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1.
Support Care Cancer ; 32(7): 418, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38849604

RESUMEN

PURPOSE: Patients with cancer often experience nutritional challenges and are vulnerable to muscle mass loss. While substantial research is directed towards understanding how nutritional interventions affect clinical outcomes, insights into patients' personal experiences during these trials remain limited. This qualitative study aimed to gain a deeper understanding of how participation in the Protein Recommendations to Increase Muscle (PRIMe) trial affected patients' relationships with food. METHODS: A subset of patients who completed a minimum of one follow-up visit in the PRIMe trial participated in a semi-structured interview about their experience implementing dietary modifications to increase protein intake. Data from 26 patients with a recent diagnosis of stage II-IV colorectal cancer (non-cachectic) were included. Interviews were audio recorded, transcribed verbatim, and qualitative content analysis was applied. RESULTS: Most patients were male (65.4%) with stage II or III (69.2%) colorectal cancer and were a mean age of 57 ± 10 years. Five key themes emerged to provide a deeper understanding of patients' relationship with food after the PRIMe trial: (1) new positive perspectives on nutrition and coping with a cancer diagnosis; (2) embracing a comprehensive approach to food and nutrition; (3) facilitators promoting adherence to the intervention; (4) barriers challenging adherence to the intervention; and (5) shaping future dietary intake. CONCLUSION: This qualitative study explored the emotional and psychological effects of a clinical nutrition trial on patients, focusing on their relationship with food. It underscored the trial's comprehensive intervention and its enduring influence on patients, extending beyond the immediate intervention phase. The role of current perspectives, motivation, and knowledge acquisition on ability to adhere to dietary changes to increase protein intake were emphasized by patients and are key considerations for both clinicians and researchers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02788955; registration posted on 2016-06-02.


Asunto(s)
Neoplasias Colorrectales , Proteínas en la Dieta , Investigación Cualitativa , Humanos , Neoplasias Colorrectales/dietoterapia , Neoplasias Colorrectales/psicología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Proteínas en la Dieta/administración & dosificación , Adaptación Psicológica , Adulto
2.
PeerJ ; 12: e17559, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38854798

RESUMEN

Background: To investigate the effects of arsenic trioxide (ATO) on human colorectal cancer cells (HCT116) growth and the role of transient receptor potential melastatin 4 (TRPM4) channel in this process. Methods: The viability of HCT116 cells was assessed using the CCK-8 assay. Western blot analysis was employed to examine the protein expression of TRPM4. The apoptosis of HCT116 cells was determined using TUNEL and Flow cytometry. Cell migration was assessed through the cell scratch recovery assay and Transwell cell migration assay. Additionally, Transwell cell invasion assay was performed to determine the invasion ability of HCT116 cells. Results: ATO suppressed the viability of HCT116 cells in a dose-dependent manner, accompanied by a decline in cell migration and invasion, and an increase in apoptosis. 9-phenanthroline (9-Ph), a specific inhibitor of TRPM4, abrogated the ATO-induced upregulation of TRPM4 expression. Additionally, blocking TRPM4 reversed the effects of ATO on HCT116 cells proliferation, including restoration of cell viability, migration and invasion, as well as the inhibition of apoptosis. Conclusion: ATO inhibits CRC cell growth by inducing TRPM4 expression, our findings indicate that ATO is a promising therapeutic strategy and TRPM4 may be a novel target for the treatment of CRC.


Asunto(s)
Apoptosis , Trióxido de Arsénico , Movimiento Celular , Proliferación Celular , Supervivencia Celular , Neoplasias Colorrectales , Canales Catiónicos TRPM , Humanos , Canales Catiónicos TRPM/metabolismo , Canales Catiónicos TRPM/antagonistas & inhibidores , Canales Catiónicos TRPM/genética , Trióxido de Arsénico/farmacología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Células HCT116 , Movimiento Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Óxidos/farmacología , Antineoplásicos/farmacología , Invasividad Neoplásica , Arsenicales/farmacología
3.
World J Gastroenterol ; 30(20): 2726-2730, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38855153

RESUMEN

The screening of colorectal cancer (CRC) is pivotal for both the prevention and treatment of this disease, significantly improving early-stage tumor detection rates. This advancement not only boosts survival rates and quality of life for patients but also reduces the costs associated with treatment. However, the adoption of CRC screening methods faces numerous challenges, including the technical limitations of both noninvasive and invasive methods in terms of sensitivity and specificity. Moreover, socioeconomic factors such as regional disparities, economic conditions, and varying levels of awareness affect screening uptake. The coronavirus disease 2019 pandemic further intensified these cha-llenges, leading to reduced screening participation and increased waiting periods. Additionally, the growing prevalence of early-onset CRC necessitates innovative screening approaches. In response, research into new methodologies, including artificial intelligence-based systems, aims to improve the precision and accessibility of screening. Proactive measures by governments and health organizations to enhance CRC screening efforts are underway, including increased advocacy, improved service delivery, and international cooperation. The role of technological innovation and global health collaboration in advancing CRC screening is undeniable. Technologies such as artificial intelligence and gene sequencing are set to revolutionize CRC screening, making a significant impact on the fight against this disease. Given the rise in early-onset CRC, it is crucial for screening strategies to continually evolve, ensuring their effectiveness and applicability.


Asunto(s)
COVID-19 , Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Detección Precoz del Cáncer/métodos , COVID-19/diagnóstico , COVID-19/epidemiología , Inteligencia Artificial , Tamizaje Masivo/métodos , Tamizaje Masivo/organización & administración , SARS-CoV-2/aislamiento & purificación , Calidad de Vida , Colonoscopía
4.
Theranostics ; 14(8): 3317-3338, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38855188

RESUMEN

Metastasis is one of the key factors of treatment failure in late-stage colorectal cancer (CRC). Metastatic CRC frequently develops resistance to chemotherapeutic agents. This study aimed to identify the novel regulators from "hidden" proteins encoded by long noncoding RNAs (lncRNAs) involved in tumor metastasis and chemoresistance. Methods: CRISPR/Cas9 library functional screening was employed to identify the critical suppressor of cancer metastasis in highly invasive CRC models. Western blotting, immunofluorescence staining, invasion, migration, wound healing, WST-1, colony formation, gain- and loss-of-function experiments, in vivo experimental metastasis models, multiplex immunohistochemical staining, immunohistochemistry, qRT-PCR, and RT-PCR were used to assess the functional and clinical significance of FOXP3, PRDM16-DT, HNRNPA2B1, and L-CHEK2. RNA-sequencing, co-immunoprecipitation, qRT-PCR, RT-PCR, RNA affinity purification, RNA immunoprecipitation, MeRIP-quantitative PCR, fluorescence in situ hybridization, chromatin immunoprecipitation and luciferase reporter assay were performed to gain mechanistic insights into the role of PRDM16-DT in cancer metastasis and chemoresistance. An oxaliplatin-resistant CRC cell line was established by in vivo selection. WST-1, colony formation, invasion, migration, Biacore technology, gain- and loss-of-function experiments and an in vivo experimental metastasis model were used to determine the function and mechanism of cimicifugoside H-1 in CRC. Results: The novel protein PRDM16-DT, encoded by LINC00982, was identified as a cancer metastasis and chemoresistance suppressor. The down-regulated level of PRDM16-DT was positively associated with malignant phenotypes and poor prognosis of CRC patients. Transcriptionally regulated by FOXP3, PRDM16-DT directly interacted with HNRNPA2B1 and competitively decreased HNRNPA2B1 binding to exon 9 of CHEK2, resulting in the formation of long CHEK2 (L-CHEK2), subsequently promoting E-cadherin secretion. PRDM16-DT-induced E-cadherin secretion inhibited fibroblast activation, which in turn suppressed CRC metastasis by decreasing MMP9 secretion. Cimicifugoside H-1, a natural compound, can bind to LEU89, HIS91, and LEU92 of FOXP3 and significantly upregulated PRDM16-DT expression to repress CRC metastasis and reverse oxaliplatin resistance. Conclusions: lncRNA LINC00982 can express a new protein PRDM16-DT to function as a novel regulator in cancer metastasis and drug resistance of CRC. Cimicifugoside H-1 can act on the upstream of the PRDM16-DT signaling pathway to alleviate cancer chemoresistance.


Asunto(s)
Neoplasias Colorrectales , Proteínas de Unión al ADN , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia , ARN Largo no Codificante , Factores de Transcripción , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Humanos , Resistencia a Antineoplásicos/genética , Animales , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Ratones , Línea Celular Tumoral , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Oxaliplatino/farmacología , Oxaliplatino/uso terapéutico , Empalme del ARN/genética , Movimiento Celular/efectos de los fármacos , Ratones Desnudos , Ratones Endogámicos BALB C
5.
Genome Med ; 16(1): 81, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38872215

RESUMEN

BACKGROUND: Early detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population. METHODS: To develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants. RESULTS: Three trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose-response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32). CONCLUSIONS: Our comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity.


Asunto(s)
Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Medición de Riesgo , Polimorfismo de Nucleótido Simple , Teorema de Bayes , Factores de Riesgo
6.
J Transl Med ; 22(1): 544, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38844980

RESUMEN

BACKGROUND: Several studies have demonstrated a strong correlation between impaired Succinate dehydrogenase (SDH) function and the advancement of tumors. As a subunit of SDH, succinate dehydrogenase complex subunit C (SDHC) has been revealed to play tumor suppressive roles in several cancers, while its specific role in colorectal cancer (CRC) still needs further investigation. METHODS: Online database were utilized to investigate the expression of SDHC in colorectal cancer and to assess its correlation with patient prognosis. Cell metastasis was assessed using transwell and wound healing assays, while tumor metastasis was studied in a nude mice model in vivo. Drug screening and RNA sequencing were carried out to reveal the tumor suppressor mechanism of SDHC. Triglycerides, neutral lipids and fatty acid oxidation were measured using the Triglyceride Assay Kit, BODIPY 493/503 and Colorimetric Fatty Acid Oxidation Rate Assay Kit, respectively. The expression levels of enzymes involved in fatty acid metabolism and the PI3K/AKT signaling pathway were determined by quantitative real-time PCR and western blot. RESULTS: Downregulation of SDHC was found to be closely associated with a poor prognosis in CRC. SDHC knockdown promoted CRC metastasis both in vitro and in vivo. Through drug screening and Gene set enrichment analysis, it was discovered that SDHC downregulation was positively associated with the fatty acid metabolism pathways significantly. The effects of SDHC silencing on metastasis were reversed when fatty acid synthesis was blocked. Subsequent experiments revealed that SDHC silencing activated the PI3K/AKT signaling axis, leading to lipid accumulation by upregulating the expression of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) and reduction of fatty acid oxidation rate by suppressing the expression of acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1A (CPT1A). CONCLUSIONS: SDHC deficiency could potentially enhance CRC metastasis by modulating the PI3K/AKT pathways and reprogramming lipid metabolism.


Asunto(s)
Neoplasias Colorrectales , Ácidos Grasos , Ratones Desnudos , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas c-akt , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Humanos , Ácidos Grasos/metabolismo , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Fosfatidilinositol 3-Quinasas/metabolismo , Pronóstico , Transducción de Señal , Masculino , Femenino , Regulación hacia Abajo/genética , Técnicas de Silenciamiento del Gen , Ratones , Metabolismo de los Lípidos/genética , Ratones Endogámicos BALB C
7.
Cancer Med ; 13(11): e7330, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38845478

RESUMEN

OBJECTIVES: Patients with advanced colorectal cancer (CRC) have multiple concurrent physical and psychological symptoms. This study aimed to explore the relationship between anxiety, depression, and symptom burden in advanced CRC. METHODS: A multicenter cross-sectional study was conducted in 10 cancer centers from geographically and economically diverse sites in China. A total of 454 patients with advanced CRC completed the Hospital Anxiety and Depression Scale and the MD Anderson Symptom Inventory. Multiple regression analysis was applied to explore the relationship between anxiety, depression and symptom burden. RESULTS: About one-third of the patients showed symptoms of anxiety or depression. Patients with anxiety or depression reported significantly higher symptom burden than those without (p < 0.001). Patients with anxiety or depression reported a higher proportion of moderate-to-severe (MS) symptom number than those without (p < 0.001). About 52% of the patients with anxiety or depression reported at least three MS symptoms. The prevalence of MS symptoms was ranging from 7.3% (shortness of breath) to 22% (disturbed sleep), and in patients with anxiety or depression was 2-10 times higher than in those without (p < 0.001). Disease stage (ß = -2.55, p = 0.003), anxiety (ß = 15.33, p < 0.001), and depression (ß = 13.63, p < 0.001) were associated with higher symptom burden. CONCLUSIONS: Anxiety and depression in patients with advanced cancer correlated with higher symptom burden. Findings may lead oncology professionals to pay more attention to unrecognized and untreated psychological symptoms in symptom management for advanced cancer patients.


Asunto(s)
Ansiedad , Neoplasias Colorrectales , Depresión , Humanos , Neoplasias Colorrectales/psicología , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/complicaciones , Masculino , Femenino , Estudios Transversales , Persona de Mediana Edad , Depresión/epidemiología , Depresión/etiología , Depresión/psicología , Ansiedad/epidemiología , Ansiedad/psicología , Anciano , China/epidemiología , Prevalencia , Adulto , Anciano de 80 o más Años , Calidad de Vida , Carga Sintomática
8.
Nat Commun ; 15(1): 4771, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38839755

RESUMEN

Cancer patients often undergo rounds of trial-and-error to find the most effective treatment because there is no test in the clinical practice for predicting therapy response. Here, we conduct a clinical study to validate the zebrafish patient-derived xenograft model (zAvatar) as a fast predictive platform for personalized treatment in colorectal cancer. zAvatars are generated with patient tumor cells, treated exactly with the same therapy as their corresponding patient and analyzed at single-cell resolution. By individually comparing the clinical responses of 55 patients with their zAvatar-test, we develop a decision tree model integrating tumor stage, zAvatar-apoptosis, and zAvatar-metastatic potential. This model accurately forecasts patient progression with 91% accuracy. Importantly, patients with a sensitive zAvatar-test exhibit longer progression-free survival compared to those with a resistant test. We propose the zAvatar-test as a rapid approach to guide clinical decisions, optimizing treatment options and improving the survival of cancer patients.


Asunto(s)
Neoplasias Colorrectales , Pez Cebra , Animales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Humanos , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Medicina de Precisión/métodos , Masculino , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Supervivencia sin Progresión , Modelos Animales de Enfermedad , Avatar
9.
BMC Cancer ; 24(1): 683, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38840078

RESUMEN

BACKGROUND: MicroRNAs (miRNAs) emerge in various organisms, ranging from viruses to humans, and play crucial regulatory roles within cells, participating in a variety of biological processes. In numerous prediction methods for miRNA-disease associations, the issue of over-dependence on both similarity measurement data and the association matrix still hasn't been improved. In this paper, a miRNA-Disease association prediction model (called TP-MDA) based on tree path global feature extraction and fully connected artificial neural network (FANN) with multi-head self-attention mechanism is proposed. The TP-MDA model utilizes an association tree structure to represent the data relationships, multi-head self-attention mechanism for extracting feature vectors, and fully connected artificial neural network with 5-fold cross-validation for model training. RESULTS: The experimental results indicate that the TP-MDA model outperforms the other comparative models, AUC is 0.9714. In the case studies of miRNAs associated with colorectal cancer and lung cancer, among the top 15 miRNAs predicted by the model, 12 in colorectal cancer and 15 in lung cancer were validated respectively, the accuracy is as high as 0.9227. CONCLUSIONS: The model proposed in this paper can accurately predict the miRNA-disease association, and can serve as a valuable reference for data mining and association prediction in the fields of life sciences, biology, and disease genetics, among others.


Asunto(s)
MicroARNs , Redes Neurales de la Computación , Humanos , MicroARNs/genética , Predisposición Genética a la Enfermedad , Biología Computacional/métodos , Neoplasias Colorrectales/genética , Neoplasias Pulmonares/genética , Algoritmos
10.
Genome Med ; 16(1): 77, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38840170

RESUMEN

BACKGROUND: Colorectal cancer (CRC) arises from complex interactions between host and environment, which include the gut and tissue microbiome. It is hypothesized that epigenetic regulation by gut microbiota is a fundamental interface by which commensal microbes dynamically influence intestinal biology. The aim of this study is to explore the interplay between gut and tissue microbiota and host DNA methylation in CRC. METHODS: Metagenomic sequencing of fecal samples was performed on matched CRC patients (n = 18) and healthy controls (n = 18). Additionally, tissue microbiome was profiled with 16S rRNA gene sequencing on tumor (n = 24) and tumor-adjacent normal (n = 24) tissues of CRC patients, while host DNA methylation was assessed through whole-genome bisulfite sequencing (WGBS) in a subset of 13 individuals. RESULTS: Our analysis revealed substantial alterations in the DNA methylome of CRC tissues compared to adjacent normal tissues. An extensive meta-analysis, incorporating publicly available and in-house data, identified significant shifts in microbial-derived methyl donor-related pathways between tumor and adjacent normal tissues. Of note, we observed a pronounced enrichment of microbial-associated CpGs within the promoter regions of genes in adjacent normal tissues, a phenomenon notably absent in tumor tissues. Furthermore, we established consistent and recurring associations between methylation patterns of tumor-related genes and specific bacterial taxa. CONCLUSIONS: This study emphasizes the pivotal role of the gut microbiota and pathogenic bacteria in dynamically shaping DNA methylation patterns, impacting physiological homeostasis, and contributing to CRC tumorigenesis. These findings provide valuable insights into the intricate host-environment interactions in CRC development and offer potential avenues for therapeutic interventions in this disease.


Asunto(s)
Neoplasias Colorrectales , Metilación de ADN , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/microbiología , Microbioma Gastrointestinal/genética , Femenino , Masculino , Persona de Mediana Edad , Epigénesis Genética , Anciano , Islas de CpG , Metagenómica/métodos , Metagenoma , Microbiota/genética , Heces/microbiología , ARN Ribosómico 16S/genética
11.
Mol Biomed ; 5(1): 21, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38844562

RESUMEN

Colorectal carcinoma (CRC) stands as a pressing global health issue, marked by the unbridled proliferation of immature cells influenced by multifaceted internal and external factors. Numerous studies have explored the intricate mechanisms of tumorigenesis in CRC, with a primary emphasis on signaling pathways, particularly those associated with growth factors and chemokines. However, the sheer diversity of molecular targets introduces complexity into the selection of targeted therapies, posing a significant challenge in achieving treatment precision. The quest for an effective CRC treatment is further complicated by the absence of pathological insights into the mutations or alterations occurring in tumor cells. This study reveals the transfer of signaling from the cell membrane to the nucleus, unveiling recent advancements in this crucial cellular process. By shedding light on this novel dimension, the research enhances our understanding of the molecular intricacies underlying CRC, providing a potential avenue for breakthroughs in targeted therapeutic strategies. In addition, the study comprehensively outlines the potential immune responses incited by the aberrant activation of signaling pathways, with a specific focus on immune cells, cytokines, and their collective impact on the dynamic landscape of drug development. This research not only contributes significantly to advancing CRC treatment and molecular medicine but also lays the groundwork for future breakthroughs and clinical trials, fostering optimism for improved outcomes and refined approaches in combating colorectal carcinoma.


Asunto(s)
Neoplasias Colorrectales , Terapia Molecular Dirigida , Transducción de Señal , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/inmunología , Humanos , Transducción de Señal/efectos de los fármacos , Terapia Molecular Dirigida/métodos , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología
12.
Oncol Res ; 32(6): 1047-1061, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38827317

RESUMEN

Background: Colorectal cancer (CRC) is one of the most frequently diagnosed cancers. In many cases, the poor prognosis of advanced CRC is associated with resistance to treatment with chemotherapeutic drugs such as 5-Fluorouracil (5-FU). The epithelial-to-mesenchymal transition (EMT) and dysregulation in protein methylation are two mechanisms associated with chemoresistance in many cancers. This study looked into the effect of 5-FU dose escalation on EMT and protein methylation in CRC. Materials and Methods: HCT-116, Caco-2, and DLD-1 CRC cell lines were exposed to dose escalation treatment of 5-FU. The motility and invasive potentials of the cells before and after treatment with 5-FU were investigated through wound healing and invasion assays. This was followed by a Western blot which analyzed the protein expressions of the epithelial marker E-cadherin, mesenchymal marker vimentin, and the EMT transcription factor (EMT-TF), the snail family transcriptional repressor 1 (Snail) in the parental and desensitized cells. Western blotting was also conducted to study the protein expressions of the protein methyltransferases (PMTs), Euchromatic histone lysine methyltransferase 2 (EHMT2/G9A), protein arginine methyltransferase (PRMT5), and SET domain containing 7/9 (SETD7/9) along with the global lysine and arginine methylation profiles. Results: The dose escalation method generated 5-FU desensitized CRC cells with distinct morphological features and increased tolerance to high doses of 5-FU. The 5-FU desensitized cells experienced a decrease in migration and invasion when compared to the parental cells. This was reflected in the observed reduction in E-cadherin, vimentin, and Snail in the desensitized cell lines. Additionally, the protein expressions of EHMT2/G9A, PRMT5, and SETD7/9 also decreased in the desensitized cells and global protein lysine and arginine methylation became dysregulated with 5-FU treatment. Conclusion: This study showed that continuous, dose-escalation treatment of 5-FU in CRC cells generated 5-FU desensitized cancer cells that seemed to be less aggressive than parental cells.


Asunto(s)
Movimiento Celular , Neoplasias Colorrectales , Transición Epitelial-Mesenquimal , Fluorouracilo , Humanos , Fluorouracilo/farmacología , Fluorouracilo/administración & dosificación , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Antimetabolitos Antineoplásicos/farmacología , Resistencia a Antineoplásicos , Relación Dosis-Respuesta a Droga , Metiltransferasas/metabolismo , Metiltransferasas/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Metilación , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/genética
13.
Am J Gastroenterol ; 119(6): 1056-1065, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38832708

RESUMEN

INTRODUCTION: Ultra-processed food (UPF) intake has been associated with a higher risk of obesity, hypertension, type 2 diabetes, and cardiovascular diseases. The initial data on the relationship between UPF consumption and cancer risk were derived from retrospective observational studies with conflicting results. This systematic review and meta-analysis of prospective cohort studies aimed to investigate the association between UPF consumption and gastrointestinal cancer risk. METHODS: PubMed, Embase, and Cochrane databases were searched for prospective cohort studies that compared the highest vs the lowest level of UPF consumption according to NOVA food classification and reported the risk of gastrointestinal cancers by subsite. The association with cancer was quantified as hazard ratios (HR) using a random-effects model. RESULTS: Five prospective cohort studies were included in this review comprising 1,128,243 participants (241,201 participants in the highest and 223,366 in the lowest levels of UPF consumption). The mean follow-up ranged from 5.4 to 28 years. The highest UPF consumption was significantly associated with an increased risk of colorectal cancer (HR 1.11; 95% confidence interval [CI] 1.03-1.21; P = 0.01; I2 = 31%), colon cancer (HR 1.12; 95% CI 1.02-1.23; P = 0.02; I2 = 0%), and non-cardia gastric cancer (HR 1.43; 95% CI 1.02-2.00; P = 0.04; I2 = 0%) compared with the lowest UPF intake. However, no association was found between high UPF consumption and hepatocellular, esophageal, pancreatic, gastric cardia, and rectal cancer. DISCUSSION: The highest level of UPF consumption was significantly associated with colorectal and non-cardia gastric cancer.


Asunto(s)
Comida Rápida , Neoplasias Gastrointestinales , Humanos , Neoplasias Gastrointestinales/epidemiología , Neoplasias Gastrointestinales/etiología , Comida Rápida/efectos adversos , Factores de Riesgo , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/etiología , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/etiología , Alimentos Procesados
14.
Cancer Rep (Hoboken) ; 7(6): e2085, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38837682

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is the second most common cause of cancer-related death worldwide. Long noncoding RNA (lncRNA) is involved in many malignant tumors. This study aimed to clarify the role of the lncRNA plasmacytoma variant translocation 1 (PVT1) in CRC growth and metastasis. METHODS: Differentially expressed lncRNAs in CRC were analyzed using the Cancer Genome Atlas. Gene expression profiling interactive analysis and a comprehensive resource for lncRNAs from cancer arrays databases were used to analyze lncRNA PVT1 expression and CRC prognosis, respectively. Cell counting kit-8, wound healing, colony formation, Transwell, and immunofluorescence assays were used to evaluate CRC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), respectively. Tumor growth and metastasis models were used to explore the PVT1 effect on the growth and metastasis of CRC in vivo. RESULTS: PVT1 was highly expressed in CRC, associated with a poor prognosis of CRC, and showed good diagnostic value. Transfection of sh-PVT1 or pcDNA3.1-PVT1 reduced or increased the proliferation, wound healing rate, colony formation, invasion, and EMT of CRC cells. PVT1 and miR-3619-5p were co-expressed in CRC cytoplasm, and PVT1 acted as a competitive endogenous RNA (ceRNA) by sponging miR-3619-5p to up-regulate tripartite motif containing 29 (TRIM29) expression. MiR-3619-5p overexpression and TRIM29 knockdown reduced proliferation, wound healing rate, invasion, and EMT of CRC cells. However, simultaneous PVT1 and miR-3619-5p overexpression or knockdown of miR-3619-5p and TRIM29 knockdown rescued the malignant phenotype of CRC cells. CONCLUSIONS: We first clarified the ceRNA mechanism of PVT1 in CRC, which induced growth and metastasis by sponging with miR-3619-5p to regulate TRIM29.


Asunto(s)
Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , MicroARNs , ARN Largo no Codificante , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , ARN Largo no Codificante/genética , MicroARNs/genética , Proliferación Celular/genética , Ratones , Animales , Pronóstico , Transición Epitelial-Mesenquimal/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Masculino , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Ratones Desnudos , Femenino , Línea Celular Tumoral , Metástasis de la Neoplasia , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Front Public Health ; 12: 1370282, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38841678

RESUMEN

Introduction: The burden of colorectal cancer (CRC) plays a pivotal role in the global cancer epidemic. Our study reported the incidence trends in CRC and the associated effects of age, period, and birth cohort in 204 countries and territories over the past 30 years. Methods: The incidence data of CRC were extracted from the Global Burden of Disease Study (GBD) 2019. We performed the age-period-cohort (APC) model to estimate the overall annual percentage change (net drift) in the incidence rate, the annual percentage change by age group (local drift), and the relative risk (period and cohort effects) of the period and cohort in CRC during 1990-2019. This approach allows examining and distinguishing age, period, and cohort effects in incidence and potentially distinguishing colorectal cancer gaps in prevention and screening. Results: In 2019, the incidence of CRC was 2.17 (95% UI 2.00-2.34) million, of which China, the United States of America, and Japan had the highest incidence population, accounting for 45.9% of the global population. The age-standardized incidence rate (ASIR) was 26.7 (95% UI 28.9-24.6) per 100,000 people, of which 30 countries had an incidence rate greater than 40.0 per 100,000 people. From 1990 to 2019, the middle SDI region had the largest increase in incidence rate, with a net drift of 2.33% (95% CI 2.2-2.46%, p < 0.001). Globally, the incidence population was concentrated in the age group of 50-69 years, and the age group of 30-34 years had the largest increase in incidence rate (local drift 1.19% (95% CI 1.01-1.37%)). At the same time, the sex and age distributions of CRC incidence had significant heterogeneity across regions and countries. In the past 30 years, the incidence rate in 31 countries has been well controlled (net drift <0), and most of them were concentrated in high-and high-middle-SDI regions, such as Australia, Czechia, and Belgium, and the relative risk of incidence generally improved over time and consecutive young birth cohorts. CRC incidence showed an unfavorable trend (net drift ≥1%) in 89 countries, of which 27 countries were more significant (net drift >2%), mostly concentrated in the middle SDI region, such as China, Mexico, and Brazil, and the risk of period and birth cohort was unfavorable. Conclusion: Globally, the incidence of CRC has shown an overall upward trend over the past 30 years, with the exception of some countries with higher SDI values. Significant age-period-cohort differences were observed in the risk of incidence in CRC worldwide. Effective prevention and control policies need to take into account the age-period-cohort effect characteristics of different regions.


Asunto(s)
Neoplasias Colorrectales , Carga Global de Enfermedades , Humanos , Neoplasias Colorrectales/epidemiología , Incidencia , Persona de Mediana Edad , Masculino , Anciano , Femenino , Adulto , Estudios de Cohortes , Salud Global/estadística & datos numéricos , Anciano de 80 o más Años , Factores de Edad , Adulto Joven
16.
J Environ Sci (China) ; 145: 1-12, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38844310

RESUMEN

The potential association between colorectal cancer (CRC) and environmental pollutants is worrisome. Previous studies have found that some perfluoroalkyl acids, including perfluorooctane sulfonate (PFOS), induced colorectal tumors in experimental animals and promoted the migration of and invasion by CRC cells in vitro, but the underlying mechanism is unclear. Here, we investigated the effects of PFOS on the proliferation and migration of CRC cells and the potential mechanisms involving activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition (EMT). It was found that PFOS promoted the growth and migration of HCT116 cells at non-cytotoxic concentrations and increased the mRNA expression of the migration-related angiogenic cytokines vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In a mechanistic investigation, the up-stream signal pathway PI3K/Akt-NF-κB was activated by PFOS, and the process was suppressed by LY294002 (PI3K/Akt inhibitor) and BAY11-7082 (NF-κB inhibitor) respectively, leading to less proliferation of HCT116 cells. Furthermore, matrix metalloproteinases (MMP) and EMT-related markers were up-regulated after PFOS exposure, and were also suppressed respectively by LY294002 and BAY11-7082. Moreover, the up-regulation of EMT markers was suppressed by a MMP inhibitor GM6001. Taken together, our results indicated that PFOS promotes colorectal cancer cell migration and proliferation by activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition. This could be a potential toxicological mechanism of PFOS-induced malignant development of colorectal cancer.


Asunto(s)
Ácidos Alcanesulfónicos , Movimiento Celular , Neoplasias Colorrectales , Transición Epitelial-Mesenquimal , Fluorocarburos , Fluorocarburos/toxicidad , Ácidos Alcanesulfónicos/toxicidad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Colorrectales/patología , Humanos , Movimiento Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Contaminantes Ambientales/toxicidad , Células HCT116 , Proteínas Proto-Oncogénicas c-akt/metabolismo , FN-kappa B/metabolismo , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral
17.
BMC Cancer ; 24(1): 674, 2024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38825703

RESUMEN

Colorectal cancer is the leading cause of cancer death worldwide. The first and second lines of treatment for metastatic colorectal cancer (mCRC) include chemotherapy based on 5-fluorouracil. However, treatment following progression on the first and second line is still unclear. We searched PubMed, Scopus, Cochrane, and Web of Science databases for studies investigating the use of trifluridine-tipiracil with bevacizumab versus trifluridine-tipiracil alone for mCRC. We used RStudio version 4.2.3; and we considered p < 0.05 significant. Seven studies and 1,182 patients were included - 602 (51%) received trifluridine-tipiracil plus bevacizumab. Compared with control, the progression-free survival (PFS) (HR 0.52; 95% CI 0.42-0.63; p < 0.001) and overall survival (OS) (HR 0.61; 95% CI 0.52-0.70; p < 0.001) were significantly higher with bevacizumab. The objective response rate (ORR) (RR 3.14; 95% CI 1.51-6.51; p = 0.002) and disease control rate (DCR) (RR 1.66; 95% CI 1.28-2.16; p = 0.0001) favored the intervention. Regarding adverse events, the intervention had a higher rate of neutropenia (RR 1.38; 95% CI 1.19-1.59; p = 0.00001), whereas the monotherapy group had a higher risk of anemia (RR 0.60; 95% CI 0.44-0.82; p = 0.001). Our results support that the addition of bevacizumab is associated with a significant benefit in PFS, OS, ORR and DCR.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Neoplasias Colorrectales , Combinación de Medicamentos , Pirrolidinas , Timina , Trifluridina , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Bevacizumab/uso terapéutico , Bevacizumab/administración & dosificación , Trifluridina/uso terapéutico , Trifluridina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Pirrolidinas/uso terapéutico , Pirrolidinas/administración & dosificación , Metástasis de la Neoplasia , Supervivencia sin Progresión , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Uracilo/administración & dosificación , Resistencia a Antineoplásicos
18.
J Health Care Poor Underserved ; 35(2): 425-438, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38828574

RESUMEN

OBJECTIVE: There are significant inequities in colorectal cancer (CRC) screening and outcomes. Via literature review, we assessed CRC screening rates for the vulnerable populations served by free clinics. METHODS: A systematic review was conducted for publications on CRC screening in free clinics. Outcomes included CRC screening characteristics, population demographics, and limitations. A methodological quality assessment was completed. RESULTS: Out of 63 references, six studies were included, representing 8,844 participants. Black or Hispanic participants were the plurality in all but one study. All participants were uninsured. Median CRC screening rate was 48.4% (range 6.6-78.9%). Screening methods included colonoscopy, fecal occult blood test, flexible sigmoidoscopy, and fecal immunochemical test. Clinics offering only one screening method had a mean screening rate of 7.2% while those with multiple methods had a screening rate of 65.4%. CONCLUSION: Access to multiple CRC screening modalities correlates with higher screening rates in free clinics. More work is needed to increase CRC screening in free clinics.


Asunto(s)
Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/estadística & datos numéricos , Pacientes no Asegurados/estadística & datos numéricos , Accesibilidad a los Servicios de Salud , Instituciones de Atención Ambulatoria , Sangre Oculta
19.
Elife ; 122024 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-38829205

RESUMEN

Background: Comorbidity with type 2 diabetes (T2D) results in worsening of cancer-specific and overall prognosis in colorectal cancer (CRC) patients. The treatment of CRC per se may be diabetogenic. We assessed the impact of different types of surgical cancer resections and oncological treatment on risk of T2D development in CRC patients. Methods: We developed a population-based cohort study including all Danish CRC patients, who had undergone CRC surgery between 2001 and 2018. Using nationwide register data, we identified and followed patients from date of surgery and until new onset of T2D, death, or end of follow-up. Results: In total, 46,373 CRC patients were included and divided into six groups according to type of surgical resection: 10,566 Right-No-Chemo (23%), 4645 Right-Chemo (10%), 10,151 Left-No-Chemo (22%), 5257 Left-Chemo (11%), 9618 Rectal-No-Chemo (21%), and 6136 Rectal-Chemo (13%). During 245,466 person-years of follow-up, 2556 patients developed T2D. The incidence rate (IR) of T2D was highest in the Left-Chemo group 11.3 (95% CI: 10.4-12.2) per 1000 person-years and lowest in the Rectal-No-Chemo group 9.6 (95% CI: 8.8-10.4). Between-group unadjusted hazard ratio (HR) of developing T2D was similar and non-significant. In the adjusted analysis, Rectal-No-Chemo was associated with lower T2D risk (HR 0.86 [95% CI 0.75-0.98]) compared to Right-No-Chemo.For all six groups, an increased level of body mass index (BMI) resulted in a nearly twofold increased risk of developing T2D. Conclusions: This study suggests that postoperative T2D screening should be prioritised in CRC survivors with overweight/obesity regardless of type of CRC treatment applied. Funding: The Novo Nordisk Foundation (NNF17SA0031406); TrygFonden (101390; 20045; 125132).


Asunto(s)
Neoplasias Colorrectales , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Dinamarca/epidemiología , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/cirugía , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios de Cohortes , Factores de Riesgo , Incidencia , Anciano de 80 o más Años , Adulto , Sistema de Registros
20.
Proc Natl Acad Sci U S A ; 121(24): e2404668121, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38833473

RESUMEN

Developing anticancer drugs with low side effects is an ongoing challenge. Immunogenic cell death (ICD) has received extensive attention as a potential synergistic modality for cancer immunotherapy. However, only a limited set of drugs or treatment modalities can trigger an ICD response and none of them have cytotoxic selectivity. This provides an incentive to explore strategies that might provide more effective ICD inducers free of adverse side effects. Here, we report a metal-based complex (Cu-1) that disrupts cellular redox homeostasis and effectively stimulates an antitumor immune response with high cytotoxic specificity. Upon entering tumor cells, this Cu(II) complex enhances the production of intracellular radical oxidative species while concurrently depleting glutathione (GSH). As the result of heightening cellular oxidative stress, Cu-1 gives rise to a relatively high cytotoxicity to cancer cells, whereas normal cells with low levels of GSH are relatively unaffected. The present Cu(II) complex initiates a potent ferroptosis-dependent ICD response and effectively inhibits in vivo tumor growth in an animal model (c57BL/6 mice challenged with colorectal cancer). This study presents a strategy to develop metal-based drugs that could synergistically potentiate cytotoxic selectivity and promote apoptosis-independent ICD responses through perturbations in redox homeostasis.


Asunto(s)
Cobre , Glutatión , Homeostasis , Oxidación-Reducción , Animales , Ratones , Humanos , Glutatión/metabolismo , Ratones Endogámicos C57BL , Antineoplásicos/farmacología , Línea Celular Tumoral , Estrés Oxidativo/efectos de los fármacos , Sinergismo Farmacológico , Muerte Celular Inmunogénica/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Ferroptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo
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