of inducible nitric oxide synthase (iNOS) was detected with Western botting, and the mRNA expressions of iNOS, chemokine ligand 1 (CXCL-1) and interleukin-1β (IL-1β) were measured by RT-PCR. The MAFLD mice were injected with LRG1 (n=6), TGF-β1 (n=6), or both (n=6) through the caudal vein, and the live tissues were collected for HE staining and immumohistochemical detection of F4/80 expression; the mRNA expressions of iNOS, CXCL-1 and IL-1β in liver tissues were detected using RT-PCR. Results The mRNA and protein expression levels of LRG1 were significantly downregulated in the liver tissues of MAFLD mice and steatotic hepatocytes (P<0.05). Treatment of the hepatic macrophages with CM from steatosis hepatocytes significantly enhanced the mRNA expression levels of iNOS, CXCL-1 and IL-1β, and these changes were significantly inhibited by the combined treatment with TGF-β1 and LRG1 (P<0.05). In MAFLD mice, injections with either LRG1 or TGF-β1 alone reduced hepatic lipid deposition and intrahepatic macrophage infiltration, and these effects were significantly enhanced by their combined treatment, which also more strongly inhibited the mRNA expression levels of iNOS, CXCL-1 and IL-1β (P<0.05). Conclusion LRG1 inhibits hepatic macrophage infiltration by enhancing TGF-β1 signaling to alleviate fatty liver inflammation in MAFLD mice. Related Articles | Metrics | Comments（0）

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JAG1 affects monocytes-macrophages to reshape the pre-metastatic niche of triple-negative breast cancer through LncRNA MALAT1 in exosomes XU Mengqi, SHI Yutong, LIU Junping, WU Minmin, ZHANG Fengmei, HE Zhiqiang, TANG Min Journal of Southern Medical University    2023, 43 (9): 1525-1535.   DOI: 10.12122/j.issn.1673-4254.2023.09.10 Abstract （141）   HTML （10）    PDF（pc） （2356KB）（543）       Knowledge map    Save Objective To investigate the effect of JAG1 on the activities of monocytes-macrophages in pre-metastatic niche (PMN) of triple-negative breast cancer (TNBC) and explore the possible regulatory mechanism. Methods JAG1 expression in human TNBC MDA-MB-231 and MDA-MB-231B cells was detected using quantitative real-time PCR (qRT-PCR). Ten female nude mice were inoculated with MDA-MB-231 cells (n=5) or MDA-MB-231B cells (n=5) in the mammary fat pad, and 6 weeks later, the tumor tissues were collected for immunohistochemistry. Human monocytes THP-1 cells were treated with rhJAG1 or conditioned media (CM) of TNBC MDA-MB-231 and MDA-MB-231B cells to assess the direct effect of JAG1 on monocytes and its effect on monocytes in the PMN using monocyte-endothelial adhesion, Transwell assay, qRT- PCR and Western blotting. Transmission electron microscopy and nanoparticle tracking analyses were used to identify the effect of JAG1 on exosome release from the TNBC cells. MiRNAs interacting with lncRNA MALAT1 were identified by bioinformatics and validated using qRT- PCR. Results Compared with MDA-MB-231 cells, the invasive strain MDA-MB- 231B cells showed significantly higher JAG1 expression and greater liver metastasis potential (P<0.01). Both direct treatment with rhJAG1 and treatment with the conditioned media promoted adhesion and migration and affected differentiation of the monocytes (P<0.05). Transmission electron microscopy and nanoparticle tracking analysis showed that JAG1 strongly enhanced exosome secretion from MDA-MB-231 cells (P<0.01) and increased MALAT1 content in the exosomes (P<0.0001). Five candidate miRNAs related to MALAT1 and JAG1 were identified by bioinformatics analysis, and miR-26a-5p was identified as a potential target of MALAT1 in monocytes-macrophages in TMN (P<0.0001). Conclusion JAG1 can promote exocrine secretion of TNBC and increase the expression of MALAT1 to cause targeted downregulation of miR- 26a- 5p in monocytes-macrophages in the PMN, which in turn increases JAG1 expression in monocytes-macrophages to affect their adhesion, migration and osteoclast differentiation in the PMN. Related Articles | Metrics | Comments（0）

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Analysis of therapeutic mechanism of Liushen Wan against colitis-associated colorectal cancer based on network pharmacology and validation in mice ZHANG Xuefang, CHEN Yanhua, LI Zongheng, SHANG Jing, YUAN Zeting, DENG Wanli, LUO Ying, HAN Na, YIN Peihao, YIN Jun Journal of Southern Medical University    2023, 43 (7): 1051-1062.   DOI: 10.12122/j.issn.1673-4254.2023.07.01 Abstract （466）   HTML （68）    PDF（pc） （3383KB）（527）       Knowledge map    Save Objective To explore the therapeutic mechanism of Liushen Wan (LSW) against colitis-associated colorectal cancer (CAC) by network pharmacology. Methods TCMSP, BATMAN-TCM, CNKI, PubMed, Genecards, OMIM, and TTD databases were used to obtain the related targets of LSW and CAC. The common targets of LSW and CAC were obtained using Venny online website. The PPI network was constructed using Cytoscape 3.8.2 to screen the core targets of LSW in the treatment of CAC. GO and KEGG enrichment analysis were conducted using DAVID database. The therapeutic effect of LSW on CAC was evaluated in a C57BL/6J mouse model of AOM/DSS-induced CAC by observing the changes in body weight, disease activity index, colon length, and size and number of the tumor. HE staining and RT-qPCR were used to analyze the effect of LSW on inflammatory mediators. Immunohistochemistry and TUNEL staining were used to evaluate the effect of LSW on the proliferation and apoptosis of AOM/DSS-treated colon tumor cells. Immunohistochemistry and Western blotting were used to detect the effects of LSW on the expression of TLR4 proteins in CAC mice. Results Network pharmacology analysis identified 69 common targets of LSW and CAC, and 33 hub targets were screened in the PPI network. KEGG pathway enrichment analysis suggested that the effect of LSW on CAC was mediated by the Toll-like receptor signaling pathway. In the mouse model of AOM/DSS-induced CAC, LSW significantly inhibited colitis-associated tumorigenesis, reduced tumor number and tumor load (P<0.05), obviously improved histopathological changes in the colon, downregulated the mRNA levels of pro-inflammatory cytokines, and inhibited the proliferation (P<0.01) and promoted apoptosis of colon tumor cells (P<0.001). LSW also significantly decreased TLR4 protein expression in the colon tissue (P<0.05). Conclusion LSW can inhibit CAC in mice possibly by regulating the expression of TLR4 to reduce intestinal inflammation, inhibit colon tumor cell proliferation and promote their apoptosis. Related Articles | Metrics | Comments（0）

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STIP1 correlates with tumor immune infiltration and prognosis as a potential immunotherapy target: a pan-cancer bioinformatics analysis GUAN Shenyuan, SHEN Zhiyong, LIN Mingdao, DENG Haijun, FANG Yuan Journal of Southern Medical University    2023, 43 (7): 1179-1193.   DOI: 10.12122/j.issn.1673-4254.2023.07.15 Abstract （229）   HTML （15）    PDF（pc） （11859KB）（516）       Knowledge map    Save Objective To investigate the correlation of stress-inducible phosphoprotein 1 (STIP1) expression level with prognosis of different cancers and its potential role in immunotherapy. Methods TCGA, TARGET and GTEx databases were used for bioinformatic analysis of STIP1 expression level and its prognostic value in different cancers. We also detected STIP1 expression immunohistochemically in 10 pairs of colorectal cancer and adjacent tissues. We further analyzed the correlation of STIP1 expression level with tumor mutational burden, microsatellite instability, immune cell infiltration, immune regulators and outcomes of different cancers. STIP1- related proteins were identified using protein- protein interaction (PPI) network analysis, and functional enrichment analysis was performed to analyze the regulatory pathways involving STIP1. Results Bioinformatics analysis showed that STIP1 was highly expressed in most tumors compared with the normal tissues (P<0.05), which was confirmed by immunohistochemistry of the 10 pairs of colorectal cancer tissues. STIP1 expression level was correlated with clinical stages of multiple cancers (P<0.05), and in some cancer types, an upregulated STIP1 expression was correlated with a poor prognosis of the patients in terms of overall survival, disease-specific survival, disease-free survival and progression-free survival (P<0.05). STIP1 expression was significantly correlated with tumor mutational burden, microsatellite instability, immune cell infiltration and immunomodulatory factors in most tumors (P<0.05). PPI network analysis indicated that STIP1-related proteins included HSPA4, HSPA8, and HSP90AA1. KEGG enrichment analysis suggested that the high expression of STIP1 in liver cancer was related mainly with valerate metabolism, tryptophan metabolism, and butyrate metabolism pathways; HALLMARK enrichment analysis suggested high STIP1 expression in liver cancer was involved in bile acid and fatty acid metabolism. Conclusion STIP1 is up- regulated in multiple cancer types and its expression level is correlated with clinical tumor stage, tumor mutational burden, microsatellite instability, immune cell infiltration and immunomodulatory factors. Related Articles | Metrics | Comments（0）

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Neutrophil-lymphocyte and platelet-lymphocyte ratios for assessing disease activity in patients with rheumatoid arthritis receiving tofacitinib treatment TANG Juan, CHEN Juan, LIN Guoxin, ZHANG Hao, GUI Ming, LI Nannan, GU Yihong, LUO Linjuan, SUN Jian Journal of Southern Medical University    2023, 43 (10): 1651-1656.   DOI: 10.12122/j.issn.1673-4254.2023.10.01 Abstract （417）   HTML （284）    PDF（pc） （1095KB）（513）       Knowledge map    Save Objective To evaluate the value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) for assessing disease activity in patients with rheumatoid arthritis (RA) treated with tofacitinib. Methods This retrospective study was conducted among 98 RA patients in active stage treated with tofacitinib in Third Xiangya Hospital and 100 healthy control subjects from the Health Management Center of the hospital from 2019 to 2021. We collected blood samples from all the participants for measurement of erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and other blood parameters 1 month before and 6 months after tofacitinib treatment. We further evaluated PLR and NLR before and after tofacitinib treatment in the RA patients, and analyzed their correlations with RA disease activity. Results PLR and NLR increased significantly in RA patients as compared with the healthy controls. In the RA patients, PLR and NLR were positively correlated with the levels of hs-CRP, ESR, IL-6, Disease Activity Score of 28 joints-ESR (DAS28-ESR), anti-cyclic citrullinated peptide (CCP), and rheumatoid factor (RF) before and after tofacitinib treatment. Tofacitinib treatment for 6 months significantly decreased hs-CRP, ESR, IL-6, CCP, RF and DAS28-ESR levels in the RA patients. Conclusion NLR and PLR can be useful biomarkers for assessing disease activity in RApatients treated with tofacitinib. Related Articles | Metrics | Comments（0）

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Associations of circulating leptin levels with colorectal adenoma and colorectal cancer: a case-control and Mendelian randomization study ZHAO Huanling, LING Yuxiao, MI Shuai, ZHU Jiahao, FAN Jiayao, YANG Ye, WANG Jing, LI Yingjun Journal of Southern Medical University    2023, 43 (12): 1989-1997.   DOI: 10.12122/j.issn.1673-4254.2023.12.01 Abstract （277）   HTML （55）    PDF（pc） （988KB）（497）       Knowledge map    Save Objective To explore the causal association between circulating leptin levels and the risk of colorectal adenoma and colorectal cancer. Methods We collected demographic and clinical data and serum samples from 497 patients with colorectal adenoma, 955 patients with colorectal cancer, and 911 healthy individuals from the First Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang Cancer Hospital, Zhuji People's Hospital, and Lin'an District First People's Hospital. Instrumental variables of leptin were selected and genotyping tests were performed. A logistic regression model and stratified analysis were used to evaluate the association of serum leptin levels with colorectal adenoma, colorectal cancer, and the progression of colorectal adenoma to colorectal cancer. Genetic risk score (GRS) and single nucleotide polymorphisms (SNPs) were further used as instrumental variables in one-sample and two-sample Mendelian randomization analyses leveraging two-stage least squares and inverse-variance weighted methods to estimate the causal association of leptin levels with the risk of colorectal adenoma, colorectal cancer, and progression of colorectal adenoma to colorectal cancer. Results High levels of leptin, compared with its lowest quartile, were positively correlated with colorectal adenoma (P=0.005) and negatively with colorectal cancer (P<0.001) and the risk of progression of colorectal adenoma to colorectal cancer (P<0.001). Mendelian randomization analysis showed that GRS of leptin, either weighted or not, was not significantly correlated with the risk of colorectal adenoma, colorectal cancer, or the progression of colorectal adenoma to colorectal cancer, nor did the two-sample Mendelian randomization study support an association between leptin and the risk of colorectal cancer (P>0.05). Conclusion Although the case-control study suggests probable correlations of leptin with the risk of colorectal adenoma, colorectal cancer, and colorectal adenoma progression to colorectal cancer, Mendelian randomization studies did not support a causal association of leptin with the risks of colorectal adenoma, colorectal cancer, or colorectal adenoma progression to colorectal cancer. Related Articles | Metrics | Comments（0）

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High expression of death-associated protein 5 promotes glucose metabolism in gastric cancer cells and correlates with poor survival outcomes WANG Qiusheng, ZHANG Zhen, WANG Lian, WANG Yu, YAO Xinyu, WANG Yueyue, ZHANG Xiaofeng, GE Sitang, ZUO Lugen Journal of Southern Medical University    2023, 43 (7): 1063-1070.   DOI: 10.12122/j.issn.1673-4254.2023.07.02 Abstract （217）   HTML （31）    PDF（pc） （3588KB）（480）       Knowledge map    Save Objective To investigate the prognostic value of death-associated protein 5 (DAP5) in gastric cancer (GC) and its regulatory effect on aerobic glycolysis in GC cells. Methods We analyzed DAP5 expression levels in GC and adjacent tissues and its association with survival outcomes of GC patients using public databases. We collected paired samples of GC and djacent tissues from 102 patients undergoing radical resection of GC in our hospital from June, 2012 to July, 2017, and analyzed the correlation of DAP5 expression level detected immunohistochemically with the clinicopathological parameters of the patients. Cox regression analysis, Kaplan-Meier analysis, and ROC curves were used to explore the independent risk factors and the predictive value of DAP5 expression for 5-year survival of the patients. In the cell experiments, we observed the changes in aerobic glycolysis in MGC-803 cells following lentivirus-mediated DAP5 knockdown or overexpression by measuring glucose uptake and cellular lactate level and using qRT-PCR and Western blotting. Results Analysis using the public databases showed that DAP5 was highly expressed in GC and correlated with tumor progression and poor survival outcomes of the patients (P<0.05). In the clinical samples, DAP5 expression was significantly higher in GC than in the adjacent tissues (3.19±0.60 vs 1.00±0.12; t=36.863, P<0.01), and a high expression of DAP5 was associated with a reduced 5-year survival rate of the patients (17.6% vs 72.5%; χ2=29.921, P<0.05). A high DAP5 expression, T3-4, N2-3, and CEA≥5 ng/mL were identified as independent risk factors affecting 5-year survival outcomes of GC (P<0.05), for which DAP5 expression showed a prediction sensitivity, specificity and accuracy of 73.2%, 80.4% and 79.0%, respectively. In MGC-803 cells, DAP5 knockdown significantly reduced glucose uptake, lactate level and the expressions of GLUT1, HK2 and LDHA, and DAP5 overexpression produced the opposite effects (P<0.05). Conclusion A high expression of DAP5 in GC, which enhances cellular aerobic glycolysis to promote cancer progression, is correlated with a poor survival outcome and may serve as a biomarker for evaluating long-term prognosis of GC patients. Related Articles | Metrics | Comments（0）

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Isodopharicin C inhibits NLRP3 inflammasome activation and alleviates septic shock in mice CAO Hairuo, ZHANG Wei, LI Mingyuan, YANG Yanqing, LI Yuyun Journal of Southern Medical University    2023, 43 (9): 1476-1484.   DOI: 10.12122/j.issn.1673-4254.2023.09.04 Abstract （156）   HTML （22）    PDF（pc） （1633KB）（421）       Knowledge map    Save Objective To investigate the effect of Isodopharicin C (Iso C), a traditional Chinese herbal medicine extract, on NLRP3 inflammasome activation and lipopolysaccharide (LPS)-induced septic shock in mice. Methods Murine bone marrow-derived macrophages (BMDM) and human monocytic THP-1 cells were stimulated with LPS before treatment with different NLRP3 inflammasome agonists to activate canonical NLRP3 inflammasomes. The non-canonical NLRP3 inflammasomes were activated by intracellular LPS transfection, and AIM2 inflammasomes were activated with poly A:T. The cleavage of caspase-1 induced by NLRP3 activation was measured using Western blotting. The levels of NLRP3-dependent and -independent pro-inflammatory cytokines in the cell culture supernatant were detected using ELISA, and the intracellular potassium ion concentration was measured using ICP-OES. In the animal experiment, C57BL/6J mouse models of septic shock (induced by intraperitoneal LPS injection) were treated with Iso C, and the levels of IL-1β, TNF-α and IL-6 in the serum and peritoneal lavage fluid were detected using ELISA. The survival time of the mice was observed within 48 h after LPS injection and a survival curve was plotted. Results In BMDM cells, Iso C dose-dependently inhibited the activation of canonical NLRP3 inflammasomes and non-canonical NLRP3 inflammasomes (P<0.05) without obviously affecting the secretion levels of TNF-α and IL-6 (P>0.05), the activation of AIM2 inflammasomes (P>0.05), or K+ efflux, the upstream signaling of NLRP3 activation (P>0.05). Iso C inhibited the activation of canonical NLRP3 inflammasomes in human THP-1 cells. In septic C57BL/6J mice, Iso C treatment significantly reduced IL-1β levels in the serum and peritoneal lavage fluid, and prolonged the survival time of the mice (P<0.05). Conclusion Iso C specifically inhibits NLRP3 inflammasome activation and alleviates septic shock in mice, and can serve as a potential small molecule compound for treatment of inflammatory diseases. Related Articles | Metrics | Comments（0）

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EHHADH is a key gene in fatty acid metabolism pathways in hepatocellular carcinoma: a transcriptomic analysis XIE Siyu, LI Miaosheng, JIANG Fengle, YI Qian, YANG Wei Journal of Southern Medical University    2023, 43 (5): 680-693.   DOI: 10.12122/j.issn.1673-4254.2023.05.02 Abstract （242）   HTML （39）    PDF（pc） （19532KB）（419）       Knowledge map    Save Objective To explore the driving gene of hepatocellular carcinoma (HCC) occurrence and progression and its potential as new therapeutic target of HCC. Methods The transcriptome and genomic data of 858 HCC tissues and 493 adjacent tissues were obtained from TCGA, GEO, and ICGC databases. Gene Set Enrichment Analysis (GSEA) identified EHHADH (encoding enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase) as the hub gene in the significantly enriched differential pathways in HCC. The downregulation of EHHADH expression at the transcriptome level was found to correlate with TP53 mutation based on analysis of the TCGA- HCC dataset, and the mechanism by which TP53 mutation caused EHHADH downregulation was explored through correlation analysis. Analysis of the data from the Metascape database suggested that EHHADH was strongly correlated with the ferroptosis signaling pathway in HCC progression, and to verify this result, immunohistochemical staining was used to examine EHHADH expression in 30 HCC tissues and paired adjacent tissues. Results All the 3 HCC datasets showed signficnatly lowered EHHADH expression in HCC tissues as compared with the adjacent tissues (P<0.05) with a close correlation with the degree of hepatocyte de-differentiation (P<0.01). The somatic landscape of HCC cohort in TCGA dataset showed that HCC patients had the highest genomic TP53 mutation rate. The transcriptomic level of PPARGC1A, the upstream gene of EHHADH, was significantly downregulated in HCC patients with TP53 mutation as compared with those without the mutation (P<0.05), and was significantly correlated with EHHADH expression level. GO and KEGG enrichment analyses showed that EHHADH expression was significantly correlated with abnormal fatty acid metabolism in HCC. The immunohistochemical results showd that the expression level of EHHADH in HCC tissues was down-regulated, and its expression level was related to the degree of hepatocytes de-differentiation and the process of ferroptosis. Conclusion TP53 mutations may induce abnormal expression of PPARGC1A to cause downregulation of EHHADH expression in HCC. The low expression of EHHADH is closely associated with aggravation of de-differentiation and ferroptosis escape in HCC tissues, suggesting the potential of EHHADH as a therapeutic target for HCC. Related Articles | Metrics | Comments（0）

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Effect of Porphyromonas gingivalis infection on IFNGR1 palmitoylation in esophageal cancer cells SHEN Liuqing, ZHANG Dingyu, GAO Shegan Journal of Southern Medical University    2023, 43 (7): 1155-1163.   DOI: 10.12122/j.issn.1673-4254.2023.07.12 Abstract （160）   HTML （8）    PDF（pc） （2081KB）（414）       Knowledge map    Save Objective To investigate the effect of Porphyromonas gingivalis (Pg) infection on IFNGR1 palmitoylation and biological behaviors of esophageal squamous cell carcinoma (ESCC) cells and the clinical implications. Methods The expression levels of IFNGR1 protein in ESCC cell lines KYSE30 and KYSE70 were detected using Western blotting at 24 and 48 h after Pg infection, and 2-BP was used to detect IFNGR1 palmitoylation in the cells. KYSE70 cells with wild-type IFNGR1 (IFNGR1-WT cells) and with IFNGR1-C122A palmitoylation site mutation induced by site-specific mutagenesis (IFNGR1-C122A cells) were both infected with Pg, and the changes in palmitoylation of IFNGR1-C122A were analyzed using immunofluorescence and Click-iT assays. The changes in proliferation, migration and invasion ability of the infected cells were evaluated using plate cloning assay, scratch assay and Transwell assay, and IFNGR1 co-localization with lysosomal marker LAMP2 was dected using immunofluorescence assay. Immunohistochemistry was used to detect Pg infection and IFNGR1 protein expression in 50 ESCC tissues, and their correlation with the clinicopathological characteristics and survival outcomes of the patients was analyzed. Results Pg infection down-regulated the protein expression of IFNGR1 in ESCC and promoted IFNGR1 palmitoylation at site 122. In IFNGR1-WT cells, Pg infection significantly enhanced cell proliferation, migration and invasion (P<0.05). Similarly, Pg also significantly promoted proliferation, migration and invasion of IFNGR1- C122A cells, but to a lesser extent as compared with the wild-type cells (P<0.05). Immunofluorescence assay showed that Pg and ZDHHC3 promoted IFNGR1 degradation within the lysosome. Immunohistochemical studies of the ESCC tissue samples showed a negative correlation between IFNGR1 and Pg expression, and a reduced IFNGR1 expression was correlated with a poorer survival outcome of the patient. Conclusion Pg infection enhances IFNGR1 palmitoylation to promote progression of ESCC, and elimination of Pg and inhibiting IFNGR1 palmitoylation may effectively control ESCC progression. Related Articles | Metrics | Comments（0）

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METTL3 inhibitor STM2457 improves metabolic dysfunction-associated fatty liver disease by regulating mitochondrial function in mice GAO Yinan, WANG Peijun, LU Sumei, MA Wanshan Journal of Southern Medical University    2023, 43 (10): 1689-1696.   DOI: 10.12122/j.issn.1673-4254.2023.10.06 Abstract （265）   HTML （14）    PDF（pc） （4948KB）（413）       Knowledge map    Save Objective To investigate the effect of methyltransferase-like 3 (METTL3) inhibitor STM2457 in metabolic dysfunction-associated fatty liver disease (MAFLD). Methods C57BL/6J mouse models of MAFLD induced by high-fat diet feeding for 16 weeks were treated with intraperitoneal injections of STM2457 (50 mg/kg) for 2 weeks. The changes in m6A modification level in the liver tissue of the mice were determined with dot-blot hybridization, and the hepatic levels of triglyceride (TG), alanine aminotransferase (ALT) and glutathione aminotransferase (AST) were detected. The histological changes of the liver and changes in insulin resistance and metabolic profile of the mice were evaluated using HE staining, insulin tolerance tests and metabolic cages; transmission electron microscopy (TEM) was employed to examine the changes in mitochondrial morphology. In a HepG2 cell model of steatosis induced by treatment with sodium oleate/sodium palmitate for 48 h, the protective effect of STM2457 (1 μmol/L) on mitochondrial function was assessed by measuring mitochondrial membrane potential using a fluorescence probe (JC-1). Results The mouse models of MAFLD showed significant elevation of m6A modification level in the liver tissues and obviously upregulated mRNA expression of METT3 (P<0.05). Treatment with STM2457 significantly reduced body weight and liver lipid deposition and m6A modification levels, increased glucose tolerance and insulin sensitivity, lowered hepatic TG and serum ALT and AST levels, and increased respiratory entropy (RQ) in the mouse models (all P<0.05). HepG2 cells with steatosis exhibited obvious mitochondrial swelling with decreased mitochondrial membrane potential, but the STM2457-treated cells maintained a normal mitochondrial morphology with a higher membrane potential (P<0.05). Conclusion The METTL3 inhibitor STM2457 improves MAFLD by reducing high-fat diet-induced mitochondrial damage in mice. Related Articles | Metrics | Comments（0）

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FARSB stratifies prognosis and cold tumor microenvironment across different cancer types: an integrated single cell and bulk RNA sequencing analysis ZHANG Ziran, TAN Jiale, YU Zihang, LIU Chengdong, WANG Jian, WU Dehua, BAI Xue Journal of Southern Medical University    2023, 43 (5): 667-679.   DOI: 10.12122/j.issn.1673-4254.2023.05.01 Abstract （225）   HTML （43）    PDF（pc） （3849KB）（408）       Knowledge map    Save Objective Immunotherapy has brought significant clinical benefits to a subset of patients, but has thus far been disappointing in the treatment of immunologically "cold" tumors. Existing biomarkers that can precisely identify these populations are insufficient. In this context, a potential cold tumor microenvironment (TME) marker FARSB was investigated to reveal its impact on TME and patients' response to immunotherapy across pan-cancer. Methods The expression levels and mutational landscape of FARSB in pan-cancer were investigated. Kaplan-Meier and univariate Cox regression analyses were applied to analyze the prognostic significance of FARSB. Pathways affected by FARSB were investigated by gene set enrichment and variation analysis. The relationship between FARSB expression and immune infiltration was examined using the TIMER2 and R packages. Single-cell RNA sequencing (scRNA-seq) data of several cancer types from GSE72056, GSE131907, GSE132465, GSE125449 and PMID32561858 were analyzed to validate the impact of FARSB on the TME. The predictive effect of FARSB on immunotherapy efficacy was explored in 3 immune checkpoint inhibitors (ICIs)- treated cohorts (PMID32472114, GSE176307, and Riaz2017). Results FARSB expression was significantly higher in 25 tumor tissues than in normal tissues and was associated with poor prognosis in almost all tumor types. FARSB expression exhibited a strong association with several DNA damage repair pathways and was significantly associated with TP53 mutation in lung adenocarcinoma (P<0.0001, OR=2.25). FARSB characterized a typical immune desert TME and correlated with impaired expression of chemokines and chemokines receptors. Large-scale scRNA-seq analysis confirmed the immunosuppressive role of FARSB and revealed that FARSB potentially shapes the cold TME by impeding intercellular interactions. In 3 ICI- treated cohorts, FARSB demonstrated predictive value for immunotherapy. Conclusion This study provides a pan-cancer landscape of the FARSB gene by integrated single-cell and bulk DNA sequencing analysis and elucidates its biological function to promote DNA damage repair and construct the immune desert TME, suggesting the potential value of FARSB as a novel marker for stratifying patients with poor immunotherapeutic benefits and "cold" TME. Related Articles | Metrics | Comments（0）

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Sulforaphane reverses Aβ fiber-mediated M1 type microglia polarization and neuroinflammation-mediated necroptosis of neural stem cells by downregulating the MAPK/NF-κB signaling pathways ZHANG Jiafa, YANG Canhong, ZHANG Shufen, CAO Tingting, PENG Rui, GUO Weihong, YAN Yuping, XIE Shuting, PENG Xiaojia, LÜ Tianming, HUANG Tianrong Journal of Southern Medical University    2023, 43 (12): 2132-2138.   DOI: 10.12122/j.issn.1673-4254.2023.12.19 Abstract （77）   HTML （12）    PDF（pc） （2624KB）（393）       Knowledge map    Save Objective To explore the effects of sulforaphane (SFN) and Aβ25-35 fibers (fAβ25-35) on M1/M2 polarization of BV-2 cells and neuroinflammation-mediated programmed necrosis of neural stem cells. Methods BV-2 cells treated with different concentrations of fAβ25-35 and SFN were examined for changes in cell viability using the CCK-8 kit. The effect of fAβ25-35 alone or in combination with SFN or SB203580 on expressions of IL-6 and TNF-α mRNA and proteins were assessed in BV-2 cells using RT-qPCR and ELISA. CD16/32 and CD206 in the treated cells were analyzed with flow cytometry, and the cellular expressions of p-p38 and p-p65 protein were detected with Western blotting. C17.2 cells co-cultured with BV-2 cells for 24 h were examined for p-mlkl protein expression using Western blotting. Results fAβ25-35 at the concentration of 6.25 μmol/L significantly increased the viability of BV-2 cells (P<0.01) whereas fAβ25-35 beyond 50 μmol/L decreased the cell viability (P<0.0001). Treatment of BV-2 cells with SFN below 10 μmol/L for 24 h did not significant affect the cell viability (P>0.05). BV-2 cells treated with fAβ25-35 alone, as compared with the cells in the other 3 groups, showed significantly increased IL-6 and TNF-α mRNA and protein expressions (P<0.001), enhanced CD16/32 expression (P<0.05), lowered CD206 expression (P<0.01), and increased protein expressions of p-p38 and p- p65 (P<0.01). C17.2 cells co-cultured with BV-2 cells treated with fAβ25- 35, compared with the combined treatments, showed a significant reduction in the protein expression of p-mlkl (P<0.05). Conclusion SFN reverses M1 type microglia polarization and neuroinflammation-mediated programmed necrosis of neural stem cells by downregulating the MAPK/NF-κB signaling pathway in Aβ25-35-activated BV-2 cells. Related Articles | Metrics | Comments（0）

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Increased muscle mass increases risks of intervertebral disc degeneration: a two-sample Mendelian randomization study SU Chao, TIAN Yuxiao, ZHANG Qing, WAN Tianhao, XIA Di Journal of Southern Medical University    2023, 43 (12): 2029-2034.   DOI: 10.12122/j.issn.1673-4254.2023.12.06 Abstract （133）   HTML （17）    PDF（pc） （1175KB）（393）       Knowledge map    Save Objective To investigate the causal relationship between sarcopenia (SP) and intervertebral disc degeneration (IVDD) using two-sample Mendelian randomization analysis. Methods Genome-wide association study (GWAS) databases of SP (lean body mass, right and left hand grip strength) and IVDD were obtained. The single nucleotide polymorphisms (SNPs) strongly associated with exposure were obtained as an instrumental variable. After conservatively removing two confounders (smoking and sedentary life style), the causal relationship between SP and IVDD was assessed using Mendelian randomization analyses through the inverse variance weighting (IVW), weighted median (WM) and MR-Egger methods. The consistency and accuracy of the results were verified by MR-PRESSO, double validation, negative control, heterogeneity and diversity tests. Results A total of 570 SNPs associated with lean muscle mass, 97 with strong right hand grip strength, and 79 with strong left hand grip strength were included in the analysis. The results showed that lean muscle mass had a significant positive correlation with IVDD (IVW: OR=1.139, 95% CI: 1.076-1.204, P=6.619e-6) and right hand grip strength had a possible positive correlation with IVDD. After reanalysis in MR-PRESSO and selection of a new IVDD database, the results remained largely consistent with the previous results. Conclusion Increased muscle mass may increase the risk of intervertebral disc degeneration. Related Articles | Metrics | Comments（0）

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miRNA-128-3p inhibits malignant behavior of glioma cells by downregulating KLHDC8A expression YU Zhengtao, LI Jiameng, JIANG Junwen, LI You, LIN Long, XIA Ying, WANG Lei Journal of Southern Medical University    2023, 43 (9): 1447-1459.   DOI: 10.12122/j.issn.1673-4254.2023.09.01 Abstract （276）   HTML （59）    PDF（pc） （3583KB）（389）       Knowledge map    Save Objective To determine whether miRNA-128-3p regulates malignant biological behavior of glioma cells by targeting KLHDC8A. Methods Dual-luciferase reporter assays, qRT-PCR and Western blotting were used to verify the targeting of miRNA-128-3p to KLHDC8A. Edu assay, flow cytometry, Transwell assay and would healing assay were used to determine the effects of changes in miRNA-128-3p and KLHDC8A expression levels on malignant behavior of glioma cells. Rescue experiment was carried out to verify that miRNA-128-3p regulated glioma cell proliferation, apoptosis, invasion and migration by targeting KLHDC8A. Results The expression level of KLHDC8A was significantly increased in high-grade glioma tissue and was closely related to a poor survival outcome of the patients. Overexpression of KLHDC8A promoted glioma cell proliferation, migration and invasion, and miRNA-128-3p overexpression inhibited proliferative and metastatic capacities of glioma cells. Mechanistically, KLHDC8A expression was directly modulated by miRNA-128-3p, which, by targeting KLHDC8A, inhibited malignant behavior of glioma cells. Conclusion Upregulation of miRNA-128-3p inhibits uncontrolled growth of glioma cells by negatively regulating KLHDC8A expression and its downstream effectors, suggesting that the miRNA-128-3p-KLHDC8A axis may serve as a potential prognostic indicator and a therapeutic target for developing new strategies for glioma treatment. Related Articles | Metrics | Comments（0）

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Long noncoding RNA H19 promotes vascular calcification by repressing the Bax inhibitor 1/optic atrophy 1 pathway CHEN Weiren, DU Hui, SHA Yuan, ZHOU Yujie, LIANG Jing, CHEN Yundai, MA Qian, WU Xueping, QIAN Geng Journal of Southern Medical University    2023, 43 (9): 1469-1475.   DOI: 10.12122/j.issn.1673-4254.2023.09.03 Abstract （157）   HTML （15）    PDF（pc） （2382KB）（380）       Knowledge map    Save Objective To investigate whether long noncoding RNA H19 (lncRNA H19) induces vascular calcification by promoting calcium deposition, osteogenic differentiation and apoptosis via inhibiting the Bax inhibitor 1/optic atrophy 1 (BI-1/OPA1) pathway. Methods β-glycerophosphate and calcium chloride were used to induce calcification in rat vascular smooth muscle cells (VSMCs), and the effects of siH19, alone or in combination with BI-1 or OPA1 knockdown, on calcification of the cells were investigated. Osteogenic differentiation was assessed by measuring Runt-related transcription factor 2 (Runx-2) and bone morphogenetic protein 2 (BMP-2) expression with Western blotting, and cell apoptosis was evaluated by TUNEL staining and Western blotting. An ApoE-/- diabetic mouse model with high-fat feeding for 32 weeks were given an intraperitoneal injection of siH19, and the changes in calcium deposition in the aortic arch were examined using Alizarin red S staining and von Kossa staining. Results In rat VSMCs with calcification, the expression of lncRNA H19 was significantly increased, and the expressions of BI- 1 and OPA1 were significantly decreased. Downregulation of lncRNA H19 significantly increased the expressions of BI-1 and OPA1 proteins in the cells, and BI-1 knockdown further reduced OPA1 expression (P<0.001). The cells treated with siH19 showed total disappearance of the calcified nodules with significantly reduced expressions of Runx-2, BMP-2 and cleaved caspase-3 and a lowered cell apoptosis rate (P<0.001). Calcified nodules were again observed in the cells with lncRNA H19 knockdown combined with BI-1 or OPA1 knockdown, and the expressions of Runx-2, BMP-2, cleaved-caspase-3 and cell apoptosis rate all significantly increased (P<0.001). In the diabetic mouse model with high-fat feeding, siH19 treatment significantly reduced the calcification area and increased mRNA expressions of BI-I and OPA1 in the aortic arch. Conclusion LncRNA H19 promotes vascular calcification possibly by promoting calcium deposition, osteogenic differentiation and cell apoptosis via inhibiting the BI-1/OPA1 pathway. Related Articles | Metrics | Comments（0）

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Puerarin alleviates lipopolysaccharide-induced acute kidney injury in mice by modulating the SIRT1/NF-κB pathway GUO Jingjing, ZHANG Wenlong, LIANG Piao, ZHANG Longjun, PENG Lingyin, MIN Yuqi, PAN Xiaozhen, YANG Zhiying, DENG Huafei Journal of Southern Medical University    2023, 43 (7): 1248-1253.   DOI: 10.12122/j.issn.1673-4254.2023.07.22 Abstract （208）   HTML （24）    PDF（pc） （1912KB）（380）       Knowledge map    Save Objective To investigate the role of the SIRT1/NF-κB pathway in mediating the effect of puerarin against lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Methods Fifteen BALB/C mice were randomized into control group, LPS group and puerarin treatment group, and in the latter two groups, the mice were given an intraperitoneal injection of LPS (5 mg/kg), followed by daily injection of normal saline for 3 days or injection of puerarin (25 mg/kg) given 1 h later and then on a daily basis for 3 days. On day 5 after modeling, the kidney tissues were taken for histological observation and detection of cell apoptosis. The renal function indexes including urea nitrogen (BUN), serum creatinine (Scr) and kidney injury molecule 1 (KIM-1) and the levels of tumor necrosis factor (TNF-α) and interleukin 1β (IL-1β) were measured, and the expressions of SIRT1 and NF-κB-p65(acetyl K310) in the renal tissues were detected. Results Intraperitoneal injection of LPS caused obvious glomerular capillary dilatation, hyperemia, renal interstitial edema, and renal tubular epithelial cell swelling and deformation in the mice. The mouse models of LPS-induced AKI also showed significantly increased renal tubular injury score and renal cell apoptosis (P<0.01) with increased serum levels of BUN, Scr, KIM-1, TNF-α and IL-1β (P<0.01), enhanced renal expressions of TNF-α, IL-1β and NF-κB p65(acetyl K310) (P<0.01) and lowered renal expression of SIRT1 (P<0.05). Treatment with puerarin effectively alleviated LPS-induced renal interstitial edema and renal tubular epithelial cell shedding, lowered renal tubular injury score (P<0.01) and renal cell apoptosis rate (P<0.01), and decreased serum levels of BUN, Scr, KIM, TNF-α and IL-1β (P<0.01). Puerarin treatment significantly reduced TNF-α, IL-1β and NF-κB p65 (acetyl K310) expression in the renal tissue (P<0.05) and increased SIRT1 expression by 17% (P<0.05) in the mouse models. Conclusion Puerarin can effectively alleviate LPS-induced AKI in mice possibly by modulating the SIRT1/NF-κB signaling pathway. Related Articles | Metrics | Comments（0）

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Acetaldehyde dehydrogenase 2 ameliorates lung endothelial barrier and balances mitochondrial dynamics in mice with acute lung injury WANG Liya, TIAN Meihui, LI Rong, WU Yue, WANG Shasha, LÜ Heng, LIU Zhongyi, YU Ying Journal of Southern Medical University    2023, 43 (8): 1388-1395.   DOI: 10.12122/j.issn.1673-4254.2023.08.16 Abstract （114）   HTML （10）    PDF（pc） （2798KB）（379）       Knowledge map    Save Objective To investigate the protective effects of acetaldehyde dehydrogenase 2 (ALDH2) against lipopolysaccharide (LPS)- induced acute lung injury (ALI) in mice and explore the possible mechanisms. Methods Sixty C57BL/6J mice were equally randomized into Sham group, LPS group, LPS + Alda-1 (an ALDH2 agonist) group, and LPS + Daidzin (an ALDH2 inhibitor) group. After the treatment, the wet/dry lung mass ratio of the mice was measured, and the lung permeability was evaluated with Evans Blue (EB). The lung tissue pathologies were evaluated with HE staining and transmission electron microscopy. Serum levels of 4-hydroxynonenal (4-HNE) were measured with ELISA, and malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) levels were determined to measure oxidative stress levels. The expressions of ALDH2, ZO-1, Occludin, Mfn2, OPA1, Drp1, Fis1, and nuclear Nrf2 and HO-1 proteins in the lung tissues were detected using Western blotting. Results The mice with LPS-induced ALI showed severe disruption of the lung tissue structure and endothelial cell tight junctions with significantly increased the lung permeability (P<0.01), increased levels of 4-HNE and MDA (P<0.01), decreased activities of CAT and SOD (P<0.01), lowered expressions of ALDH2, ZO-1, Occludin, Mfn2, and OPA1 proteins, and increased expressions of Drp1, Fis1, and nuclear Nrf2 and HO-1 proteins (P<0.05, P<0.01). Treatment with Alda-1 significantly improved lung tissue pathologies and mitochondrial damage in ALI mice (P<0.01), increased the expressions of ALDH2, ZO-1, Occludin, OPA1, Mfn2, and nuclear Nrf2 and HO-1 proteins, and lowered the expressions of Drp1 and Fis1 proteins (P<0.05, P<0.01). Compared with Alda-1, treatment with Daidzin significantly increased the lung permeability, exacerbated mitochondrial damage, decreased the expression of ALDH2, ZO-1, Occludin, Mfn2, OPA1, and nuclear Nrf2 and HO-1 proteins, and increased expressions of Drp1 and Fis1 proteins (P<0.05, P<0.01). Conclusion ALDH2 can ameliorate LPS-induced lung endothelial barrier damage in ALI mice by maintaining the balance of mitochondrial dynamics and inhibiting oxidative stress, and the mechanism may be related to the Nrf2/HO-1 pathway. Related Articles | Metrics | Comments（0）

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High expression of CAMSAP2 promotes invasion and metastasis of gastric cancer cells by upregulating TGF-β signaling ZUO Lugen, WANG Lian, YANG Zi, LI Junjie, WANG Wenfeng, LI Jing, WANG Yueyue, SONG Xue, ZHNAG Xiaofeng, GENG Zhijun Journal of Southern Medical University    2023, 43 (9): 1460-1468.   DOI: 10.12122/j.issn.1673-4254.2023.09.02 Abstract （241）   HTML （39）    PDF（pc） （2880KB）（378）       Knowledge map    Save Objective To investigate the expression of calmodulin-regulated spectrin-associated protein 2 (CAMSAP2) in gastric cancer and its effect on gastric cancer cell invasion and metastasis. Methods The association of CAMSAP2 expression levels with progression and prognosis of gastric cancer was analyzed using public cancer data and in 106 patients receiving radical gastrectomy in our hospital from October, 2013 to October, 2017. The biological functions of CAMSAP2 were predicted using bioinformatics analysis. Gastric cancer MGC803 cells with CAMSAP2 overexpression and knockdown were observed for epithelial-mesenchymal transition (EMT), migration and invasion. A nude mouse model bearing orthotopic gastric cancer cell xenografts was established for verifying the results and exploring the underlying molecular mechanism. Results Gastric cancer tissues expressed high levels of CAMSAP2, which were positively correlated with CEA and CA19-9 (P<0.001). Cox regression analysis showed that CAMSAP2 expression level was an independent risk factor affecting the 5-year survival rate of gastric cancer patients (HR=2.969, 95% CI: 1.031-8.548). Enrichment analysis suggested that CAMSAP2 was involved in epithelial-mesenchymal transition (EMT) and TGF-β signaling. In gastric cancer cells, CAMSAP2 overexpression significantly increased the expressions of vimentin and N-cadherin, inhibited the expression of E-cadherin, and enhanced cell migration and invasion (P<0.05); CAMSAP2 knockdown produced the opposite effects in the cells (P<0.05). In the tumor- bearing mice, xenografts overexpressing CAMSAP2 showed enhanced metastasis (P<0.05), increased vimentin and N-cadherin expressions and lowered E-cadherin expression (P<0.05), and the xenografts with CAMSAP2 knockdown showed the opposite changes (P<0.05). Both the in vivo and in vitro experiments showed that CAMSAP2 overexpression increased and CAMSAP2 knockdown lowered the levels of TGF-β and p-Smad2/3 in the gastric cancer cells (P<0.05). Conclusion The high expression of CAMSAP2 contributes to disease progression and poor prognosis of gastric cancer possibly by upregulating TGF-β signaling to promote EMT. Related Articles | Metrics | Comments（0）

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Heterogeneity analysis of pancreatic cancer and identification of molecular subtypes of tumor cells based on CEACAM5, LGALS1 and CENPF gene expression SUN Jingjie, LU Peng, GUAN Shasha, LIU Songsong Journal of Southern Medical University    2023, 43 (9): 1567-1576.   DOI: 10.12122/j.issn.1673-4254.2023.09.14 Abstract （147）   HTML （15）    PDF（pc） （4630KB）（377）       Knowledge map    Save Objective To explore the heterogeneity of pancreatic cancer and new methods for tumor cell molecular subtyping and identify the signature genes in pancreatic cancer progression. Methods Based on the single-cell sequencing data of 16 pancreatic cancer tissues from the GSE155698 dataset, the single pancreatic cancer cells were classified according to EPCAM gene expression after preliminary clustering, re-clustering, and subgrouping to identify the signature genes, followed by pathway enrichment analysis and pseudo-time analysis. The key genes identified were validated using the clinical and tissue gene and protein expression data from 179 pancreatic cancer patients and 171 healthy controls. The impact of CEACAM5, LGALS1, and CENPF on proliferation, migration and invasion of pancreatic cancer cells were analyzed. Results Analysis of 48 570 cells from 16 pancreatic cancer samples revealed a total of 22 clusters, including 5 clusters of pancreatic cancer cells, which were classified into Subtype 1, Subtype 2, and Subtype 3, each exhibiting distinct gene expression patterns and functions. The signature genes were enriched in negatively regulated protein metabolic processes, ferroptosis, and antigen processing and presentation-related pathways in Subtype 1 pancreatic cancer cells; in peptide synthesis processes, translation, and ribosome-related pathways in Subtype 2; and in ATP metabolic processes, glycolysis/gluconeogenesis, and cell cycle-related pathways in Subtype 3. Subtypes 2 and 3 were potentially derived from Subtype 1, and Subtype 3 possibly represented the final developmental stage of pancreatic cancer cells. The key signature genes (CEACAM5, LGALS1, and CENPF) also exhibited different expression patterns in the developmental trajectory and showed high expressions in pancreatic cancer in association with poor prognoses. In pancreatic cancer cells, downregulation of CEACAM5, LGALS1, and CENPF significantly inhibited the proliferation, migration, and invasion abilities of the cells (P<0.05). Conclusion Pancreatic cancer cells exhibit significant heterogeneity, and CEACAM5, LGALS1, and CENPF gene expressions, which affect pancreatic cancer cell proliferation, invasion, and metastasis, can be used to identify distinct molecular subtypes during tumor cell development. Related Articles | Metrics | Comments（0）