Molecular medicine reports最新文献

{"title":"[Retracted] SDF1/CXCR4 axis facilitates the angiogenesis via activating the PI3K/AKT pathway in degenerated discs.","authors":"Hanxiang Zhang, Peng Wang, Xiang Zhang, Wenrui Zhao, Honglei Ren, Zhenming Hu","doi":"10.3892/mmr.2024.13331","DOIUrl":"10.3892/mmr.2024.13331","url":null,"abstract":"<p><p>Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the Transwell invasion assay data shown in Figs. 2E, 3E, 4E and 5E, and the Transwell migration assay data shown in Fig. 2D, were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published elsewhere prior to the submission of this paper to <i>Molecular Medicine Reports</i>, or were under consideration for publication at around the same time (some of which have already been retracted). Moreover, data were also found to be duplicated comparing the data panels in Figs. 3D and 4D, such that data which were intended to have shown the results from differently performed experiments had been derived from the same original source. In view of the fact that certain of the abovementioned data had already apparently been published previously, the Editor of <i>Molecular Medicine Reports</i> has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 22: 4163‑4172, 2020; DOI: 10.3892/mmr.2020.11498].</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"30 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11420860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pancreatic β‑cell apoptosis in type 2 diabetes is related to post‑translational modifications of p53 (Review).","authors":"Luis Antonio Flores-López, Sergio Enríquez-Flores, Ignacio De La Mora-De La Mora, Itzhel García-Torres, Gabriel López-Velázquez, Rubí Viedma-Rodríguez, Alejandro Ávalos-Rodríguez, Alejandra Contreras-Ramos, Clara Ortega-Camarillo","doi":"10.3892/mmr.2024.13317","DOIUrl":"10.3892/mmr.2024.13317","url":null,"abstract":"<p><p>Pancreatic β‑cells are the only cells that synthesize insulin to regulate blood glucose levels. Various conditions can affect the mass of pancreatic β‑cells and decrease insulin levels. Diabetes mellitus is a disease characterized by insulin resistance and chronic hyperglycemia, mainly due to the loss of pancreatic β‑cells caused by an increase in the rate of apoptosis. Additionally, hyperglycemia has a toxic effect on β‑cells. Although the precise mechanism of glucotoxicity is not fully understood, several mechanisms have been proposed. The most prominent changes are increases in reactive oxygen species, the loss of mitochondrial membrane potential and the activation of the intrinsic pathway of apoptosis due to p53. The present review analyzed the location of p53 in the cytoplasm, mitochondria and nucleus in terms of post‑translational modifications, including phosphorylation, O‑GlcNAcylation and poly‑ADP‑ribosylation, under hyperglycemic conditions. These modifications protect p53 from degradation by the proteasome and, in turn, enable it to regulate the intrinsic pathway of apoptosis through the regulation of anti‑apoptotic and pro‑apoptotic elements. Degradation of p53 occurs in the proteasome and depends on its ubiquitination by Mdm2. Understanding the mechanisms that activate the death of pancreatic β‑cells will allow the proposal of treatment alternatives to prevent the decrease in pancreatic β‑cells.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"30 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of bariatric surgery in improving diabetic cardiomyopathy: Molecular mechanisms and therapeutic perspectives (Review).","authors":"Ke Song, Dianyuan Liang, Dingqi Xiao, Aijia Kang, Yixing Ren","doi":"10.3892/mmr.2024.13323","DOIUrl":"10.3892/mmr.2024.13323","url":null,"abstract":"<p><p>Diabetic cardiomyopathy (DCM), a significant complication of diabetes mellitus, is marked by myocardial structural and functional alterations due to chronic hyperglycemia. Despite its clinical significance, optimal treatment strategies are still elusive. Bariatric surgery via sleeve gastrectomy and Roux-en-Y gastric bypass have shown promise in treating morbid obesity and associated metabolic disorders including improvements in diabetes mellitus and DCM. The present study reviews the molecular mechanisms by which bariatric surgery improves DCM, offering insights into potential therapeutic targets. Future research should further investigate the mechanistic links between bariatric surgery and DCM, to evaluate the benefits and limitations of these surgical interventions for DCM treatment. The present study aims to provide a foundation for more effective DCM therapies, contributing to the advancement of patient care.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"30 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11411234/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PDCD4 promotes inflammation/fibrosis by activating the PPAR‑γ/NF‑κB pathway in mouse atrial myocytes.","authors":"Li Yu, Yuchun Yang, Jiao Wang, Zhen Bao, Meijuan Zheng, Xi Wang, Yu Zhu, Muhuyati Wulasihan","doi":"10.3892/mmr.2024.13333","DOIUrl":"10.3892/mmr.2024.13333","url":null,"abstract":"<p><p>Fibrosis is the basis of structural remodeling in atrial fibrillation (AF), during which inflammation is crucial. Programmed cell death factor 4 (PDCD4) is a newly identified inflammatory gene, with unknown mechanisms of action in AF. The present study aimed to elucidate the effects of PDCD4 on the inflammation and structural remodeling of atrial myocytes. For this purpose, a PDCD4 overexpression plasmid (oePDCD4) and PDCD4 small interfering (si)RNA (siPDCD4) were used to modulate PDCD4 expression in mouse atrial myocytes (HL‑1 cells). The expression of PDCD4 was detected using reverse transcription‑quantitative PCR and western blot analysis. The optimal drug concentrations of peroxisome proliferator‑activated receptor γ (PPARγ) agonist (pioglitazone hydrochloride), NF‑κB inhibitor (CBL0137), PPARγ inhibitor (GW9962) and NF‑κB agonist (betulinic acid) were screened using a Cell Counting Kit‑8 assay. The levels of inflammatory factors were detected using enzyme‑linked immunosorbent assays, the expression levels of fibrosis‑related proteins and NF‑κB subunits were detected using western blot analysis, and the expression of phosphorylated (p‑)p65/p65 was detected using immunofluorescence staining. The results revealed that PDCD4 overexpression increased the levels of fibrotic factors (collagen I, collagen III, fibronectin, α‑smooth muscle actin and matrix metalloproteinase 2), pro‑inflammatory cytokines (IFN‑γ, IL‑6, IL‑17A and TNF‑α) and p‑p65, whereas it reduced the levels of anti‑inflammatory cytokines (IL‑4) in HL‑1 cells. Additionally, treatment with the PPARγ agonist and NF‑κB inhibitor reversed the levels of fibrotic‑, pro‑inflammatory and anti‑inflammatory factors in oePDCD4‑HL‑1 cells. By contrast, PDCD4 silencing exerted the opposite effects on fibrotic factors, pro‑inflammatory cytokines, anti‑inflammatory cytokines and p‑p65. In addition, treatment with the PPARγ inhibitor and NF‑κB agonist reversed the levels of fibrotic‑, pro‑inflammatory and anti‑inflammatory factors in siPDCD4‑HL‑1 cells. In conclusion, the present study demonstrated that PDCD4 may induce inflammation and fibrosis by activating the PPARγ/NF‑κB signaling pathway, thereby promoting the structural remodeling of atrial myocytes in AF.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"30 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11425064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles of small GTPases in cardiac hypertrophy (Review).","authors":"Xin Wang, Xinwen Nie, Hao Wang, Zhanhong Ren","doi":"10.3892/mmr.2024.13332","DOIUrl":"10.3892/mmr.2024.13332","url":null,"abstract":"<p><p>Cardiac hypertrophy results from the heart reacting and adapting to various pathological stimuli and its persistent development is a major contributing factor to heart failure. However, the molecular mechanisms of cardiac hypertrophy remain unclear. Small GTPases in the Ras, Rho, Rab, Arf and Ran subfamilies exhibit GTPase activity and play crucial roles in regulating various cellular responses. Previous studies have shown that Ras, Rho and Rab are closely linked to cardiac hypertrophy and that their overexpression can induce cardiac hypertrophy. Here, we review the functions of small GTPases in cardiac hypertrophy and provide additional insights and references for the prevention and treatment of cardiac hypertrophy.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"30 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11425065/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Carthamus tinctorius</i> <i>L.</i> inhibits hepatic fibrosis and hepatic stellate cell activation by targeting the PI3K/Akt/mTOR pathway.","authors":"Zhiheng Dong, Haibin Guan, Lu Wang, Lijuan Liang, Yifan Zang, Lan Wu, Lidao Bao","doi":"10.3892/mmr.2024.13314","DOIUrl":"10.3892/mmr.2024.13314","url":null,"abstract":"<p><p>Hepatic fibrosis (HF) is a process that occurs during the progression of several chronic liver diseases, for which there is a lack of effective treatment options. <i>Carthamus tinctorius L.</i> (CTL) is often used in Chinese or Mongolian medicine to treat liver diseases. However, its mechanism of action remains unclear. In the present study, CTL was used to treat rats with CCl4‑induced HF. The histopathological, biochemical and HF markers of the livers of the rats were analyzed, and CTL‑infused serum was used to treat hepatic stellate cells (HSCs) in order to detect the relevant markers of HSC activation. Protein expression pathways were detected both <i>in vitro</i> and <i>in vivo</i>. Histopathological results showed that CTL significantly improved CCl4‑induced liver injury, reduced aspartate aminotransferase and alanine aminotransferase levels, promoted E‑cadherin expression, and decreased α‑smooth muscle actin (SMA), SOX9, collagen I and hydroxyproline expression. Moreover, CTL‑infused serum was found to decrease α‑SMA and collagen I expression in HSCs. Further studies showed that CTL inhibited the activity of the PI3K/Akt/mTOR pathway in the rat livers. Following the administration of the PI3K agonist 740Y‑P to HSCs, the inhibitory effect of CTL on the PI3K/Akt//mTOR pathway was blocked. These results suggested that CTL can inhibit HF and HSC activation by inhibiting the PI3K/Akt/mTOR pathway.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"30 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11391516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginkgolic acid regulates myogenic development by influencing the proliferation and differentiation of C2C12 myoblast cells.","authors":"Hyunju Liu, Hosouk Joung","doi":"10.3892/mmr.2024.13328","DOIUrl":"https://doi.org/10.3892/mmr.2024.13328","url":null,"abstract":"<p><p>Ginkgolic acid (GA), isolated from the leaves and seed coats of <i>Ginkgo biloba</i>, exerts several biological effects, including antitumor, antibacterial, anti‑HIV and anti‑inflammatory effects. However, the effects of GA on C2C12 myoblasts remain unclear. The present study assessed cell viability with the MTT assay and evaluated colony formation through crystal violet staining. Flow cytometry was used to analyze apoptosis with Annexin V/7‑AAD staining, proliferation with Ki67 staining and cell cycle arrest. Western blotting detected myogenic markers and other relevant proteins. Myotube formation was examined by immunofluorescence, and autophagy was measured using an LC3 antibody‑based kit via flow cytometry. The present study showed that treatment of C2C12 cells with GA significantly inhibited their viability and colony formation capacity but did not trigger apoptosis, as indicated by Annexin V/7‑AAD staining. However, Ki67 staining indicates that GA exerted dose‑dependent antiproliferative effects. Further analysis revealed that GA partially inhibited the growth of C2C12 cells via cell cycle arrest in S phase, highlighting its role in the disruption of cell proliferation. Furthermore, treatment with GA impaired myoblast differentiation, as evidenced by a reduction in the expression of the myogenesis markers, the myosin‑heavy chain, myoblast determination protein 1 and myogenin, and suppressed myotube formation. Notably, during C2C12 cell differentiation, GA promoted apoptosis without affecting cell cycle progression or Ki67 expression. Mechanistically, GA could suppress nuclear extracellular signal‑regulated kinase phosphorylation, suggesting that it modulates cell proliferation pathways. Moreover, GA triggered autophagy in differentiated C2C12 cells, as confirmed by elevated LC3 II levels. These findings highlight the multifaceted effects of GA on C2C12 cells.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"30 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt7B enhances the osteogenic differentiation of lipopolysaccharide-stimulated human periodontal ligament stem cells and inhibits the M1 polarization of macrophages by binding FZD4.","authors":"Haijing Yang, Yan Zhang, Lu Zhang, Xiaojuan Tan, Min Zhi, Chunmei Wang","doi":"10.3892/mmr.2024.13327","DOIUrl":"https://doi.org/10.3892/mmr.2024.13327","url":null,"abstract":"<p><p>Periodontitis, a common oral disease characterized by the progressive infiltration of bacteria, is a leading cause of adult tooth loss. Periodontal stem cells (PDLSCs) possess good self‑renewal and multi‑potential differentiation abilities to maintain the integrity of periodontal support structure and repair defects. The present study aimed to analyze the roles of Wnt7B and frizzled4 (FZD4) in the osteogenic differentiation and macrophage polarization during periodontitis using an <i>in vitro</i> cell model. First, Wnt7B expression in the periodontitis‑affected gingival tissue of patients and lipopolysaccharide (LPS)‑stimulated PDLSCs was assessed using the GSE23586 dataset and western blot analysis, respectively. In Wnt7B‑overexpressing PDLSCs exposed to LPS, the capacity of osteogenic differentiation was evaluated by detecting alkaline phosphatase activity, the level of Alizarin Red S staining and the expression of genes related to osteogenic differentiation. Subsequently, conditioned medium from PDLSCs overexpressing Wnt7B was used for M0 macrophage culture. The expression of CD86 and INOS was examined using immunofluorescence staining and western blot analysis. In addition, reverse transcription‑quantitative PCR was employed to examine the expression of TNF‑α, IL‑6 and IL‑1β in macrophages. The binding between Wnt7B and FZD4 was estimated using co‑immunoprecipitation. In addition, FZD4 was silenced to perform the rescue experiments to elucidate the regulatory mechanism between Wnt7B and FZD4. The results demonstrated a decreased expression of Wnt7B in periodontitis‑affected gingival tissue and in LPS‑exposed PDLSCs. Wnt7B overexpression promoted the osteogenic differentiation of LPS‑exposed PDLSCs and suppressed the M1 polarization of macrophages. Additionally, Wnt7B bound to FZD4 and upregulated FZD4 expression. FZD4 silencing reversed the effects of Wnt7B overexpression on the osteogenic differentiation in LPS‑exposed PDLSCs and the M1 polarization of macrophages. In summary, Wnt7B plays an anti‑periodontitis role by binding FZD4 to strengthen the osteogenic differentiation of LPS‑stimulated PDLSCs and suppress the M1 polarization of macrophages.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"30 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of STAT4 on myocardial ischemia‑reperfusion injury and the underlying mechanisms.","authors":"Mei He, Yuexin Yu, Shuwei Ning, Jingxian Han, Zhikun Guo","doi":"10.3892/mmr.2024.13321","DOIUrl":"10.3892/mmr.2024.13321","url":null,"abstract":"<p><p>The regulation of cardiac function by the nuclear transcription factor signal transducer and activator of transcription 4 (STAT4) has been recently recognized. Nevertheless, the role and mechanisms of action of STAT4 in myocardial ischemia‑reperfusion (I/R) injury remain unknown. Consequently, the present study constructed a rat model of I/R by ligation of the left anterior descending coronary artery. Following sacrifice, the rat hearts were excised and analyzed to investigated the effects of STAT4 on I/R‑induced myocardial injury. Western blotting demonstrated that expression of STAT4 decreased significantly in the rat model of cardiac I/R and in H9C2 cells that were subjected to hypoxia and reoxygenation (H/R). The overexpression of STAT4 in H9C2 cells reduced cell damage and apoptosis induced by H/R. Furthermore, both <i>in vivo</i> and <i>in vitro</i>, the level of PI3K decreased significantly. Although the AKT protein expression levels were not altered, the AKT phosphorylation levels decreased significantly. STAT4 overexpression enhanced the expression of PI3K and AKT in the H9C2 cells. On the whole, the present study demonstrated that STAT4 alleviated I/R‑induced myocardial injury through the PI3K/AKT signaling pathway.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"30 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11391519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of cullin 3 inhibits progressive phenotypes and increases chemosensitivity in cholangiocarcinoma cells.","authors":"Kandawasri Pratummanee, Kankamol Kerdkumthong, Sittiruk Roytrakul, Phonprapavee Tantimetta, Phanthipha Runsaeng, Sompop Saeheng, Sumalee Obchoei","doi":"10.3892/mmr.2024.13322","DOIUrl":"10.3892/mmr.2024.13322","url":null,"abstract":"<p><p>Cholangiocarcinoma (CCA) is an extremely aggressive malignancy arising from the epithelial cells lining the bile ducts. It presents a substantial global health issue, with the highest incidence rates, ranging from 40‑100 cases/100,000 individuals, found in Southeast Asia, where liver fluke infection is endemic. In Europe and America, incidence rates range from 0.4‑2 cases/100,000 individuals. Globally, mortality rates range from 0.2‑2 deaths/100,000 person‑years and are increasing in most countries. Chemotherapy is the primary treatment for advanced CCA due to limited options from late‑stage diagnosis, but its efficacy is hindered by drug‑resistant phenotypes. In a previous study, proteomics analysis of drug‑resistant CCA cell lines (KKU‑213A‑FR and KKU‑213A‑GR) and the parental KKU‑213A line identified cullin 3 (Cul3) as markedly overexpressed in drug‑resistant cells. Cul3, a scaffold protein within CUL3‑RING ubiquitin ligase complexes, is crucial for ubiquitination and proteasome degradation, yet its role in drug‑resistant CCA remains to be elucidated. The present study aimed to elucidate the role of Cul3 in drug‑resistant CCA cell lines. Reverse transcription‑quantitative PCR and western blot analyses confirmed significantly elevated Cul3 mRNA and protein levels in drug‑resistant cell lines compared with the parental control. Short interfering RNA‑mediated Cul3 knockdown sensitized cells to 5‑fluorouracil and gemcitabine and inhibited cell proliferation, colony formation, migration and invasion. In addition, Cul3 knockdown induced G₀/G₁ cell cycle arrest and suppressed key cell cycle regulatory proteins, cyclin D, cyclin‑dependent kinase (CDK)4 and CDK6. Bioinformatics analysis of CCA patient samples using The Cancer Genome Atlas data revealed Cul3 upregulation in CCA tissues compared with normal bile duct tissues. STRING analysis of upregulated proteins in drug‑resistant CCA cell lines identified a highly interactive Cul3 network, including COMM Domain Containing 3, Ariadne RBR E3 ubiquitin protein ligase 1, Egl nine homolog 1, Proteasome 26S Subunit Non‑ATPase 13, DExH‑box helicase 9 and small nuclear ribonucleoprotein polypeptide G, which showed a positive correlation with Cul3 in CCA tissues. Knocking down Cul3 significantly suppressed the mRNA expression of these genes, suggesting that Cul3 may act as an upstream regulator of them. Gene Ontology analysis revealed that the majority of these genes were categorized under binding function, metabolic process, cellular anatomical entity, protein‑containing complex and protein‑modifying enzyme. Taken together, these findings highlighted the biological and clinical significance of Cul3 in drug resistance and progression of CCA.</p>","PeriodicalId":18818,"journal":{"name":"Molecular medicine reports","volume":"30 5","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}