RESUMEN
Cell senescence genes play a vital role in the pathogenesis of colorectal cancer, a process that may involve the triggering of genetic variations and reversible phenotypes caused by epigenetic modifications. However, the specific regulatory mechanisms remain unclear. Using CellAge and The Cancer Genome Atlas databases and in-house RNA-seq data, DNA methylation-modified cellular senescence genes (DMCSGs) were validated by Support Vector Machine and correlation analyses. In 1150 cases and 1342 controls, we identified colorectal cancer risk variants in DMCSGs. The regulatory effects of gene, variant, and DNA methylation were explored through dual-luciferase and 5-azacytidine treatment experiments, complemented by multiple database analyses. Biological functions of key gene were evaluated via cell proliferation assays, SA-ß-gal staining, senescence marker detection, and immune infiltration analyses. The genetic variant rs4558926 in the downstream of TACC3 was significantly associated with colorectal cancer risk (OR = 1.35, P = 3.22 × 10-4). TACC3 mRNA expression increased due to rs4558926 C > G and decreased DNA methylation levels. The CpG sites in the TACC3 promoter region were regulated by rs4558926. TACC3 knockdown decreased proliferation and senescence in colorectal cancer cells. In addition, subjects with high-TACC3 expression presented an immunosuppressive microenvironment. These findings provide insights into the involvement of genetic variants of cellular senescence genes in the development and progression of colorectal cancer.
Asunto(s)
Neoplasias Colorrectales , Metilación de ADN , Epigénesis Genética , Proteínas Asociadas a Microtúbulos , Humanos , Proteínas de Ciclo Celular/genética , Senescencia Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Islas de CpG , ADN , Regulación Neoplásica de la Expresión Génica , Proteínas Asociadas a Microtúbulos/genética , Microambiente TumoralRESUMEN
Oncogenic-driven lipogenic metabolism is a common hallmark of colorectal cancer (CRC) progression. Therefore, there is an urgent need to develop novel therapeutic strategies for metabolic reprogramming. Herein, the metabolic profiles in the plasma between CRC patients and paired healthy controls were compared using metabolomics assays. Matairesinol downregulation was evident in CRC patients, and matairesinol supplementation significantly represses CRC tumorigenesis in azoxymethane/dextran sulfate sodium (AOM/DSS) colitis-associated CRC mice. Matairesinol rewired lipid metabolism to improve the therapeutic efficacy in CRC by inducing mitochondrial damage and oxidative damage and blunting ATP production. Finally, matairesinol-loaded liposomes significantly promoted the enhanced antitumor activity of 5-Fu/leucovorin combined with oxaliplatin (FOLFOX) in CDX and PDX mouse models by restoring chemosensitivity to the FOLFOX regimen. Collectively our findings highlight matairesinol-mediated lipid metabolism reprogramming as a novel druggable strategy to restore CRC chemosensitivity, and this nanoenabled approach for matairesinol will improve the chemotherapeutic efficacy with good biosafety.
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Colitis , Neoplasias Colorrectales , Ratones , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Metabolismo de los Lípidos , Furanos/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
Immunogenic cell death (ICD), a type of cell death that activates the tumor-specific immune response and thus exerts anti-tumor effects, is an emerging target in tumor therapy, but research on ICD-related genes (ICDGs) in colorectal cancer (CRC) remains limited. This study aimed to identify the CRC-specific ICDGs and explore their potential roles. Through RNA sequencing for tissue samples from CRC patients and integration with The Cancer Genome Atlas (TCGA) data, we identified 33 differentially expressed ICDGs in CRC. We defined the ICD score based on these genes in single-cell data, where a high score indicated an immune-active microenvironment. Additionally, molecular subtypes identified in bulk RNA data showed distinct immune landscapes. The ICD-related signature constructed with machine learning effectively distinguished patients' prognosis. The summary data-based Mendelian randomization (SMR) and colocalization analysis prioritized CFLAR for its positive association with CRC risk. Molecular docking revealed its stable binding with chemotherapeutic drugs like irinotecan. Furthermore, experimental validation confirmed CFLAR overexpression in CRC samples, and its knockdown inhibited tumor cell proliferation. Overall, this study expands the understanding of the potential roles and mechanisms of ICDGs in CRC and highlights CFLAR as a promising target for CRC.
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Neoplasias Colorrectales , Muerte Celular Inmunogénica , Humanos , Análisis de la Aleatorización Mendeliana , Simulación del Acoplamiento Molecular , Transcriptoma , Neoplasias Colorrectales/genética , Microambiente TumoralRESUMEN
OBJECTIVES: Laparoscopic resection for rectal cancer is currently the predominant treatment modality for rectal tumors, with an ongoing focus on reducing the incidence of postoperative complications. In an effort to decrease the occurrence of anastomotic leakage, two additional steps worth considering are reinforcing the anastomosis with a barbed suture and retaining an anal drain as part of the procedure. The results of the operation were analyzed by comparing them to cases where the anastomosis was performed with a stapler alone. METHODS: This study retrospectively analyzed patients who underwent laparoscopic radical rectal cancer surgery between July 2020 and March 2023. The patients were categorized into three cohorts based on the postoperative management following instrumented anastomosis: cohort A, the instrumented anastomosis alone group; cohort B, the reinforced suture group; and cohort C, the reinforced suture and indwelling transanal drainage tube group. Propensity score matching was performed twice in a 1:1 ratio, comparing cohort B to cohort A and cohort C to cohort B. The objective was to compare the benefits and drawbacks among the different groups in terms of operative time, postoperative outcomes and operative costs. RESULTS: 529 patients with laparoscopic resection for rectal cancer were eligible for inclusion. the instrumented anastomosis alone group, reinforced suture group and the reinforced suture and indwelling transanal drainage tube group were performed in 205 patients, 198 patients and 126 patients, respectively. Cohort A and Cohort B differed in three variables after PSM: total operative time (p = 0.018), postoperative hospital stay (p < 0.001) and incidence of anastomotic leakage (p = 0.038). Cohort B had a longer total operative time, shorter postoperative hospital stay and a lower incidence of anastomotic leakage. Similarly, cohort C had less postoperative drainage (P = 0.01) and a longer postoperative hospital stay (P = 0.003) when cohort B and cohort C were matched for propensity scores. There was no significant difference in the cost of surgery between the three cohorts. CONCLUSIONS: The incorporation of barbed suture reinforcement significantly reduces the occurrence of postoperative anastomotic leakage in rectal cancer surgeries. On the other hand, although trans-anal drainage was used as an additional measure to the reinforcement suture of the anastomosis, the utilization of trans-anal drainage tubes does not demonstrate a significant improvement in surgical outcomes.
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Laparoscopía , Neoplasias del Recto , Humanos , Fuga Anastomótica/epidemiología , Fuga Anastomótica/etiología , Fuga Anastomótica/prevención & control , Puntaje de Propensión , Estudios Retrospectivos , Neoplasias del Recto/cirugía , Neoplasias del Recto/patología , Anastomosis Quirúrgica/métodos , Drenaje/métodos , Laparoscopía/efectos adversos , Suturas/efectos adversosRESUMEN
The Hippo signalling pathway plays a crucial role in carcinogenesis. Therefore, we hypothesized that genetic variants in genes related to this pathway are associated with the colorectal cancer risk. A case-control study including 1150 patients and 1342 controls was performed to assess the association of genetic variants of genes involved in the Hippo signalling pathway with the risk of colorectal cancer. The results were corrected for multiple comparisons using the false discovery rate (FDR). We used a regression model to determine the effects of single-nucleotide polymorphisms (SNPs) on the survival of patients with colorectal cancer in The Cancer Genome Atlas (TCGA) datasets. An expression quantitative trait loci (eQTL) analysis was performed using TCGA datasets and the Genotype-Tissue Expression (GTEx) project. Gene Expression Omnibus (GEO) datasets were used to provide additional data on the expression of genes in colorectal cancer. The SCRIB rs13251492 G allele was associated with a significantly decreased risk of colorectal cancer (odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.70-0.89, P = 7.76 × 10-5, P(FDR) = 6.98 × 10-4). Patients with the rs13251492 AG/GG allele experienced a longer recurrence-free survival (RFS) time (hazard ratio (HR) = 0.64, 95% CI = 0.42-0.99, P = 0.049) than patients with the rs13251492 A allele. The eQTL analysis revealed a significant association between rs13251492 and the expression of the SCRIB mRNA in colorectal tumors. Dual-luciferase reporter assays in DLD-1 and HCT116 cells revealed a lower enhancer activity of the rs13251492 G allele than the A allele. In addition, the SCRIB mRNA was expressed at markedly higher levels in colorectal cancer tissues than in normal tissues. Therefore, we identified the SCRIB rs13251492 variant as a novel colorectal cancer susceptibility locus and provided evidence of its functional relevance.
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Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Proteínas de la Membrana/genética , Polimorfismo de Nucleótido Simple , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal/genética , Proteínas Supresoras de Tumor/genética , Estudios de Casos y Controles , China , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Bases de Datos Genéticas , Femenino , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Vía de Señalización Hippo , Humanos , Masculino , Fenotipo , Sitios de Carácter Cuantitativo , Medición de Riesgo , Factores de RiesgoRESUMEN
The N6-methyladenosine (m6A) modification plays important regulatory roles in gene expression, cancer occurrence and metastasis. Herein, we aimed to explore the association between genetic variants in m6A modification genes and susceptibility to colorectal cancer. We used logistic regression models to investigate the associations between candidate single-nucleotide polymorphisms (SNPs) in 20 m6A modification genes and colorectal cancer risk. The false discovery rate (FDR) method was used for multiple comparisons. Dual luciferase assays and RNA m6A quantifications were applied to assess transcriptional activity and measure m6A levels, respectively. We found that SND1 rs118049207 was significantly associated with colorectal cancer risk in a Nanjing population (odds ratio (OR) = 1.69, 95% confidence interval (95% CI) = 1.31-2.18, P = 6.51 × 10-6). This finding was further replicated in an independent Beijing population (OR = 1.36, 95% CI = 1.04-1.79, P = 2.41 × 10-2) and in a combined analysis (OR = 1.52, 95% CI = 1.27-1.84, P = 8.75 × 10-6). Stratification and interaction analyses showed that SND1 rs118049207 multiplicatively interacted with the sex and drinking status of the patients to enhance their colorectal cancer risk (P = 1.56 × 10-3 and 1.41 × 10-2, respectively). Furthermore, rs118049207 served as an intronic enhancer on SND1 driven by DMRT3. SND1 mRNA expression was markedly increased in colorectal tumour tissues compared with adjacent normal tissues. The colorimetric m6A quantification strategy revealed that SND1 could alter m6A levels in colorectal cancer cell lines. Our findings indicated that genetic variants in m6A modification genes might be promising predictors of colorectal cancer risk.
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Adenosina/análogos & derivados , Neoplasias Colorrectales/genética , Endonucleasas/genética , Predisposición Genética a la Enfermedad , Adenosina/metabolismo , Anciano , Estudios de Casos y Controles , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Metilación , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Procesamiento Postranscripcional del ARN , ARN Mensajero/metabolismoRESUMEN
Colorectal cancer (CRC) is a common digestive tract malignancy, which is characterized by high mortality, morbidity, and poor prognosis. Replication factor C subunit 2 (RFC2), one RFC family member, was reported to be related to various malignancies and plays an important role in proliferation, invasion, and metastasis. Nonetheless, the RFC2 biological role within CRC is still unknown. RFC2 expression profiles in CRC tissues were collected based on The Cancer Genome Atlas database, whereas miR-744 and RFC2 expression levels were detected in human CRC tissues. miR-744 and RFC2 effects on the proliferation of CRC were assessed both in vivo and in vitro. RFC2 was recognized to be a direct miR-744 target through luciferase reporter assay. RFC2 upregulation was observed within CRC tissues, and a high RFC2 level showed a correlation with poor clinicopathological symptoms. RFC2 knockdown inhibited CRC cell proliferation through promoting cell cycle arrest at the G1 phase, which was achieved by cyclin E2 (CCNE2) downregulation in vivo and in vitro. miR-744 was identified to be the tumor suppressor microRNA, which targeted RFC2 directly for inhibiting the proliferation of CRC cells both in vivo and in vitro. miR-744 downregulation was detected within CRC tissue, and messenger RNA expression showed a negative correlation with RFC2 expression within CRC tissues. Our study demonstrates that the miR-744/RFC2/CCNE2 axis potentially provides a candidate for a treatment strategy for CRC.
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Neoplasias Colorrectales/patología , Ciclinas/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , MicroARNs/metabolismo , Proteína de Replicación C/metabolismo , Animales , Ciclo Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Ciclinas/genética , Humanos , Masculino , Ratones , Ratones Desnudos , MicroARNs/genética , Proteína de Replicación C/genéticaRESUMEN
OBJECTIVE: Pancreatic cancer is a kind of high malignant tumor with a poor prognosis. The aim is to determine whether the dilated bile duct can be used to reconstruct the vessels. METHODS: An animal model of jugular vein and portal vein reconstruction was established using the bile duct. A total of 20 landrace pigs were selected to undergo jugular vein reconstruction or portal vein reconstruction using the bile duct as a patch or bridge. The patency was evaluated by color Doppler, the reconstructed segments were removed and examined macroscopically and histologically at specified intervals, and the results were compared with synthetic vessels (IMPRA straight, 10s03-19). RESULTS: The lumen was patent, although a low level thrombosis was observed when jugular or portal vein patching was used. For bridging, stenosis of the lumen was observed, and necrosis appeared when the bile duct was used for bridging, indicating that it is feasible to reconstruct the jugular vein and portal vein with a bile duct patch. However, the bridge was not feasible possibly due to loss of blood supply, and consequent necrosis and fibrosis. CONCLUSION: The bile duct is technically feasible, but the outcomes are unsatisfactory.
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Bioprótesis , Implantación de Prótesis Vascular/instrumentación , Prótesis Vascular , Conducto Colédoco/trasplante , Venas Yugulares/cirugía , Páncreas/cirugía , Vena Porta/cirugía , Animales , Implantación de Prótesis Vascular/efectos adversos , Conducto Colédoco/patología , Conducto Colédoco/fisiopatología , Estudios de Factibilidad , Femenino , Fibrosis , Supervivencia de Injerto , Venas Yugulares/patología , Venas Yugulares/fisiopatología , Masculino , Modelos Animales , Necrosis , Vena Porta/patología , Vena Porta/fisiopatología , Sus scrofa , Factores de Tiempo , Grado de Desobstrucción VascularRESUMEN
Peroxisome proliferator-activator receptor (PPAR) γ is a nuclear hormone receptor that regulates glucose homeostasis, lipid metabolism, and adipocyte function. It has been shown that activation of PPARγ can reduce the incidence of gallstone. Herein we aimed to clarify the role of PPARγ in the reduction of gallstones. The plasmid containing the coding sequence of PPARγ was constructed and transfected in the human liver cell line (L02 cells). Western blot and RT-PCR were used to detect hydroxyl-methyl-glutaryl-CoA reductase (HMGCR), sterol regulatory element-binding proteins 2 (SREBP2), 7α-hydroxylase (CYP7A1), adenosine triphosphate-binding cassette (ABC) sterol transporters G5 and G8 (ABCG5, ABCG8) and liver X receptor α (LXRα). The Amplex Red cholesterol assay kit was used to detect the intracellular or extracellular cholesterol level. Our data showed that PPARγ overexpression caused significant decreases in both extracellular and intracellular cholesterol in the L02 cells. The further studies indicated PPARγ overexpression substantially decreased expression of HMGCR and SREBP-2, increased expression of CYP7A1, ABCG5, ABCG8 and LXRα. These results indicated that upregulation of PPARγ may reduce cholesterol levels through multiple-pathways including HMGCR/SREBP2-mediated biosynthesis, CYP7A1-mediated transformation, and ABCG5/ABCG8-mediated efflux. We thus suggest that PPARγ might have beneficial effects for cholesterol gallstones diseases.
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Colesterol/metabolismo , Hepatocitos/metabolismo , PPAR gamma/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/metabolismo , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/metabolismo , Línea Celular , Colesterol 7-alfa-Hidroxilasa/genética , Colesterol 7-alfa-Hidroxilasa/metabolismo , Escherichia coli/genética , Humanos , Hidroximetilglutaril-CoA Reductasas/genética , Hidroximetilglutaril-CoA Reductasas/metabolismo , Lipoproteínas/genética , Lipoproteínas/metabolismo , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , PPAR gamma/genética , Plásmidos , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , TransfecciónRESUMEN
BACKGROUND: The cholesterol gallstones diseases (CGD) is highly correlated with metabolic syndrome and type 2 diabetes. The present study aimed to investigate preventive effects of pioglitazone (PIO), an antidiabetic drug, on the CGD in guinea pigs fed with a lithogenic diet (LD). METHODS: The guinea pigs were fed with the LD for 8 weeks. All guinea pigs were grouped as follows: low fat diet; LD; LD plus PIO (4 mg/kg); LD plus PIO (8 mg/kg); LD plus ezetimibe (EZE) (2 mg/kg). Gallbladder stones were observed using microscopy. The profile of biliary composition, and blood glucose, insulin and lipid were analyzed. The liver or ileum was harvested for determinations of hydroxyl-methyl-glutaryl-CoA reductase (HMGCR), sterol regulatory element-binding proteins 2 (SREBP2), 7α-hydroxylase (CYP7A1), adenosine triphosphate-binding cassette (ABC) sterol transporters G5 and G8 (ABCG5, ABCG8), bile salt export pump (BSEP), Niemann-Pick C1-Like 1 (NPC1L1) and acetyl-coenzyme A cholesterol acyltransferase (ACAT2) by Western blot. The gallbladders were used for histological examination. RESULTS: The LD successfully induced gallstone. Both pioglitazone and ezetimibe prevented gallstone formation, as well as hepatic and cholecystic damages. Pioglitazone significantly decreased HMGCR and SREBP2, but increased CYP7A1, ABCG5, ABCG8, and BSEP in the liver. Pioglitazone also remarkably decreased NPC1L1 and ACAT2, while increased ABCG5/8 in the intestine. The beneficial alterations of cholesterol and bile acids in the bile, as well as profile of glucose, insulin and lipid in the blood were found in the guinea pigs treated with pioglitazone. CONCLUSION: Pioglitazone has a noticeable benefit towards the CGD, which is involved in changes of synthesis, transformation, absorption, and transportation of cholesterol.
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Ácidos y Sales Biliares/administración & dosificación , Colesterol en la Dieta/administración & dosificación , Colesterol/metabolismo , Cálculos Biliares/prevención & control , Homeostasis/efectos de los fármacos , Pioglitazona/administración & dosificación , Transportadoras de Casetes de Unión a ATP/análisis , Animales , Anticolesterolemiantes , Colesterol 7-alfa-Hidroxilasa/análisis , Dieta , Ezetimiba/administración & dosificación , Vesícula Biliar/química , Vesícula Biliar/metabolismo , Vesícula Biliar/patología , Cálculos Biliares/etiología , Cobayas , Hidroximetilglutaril-CoA Reductasas/análisis , Hipoglucemiantes , Hígado/química , Hígado/metabolismo , Hígado/patología , Masculino , Proteína 2 de Unión a Elementos Reguladores de Esteroles/análisisRESUMEN
BACKGROUND: Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit. METHODS: In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed. RESULTS: Patients carrying SMAD4 mutations (SMAD4mut, n = 8) or NF1 mutations (NF1mut, n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4wt, n = 25) (P = 0.0081) or wildtype NF1 (NF1wt, n = 29) (P = 0.0028), respectively. None of the SMAD4mut or NF1mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4mut and NF1mut showed the shortest PFS among all the patients. CONCLUSIONS: Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients.
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Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Mutación , Neurofibromina 1/genética , Proteína Smad4/genética , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
BACKGROUND: This study aimed to investigate the clinical outcome of complete mesocolic excision (CME) with a caudal-to-cranial medial approach in the treatment of right colon cancer. METHODS: The clinical data of 172 patients who underwent laparoscopic CME for right colon cancer and were admitted to the First Affiliated Hospital of Nanjing Medical University from January 2010 to April 2015 were retrospectively analyzed. The 3-year disease-free survival (DFS) and overall survival (OS) in relation to gender, age, history of abdominal surgery, tumor size, complications, and tumor-node-metastasis (TNM) classification were analyzed using the Kaplan-Meier survival curves. RESULTS: A total of 172 patients with 94 males and 78 females were included. The average surgical time was 113.5 ± 34.4 min, blood loss was 74.2 ± 28.1 mL, and the number of lymph nodes retrieved was 23.3 ± 9.2. No readmission or death occurred within 30 days after surgery. Postoperative complications occurred in 16.3% of the patients, which included wound infection (3 patients), chylous fistula (22 patients), anastomotic leakage (1 patient), anastomotic bleeding (1 patient), and lung infection (1 patient). The 3-year DFS and OS were 81.7 and 89.1%, respectively. The rate of DFS and OS was significantly higher in stages I and II compared with that in stage III (P < 0.05), and in stages IIIA and IIIB compared with that in stage IIIC (P < 0.05). CONCLUSIONS: Laparoscopic CME with a caudal-to-cranial medial approach in the treatment of right colon cancer had good short-term efficacy and satisfactory oncological outcome.
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Colectomía/efectos adversos , Neoplasias del Colon/cirugía , Ganglios Linfáticos/patología , Mesocolon/cirugía , Complicaciones Posoperatorias/epidemiología , Adulto , Anciano , Pérdida de Sangre Quirúrgica/estadística & datos numéricos , Colectomía/métodos , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Laparoscopía/efectos adversos , Laparoscopía/métodos , Escisión del Ganglio Linfático/estadística & datos numéricos , Masculino , Mesocolon/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Tempo Operativo , Complicaciones Posoperatorias/etiología , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Previous studies have shown that lactate dehydrogenase-A (LDH-A) is strongly expressed in several malignancies, that LDH-A expression is associated with poor prognosis, and that LDH-A inhibition severely diminishes tumorigenicity. However, little is known about the implications of LDH-A expression in intrahepatic cholangiocarcinoma. The purpose of this study was to investigate the expression of LDH-A and to clarify its effect on intrahepatic cholangiocarcinoma. METHODS: We studied the expression of LDH-A in tissue samples from patients with intrahepatic cholangiocarcinoma (n = 54) using the ultrasensitive surfactant protein (S-P) immunohistochemical method. We then inhibited LDH-A using small hairpin RNA (shRNA) in the cholangiocarcinoma cell line HuCCT-1 in vitro to study the role it plays in promoting growth and escaping apoptosis. RESULTS: We report that LDH-A was overexpressed in 52 of 54 (96%) paraffin-embedded cancer tissue samples and 0 of 54 para-carcinoma tissue samples. Reduction of LDH-A by RNA interference (RNAi) inhibited cell growth and induced apoptosis in HuCCT-1 cells. This result correlated with the elevation of cytoplasmic reactive oxygen species (ROS) levels. CONCLUSIONS: LDH-A expression is closely correlated with histopathological variables of intrahepatic cholangiocarcinoma, indicating that LDH-A may serve as a new treatment target.
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Neoplasias de los Conductos Biliares/metabolismo , Conductos Biliares Intrahepáticos/metabolismo , Biomarcadores de Tumor/metabolismo , Colangiocarcinoma/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Apoptosis , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/terapia , Conductos Biliares Intrahepáticos/patología , Biomarcadores de Tumor/genética , Western Blotting , Proliferación Celular , Colangiocarcinoma/patología , Colangiocarcinoma/terapia , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/genética , Lactato Deshidrogenasa 5 , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales CultivadasRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0295126.].
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Purpose: Cystatin C (CysC), beyond its biomarker role of renal function, has been implicated in various physical and pathological activities. However, the impact of serum CysC on cancer mortality in a general population remains unknown. We aimed to examine the associations of serum CysC concentrations with total mortality and mortality of 12 site-specific cancers. Methods: We included 241,008 participants of the UK Biobank cohort with CysC measurements who had normal creatinine-based estimated glomerular filtration rates and were free of cancer and renal diseases at baseline (2006-2010). Death information was obtained from the National Health Service death records through 28 February 2021. Multivariable Cox proportional hazards models were used to compute hazard ratios (HR) per one standard deviation increase in log-transformed CysC concentrations and 95% confidence intervals (95% CI) for mortality. Results: Over a median follow-up of 12.1 (interquartile range, 11.3-12.8) years, 5,744 cancer deaths occurred. We observed a positive association between serum CysC concentrations and total cancer mortality (HR = 1.16, 95% CI: 1.12-1.20). Specifically, participants with higher serum CysC concentrations had increased mortality due to lung cancer (HR = 1.12, 95% CI: 1.05-1.20), blood cancer (HR = 1.29, 95% CI: 1.16-1.44), brain cancer (HR = 1.19, 95% CI: 1.04-1.36), esophageal cancer (HR = 1.20, 95% CI: 1.05-1.37), breast cancer (HR = 1.18, 95% CI: 1.03-1.36), and liver cancer (HR = 1.49, 95% CI: 1.31-1.69). Conclusion: Our findings indicate that higher CysC concentrations are associated with increased mortality due to lung, blood, brain, esophageal, breast, and liver cancers. Future studies are necessary to clarify underlying mechanisms.
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Background: Previously, long non-coding RNA (lncRNA) gene AP001469.3 was reported to participate in the construction of an immune-related lncRNA signature, which showed promising clinical predictive value in colorectal cancer (CRC) patients. However, the clinical and immunological significance and biological function of AP001469.3 in CRC remain unclear. In this study, we aim to explore the roles of AP001469.3 in CRC progression, thereby opening an avenue for CRC treatment. Methods: Our study collected data from The Cancer Genome Atlas (TCGA) database and investigated the role of AP001469.3 in CRC through bioinformatics analysis. Cell-type Identification By Estimating Relative Subsets Of known RNA Transcripts (CIBERSORT) and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) methods evaluated the immune infiltration. The biological functions of AP001469.3 in CRC were validated by in vitro experiments. Gene set enrichment analysis (GSEA) was used to estimate the enrichment of functional pathways and gene signatures. Results: In this work, high expression of AP001469.3 was found in CRC and was positively associated with tumor-node-metastasis (TNM) stage in CRC. AP001469.3 expression had a strong relationship with microsatellite instability (MSI) in colon adenocarcinoma (COAD). Additionally, AP001469.3 expression was associated with StromalScore, ImmuneScore, ESTIMATEScore, immune cell infiltration (ICI) levels and immune checkpoint (ICP) genes expression in CRC. Subsequent results showed that immunotherapy could be more effective in CRC patients with low-AP001469.3 expression using the immunophenoscore (IPS). We confirmed that the transcript of AP001469.3 gene ENST00000430259 was highly expressed in CRC tissues and cell lines. In vitro experiments indicated that ENST00000430259 knockdown reduced the proliferation, migration and invasion of CRC cells. Finally, our GSEA results showed that the majority of the differentially enriched signaling pathways between the high- and low-AP001469.3 expression groups were immune-related. Conclusions: Taken together, our study demonstrates that lncRNA gene AP001469.3 is associated with immunological characteristics in CRC and promotes malignant progression of CRC. Moreover, AP001469.3 can be potentially used as an immunotherapeutic indicator and a therapeutic target for CRC patients.
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Primary colon cancers arising from the left and right sides exhibit distinct clinical and molecular characteristics. Sidedness-associated heterogeneity relies intricately on the oncogenic properties of cancer cells and multicellular interactions in tumor microenvironments. Here, combining transcriptomic profiling of 426,863 single cells from 105 colon cancer patients and validation with spatial transcriptomics and large-scale histological analysis, we capture common transcriptional heterogeneity patterns between left- and right-sided malignant epithelia through delineating two side-specific expression meta-programs. The proliferation stemness meta-program is notably enriched in left-sided malignant epithelia that colocalize with Mph-PLTP cells, activated regulatory T cells (Tregs), and exhausted CD8-LAYN cells, constituting the glucose metabolism reprogramming niche. The immune secretory (IS) meta-program exhibits specific enrichment in right-sided malignant epithelia, especially in smoking patients with right-sided colon cancer. The IShigh malignant epithelia spatially localize in hypoxic regions and facilitate immune evasion through attenuating Mph-SPP1 cell antigen presentation and recruiting innate-like cytotoxicity-reduced CD8-CD161 cells.
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Neoplasias del Colon , Microambiente Tumoral , Humanos , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Neoplasias del Colon/genética , Microambiente Tumoral/inmunología , Regulación Neoplásica de la Expresión Génica , Linfocitos T Reguladores/inmunología , Perfilación de la Expresión Génica , Transcriptoma/genética , Masculino , FemeninoRESUMEN
Retinol-binding protein 4 (RBP4) is closely associated with a variety of abnormal glycolipid metabolism diseases such as insulin resistance, obesity, diabetes mellitus, and metabolic syndrome. Part 1 Twenty-four male C57/B6 mice were randomly divided into a normal control group (group C, n = 8), a gallstone group (group G, n = 8), and a medication group (group M, n = 8). Serum RBP4 levels were measured by ELISA. RBP4 expression in liver and adipose tissue was detected by western blotting. The transcription of RBP-4 mRNA, PPAR-γ mRNA in the liver was measured using real-time PCR. The incidences of gallstone formation were 0/8 (group C), 7/8 (group G), and 2/8 (group M) (p < 0.01). Group G had significantly higher body weight, adipose mass, fasting glucose (FG), serum RBP4, total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) than group C. In group M, pioglitazone decreased body weight, adipose mass, levels of serum RBP4, FG, TC, and TG, and it increased levels of HDL-C. Pioglitazone downregulated RBP4 expression in hepatic and adipose tissue and prevented decreases in PPAR-γmRNA levels induced by lithogenic diet. Part 2 Metabolism indices, including serum RBP4, FG, TC, TG, HDL-C, low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) of 110 human cholesterol gallstone patients and 73 healthy controls were collected for further analysis. Patients with gallstones had elevated levels of serum RBP4, FG, TC, TG, ALT, and AST, and had decreased HDL-C levels compared to those of healthy controls. Elevated RBP4 is associated with the morbidity of cholesterol gallstones and metabolic syndrome. RBP4 may play an important role in the course of cholesterol gallstone formation.
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Colesterol/metabolismo , Cálculos Biliares/sangre , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Estudios de Casos y Controles , Regulación hacia Abajo/efectos de los fármacos , Femenino , Glucolípidos/metabolismo , Humanos , Hipoglucemiantes/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Lipoproteínas HDL/sangre , Lipoproteínas LDL , Hígado/metabolismo , Masculino , Síndrome Metabólico/sangre , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Pioglitazona , Proteínas Plasmáticas de Unión al Retinol/genética , Estudios Retrospectivos , Factores de Riesgo , Espectroscopía Infrarroja por Transformada de Fourier , Tiazolidinedionas/farmacología , Adulto JovenRESUMEN
OBJECTIVE: Since circRNA can be utilized as a potential diagnostic marker for cancer, to explore the regulatory mechanism of colorectal cancer (CRC) using bioinformatics, the public database of circRNA was mined. METHODS: CRC differentially expressed miRNAs were screened in the Cancer Genome Atlas (TCGA) database, CRC differentially expressed circRNAs were searched in the Gene Expression Omnibus (GEO) database, the two databases were combined to identify CRC differentially expressed mRNAs, and a circRNA-miRNAâmRNA regulatory network was constructed by combining a plurality of target prediction databases to identify key genes. The upstream circRNA and regulatory axis of the key genes were identified for gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis to explore the biological functions of circRNA in CRC using the regulatory axis. RESULTS: After the screening of the GSE21815 dataset, a total of 22 differentially expressed circRNAs were obtained, with 12 upregulated and 10 downregulated genes. Similarly, the GSE126094 dataset yielded 104 differentially expressed circRNAs, comprising 56 upregulated and 48 downregulated genes. Among the differentially expressed circRNAs, five were identified, with VDAC3 and SETD2 showing downregulated expression, while RAD23B, RPPH1, and MYBL2 exhibited upregulated expression. Following the selection process, five DEcircRNAs, eight target miRNAs, and 105 target DEmRNAs were identified. The protein-protein interaction (PPI) network revealed close relationships among the mRNAs, with E2F2, E2F3, CCND1, TNRC6A, and KAT2B identified as key genes. Notably, CCND1 emerged as a critical gene in the PPI network. Through the upregulation of has-circ-0087862, which binds to miR-892b, the translation inhibition of CCND1 by miR-892b was attenuated, leading to enhanced CCND1 expression. Functional enrichment analysis indicated that CCND1 was involved in protein binding and positive regulation of cellular processes, among other functions. CONCLUSION: The differentially expressed genes (DEGs) in CRC markedly affected the survival time of patients. CircRNAs could be utilized as diagnostic markers of CRC, and the key genes in CRC could be screened out by bioinformatics, which would be helpful to understand the drug targets for the treatment of human immunodeficiency virus (HIV)-related CRC patients.
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Neoplasias Colorrectales , MicroARNs , Humanos , ARN Circular/genética , Redes Reguladoras de Genes , Detección Precoz del Cáncer , MicroARNs/genética , ARN Mensajero/genética , Biología Computacional , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismoRESUMEN
Background: Cancer risk is influenced by calcium signaling in intracellular and intercellular signaling pathways. However, the relationship between the calcium signaling pathway and colorectal cancer risk remains unknown. We aim to evaluate the role of genetic variants in calcium signaling pathway genes in colorectal cancer risk through the tumor microenvironment. Methods: An analysis of genetic variants in the calcium signaling pathway was conducted using a case-control study that included 1150 colorectal cancer patients and 1342 non-cancer patients. Using the regression model, we assessed whether single-nucleotide polymorphisms (SNPs) increase the risk of colorectal cancer. We also performed a dual luciferase reporter gene assay using HCT116 cell lines and DLD1 cell lines to demonstrate the regulatory relationship between SNP and candidate risk gene. We evaluated the expression of candidate risk gene in different populations. In addition, we also evaluated candidate risk gene and 22 immune cells correlation studies. Results: There was a significant association between the PDE1C rs12538364 T allele and colorectal cancer risk [odds ratio (OR) = 1.57, 95% confidence interval (CI) = 1.30 - 1.90, P = 3.07 × 10-6, P FDR = 0.004]. Mutation of intron region rs1538364 C to T locus reduces promoter activity of PDE1C in DLD1 and HCT116 cell lines (P < 0.05). We identified that PDE1C is significantly down-regulated in colorectal cancer, closely associated with 22 immune cells. Finally, we found that PDE1C could be the biomarker for individual immunotherapy of colorectal cancer. Conclusion: According to our findings, PDE1C may be a key factor contributing to colorectal cancer, thus improving individual immunotherapy for the disease. The potential mechanism by which polymorphisms in the calcium signaling pathway genes may participate in the pathogenesis of colorectal cancer through the tumor microenvironment.