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Oxaliplatin resistance poses a significant challenge in colorectal cancer (CRC) therapy, necessitating further investigation into the underlying molecular mechanisms. This study aimed to elucidate the regulatory role of SNHG4 in oxaliplatin resistance and ferroptosis in CRC. Our findings revealed that treatment with oxaliplatin led to downregulation of SNHG4 expression in CRC cells, while resistant CRC cells exhibited higher levels of SNHG4 compared to parental cells. Silencing SNHG4 attenuated oxaliplatin resistance and reduced the expression of resistance-related proteins MRD1 and MPR1. Furthermore, induction of ferroptosis effectively diminished oxaliplatin resistance in both parental and resistant CRC cells. Notably, ferroptosis induction resulted in decreased SNHG4 expression, whereas SNHG4 overexpression suppressed ferroptosis. Through FISH, RIP, and RNA pull-down assays, we identified the cytoplasmic localization of both SNHG4 and PTEN, establishing that SNHG4 directly targets PTEN, thereby reducing mRNA stability in CRC cells. Silencing PTEN abrogated the impact of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells. In vivo experiments further validated the influence of SNHG4 on oxaliplatin resistance and ferroptosis in CRC cells through PTEN regulation. In conclusion, SNHG4 promotes resistance to oxaliplatin in CRC cells by suppressing ferroptosis through instability of PTEN, thus serves as a target for patients with oxaliplatin-base chemoresistance.
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Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Oxaliplatina , PTEN Fosfo-Hidrolase , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Nus , Oxaliplatina/farmacologia , PTEN Fosfo-Hidrolase/metabolismo , PTEN Fosfo-Hidrolase/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , MasculinoRESUMO
BACKGROUND: The role of novel circular RNAs (circRNAs) in colorectal cancer (CRC) remains to be determined. This study aimed to identify a novel circRNA involved in CRC pathogenesis, assess its diagnostic value, and construct a regulatory network. METHODS: Differential expression analysis was conducted using circRNA datasets to screen for differentially expressed circRNAs. The expression of selected circRNAs was validated in external datasets and clinical samples. Diagnostic value of plasma circRNA levels in CRC was assessed. A competing endogenous RNA (ceRNA) network was constructed for the circRNA using TCGA dataset. RESULTS: Analysis of datasets revealed that hsa_circ_101303 was significantly overexpressed in CRC tissues compared to normal tissues. The upregulation of hsa_circ_101303 in CRC tissues was further confirmed through the GSE138589 dataset and clinical samples. High expression of hsa_circ_101303 was associated with advanced N stage, M stage, and tumor stage in CRC. Plasma levels of hsa_circ_101303 were markedly elevated in CRC patients and exhibited moderate diagnostic ability for CRC (AUC = 0.738). The host gene of hsa_circ_101303 was also found to be related to the TNM stage of CRC. Nine miRNAs were identified as target miRNAs for hsa_circ_101303, and 27 genes were identified as targets of these miRNAs. Subsequently, a ceRNA network for hsa_circ_101303 was constructed to illustrate the interactions between the nine miRNAs and 27 genes. CONCLUSIONS: The study identifies hsa_circ_101303 as a highly expressed circRNA in CRC, which is associated with the progression of the disease. Plasma levels of hsa_circ_101303 show promising diagnostic potential for CRC. The ceRNA network for hsa_circ_101303 provides valuable insights into the regulatory mechanisms underlying CRC.
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Biomarcadores Tumorais , Neoplasias Colorretais , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs , RNA Circular , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , RNA Circular/genética , RNA Circular/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Masculino , Feminino , MicroRNAs/genética , MicroRNAs/sangue , Pessoa de Meia-Idade , Perfilação da Expressão Gênica , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Oxaliplatin-based chemotherapy is the first-line treatment for colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) have been implicated in chemotherapy sensitivity. This study aimed to identify lncRNAs related to oxaliplatin sensitivity and predict the prognosis of CRC patients underwent oxaliplatin-based chemotherapy. METHODS: Data from the Genomics of Drug Sensitivity in Cancer (GDSC) was used to screen for lncRNAs related to oxaliplatin sensitivity. Four machine learning algorithms (LASSO, Decision tree, Random-forest, and support vector machine) were applied to identify the key lncRNAs. A predictive model for oxaliplatin sensitivity and a prognostic model based on key lncRNAs were established. The published datasets, and cell experiments were used to verify the predictive value. RESULTS: A total of 805 tumor cell lines from GDSC were divided into oxaliplatin sensitive (top 1/3) and resistant (bottom 1/3) groups based on their IC50 values, and 113 lncRNAs, which were differentially expressed between the two groups, were selected and incorporated into four machine learning algorithms, and seven key lncRNAs were identified. The predictive model exhibited good predictions for oxaliplatin sensitivity. The prognostic model exhibited high performance in patients with CRC who underwent oxaliplatin-based chemotherapies. Four lncRNAs, including C20orf197, UCA1, MIR17HG, and MIR22HG, displayed consistent responses to oxaliplatin treatment in the validation analysis. CONCLUSION: Certain lncRNAs were associated with oxaliplatin sensitivity and predicted the response to oxaliplatin treatment. The prognostic models established based on the key lncRNAs could predict the prognosis of patients given oxaliplatin-based chemotherapy.
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BACKGROUND: The tumor microenvironment (TME) plays a crucial role in tumorigenesis, progression, and therapeutic response in many cancers. This study aimed to comprehensively investigate the role of TME in colorectal cancer (CRC) by generating a TMEscore based on gene expression. METHODS: The TME patterns of CRC datasets were investigated, and the TMEscores were calculated. An unsupervised clustering method was used to divide samples into clusters. The associations between TMEscores and clinical features, prognosis, immune score, gene mutations, and immune checkpoint inhibitors were analyzed. A TME signature was constructed using the TMEscore-related genes. The results were validated using external and clinical cohorts. RESULTS: The TME pattern landscape was for CRC was examined using 960 samples, and then the TMEscore pattern of CRC datasets was evaluated. Two TMEscore clusters were identified, and the high TMEscore cluster was associated with early-stage CRC and better prognosis in patients with CRC when compared with the low TMEscore clusters. The high TMEscore cluster indicated elevated tumor cell scores and tumor gene mutation burden, and decreased tumor purity, when compared with the low TMEscore cluster. Patients with high TMEscore were more likely to respond to immune checkpoint therapy than those with low TMEscore. A TME signature was constructed using the TMEscore-related genes superimposing the results of two machine learning methods (LASSO and XGBoost algorithms), and a TMEscore-related four-gene signature was established, which had a high predictive value for discriminating patients from different TMEscore clusters. The prognostic value of the TMEscore was validated in two independent cohorts, and the expression of TME signature genes was verified in four external cohorts and clinical samples. CONCLUSION: Our study provides a comprehensive description of TME characteristics in CRC and demonstrates that the TMEscore is a reliable prognostic biomarker and predictive indicator for patients with CRC undergoing immunotherapy.
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Neoplasias Colorretais , Microambiente Tumoral , Humanos , Prognóstico , Microambiente Tumoral/genética , Imunoterapia , Algoritmos , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapiaRESUMO
BACKGROUND: Little is known about the role of serine peptidase inhibitor Kazal type 4 (SPINK4) in colorectal cancer (CRC) and ferroptosis. Therefore, this study aimed to determine the effect of SPINK4 on CRC pathogenesis and ferroptosis. METHODS: SPINK4 expression was analyzed in public datasets and examined using immunohistochemistry. The biological function of SPINK4 in CRC cell lines and its effect on ferroptosis were tested. An immunofluorescence assay was performed to determine the location of SPINK4 in cells, and mouse models were established to determine the effects of SPINK4 in vivo. RESULTS: CRC datasets and clinical samples analysis revealed that SPINK4 mRNA and protein levels were significantly reduced in CRC tissues compared to control tissues (P < 0.05). Two CRC cell lines (HCT116 and LoVo) were selected, and the in vitro and in vivo experiments showed that overexpression of SPINK4 greatly promotes the proliferation and metastasis of CRC cells and tumor growth (P < 0.05). The immunofluorescence assay indicated that SPINK4 is mainly located in the nucleoplasm and nucleus of CRC cells. Furthermore, SPINK4 expression was reduced after cell ferroptosis induced by Erastin, and overexpression of SPINK4 greatly inhibited ferroptosis in CRC cells. The results of mouse model further demonstrated that SPINK4 overexpression inhibited CRC cell ferroptosis and facilitated tumor growth. CONCLUSIONS: SPINK4 was decreased in CRC tissues and promoted cell proliferation and metastasis; overexpression of SPINK4 inhibited CRC cell ferroptosis.
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Neoplasias Colorretais , Ferroptose , Inibidores de Serinopeptidase do Tipo Kazal , Animais , Camundongos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/patologia , Inibidores de Serinopeptidase do Tipo Kazal/genética , Inibidores de Serinopeptidase do Tipo Kazal/metabolismoRESUMO
BACKGROUND: Aberrant expression of miRNAs have been implicated in cancers, but the role of miRNAs in colorectal cancer (CRC) remains need to be elucidated. This study aimed to identify miRNAs that related to colorectal cancer (CRC) pathogenesis and determine the diagnostic value. METHODS: Three GEO datasets (GSE128449, GSE35602 and GSE49246) with 131 samples were used to screen miRNAs that differential expression between tumor and control tissues. The expression of the identified miRNAs was validated in 50 clinical tissue samples and the GSE35834 dataset. The clinical significance of these miRNAs was analyzed in the TCGA dataset and clinical tissue samples. The expression of miRNAs in tissues and plasma samples were tested by RT-PCR assay in clinical samples, and their diagnostic value was determined. RESULTS: The analysis of three GEO datasets revealed that miR-595 and miR-1237 were upregulated, while miR-126, miR-139, and miR-143 were downregulated in CRC tissues compared to control tissues. The differential expression of the five miRNAs in CRC tissues was confirmed using clinical tissue samples and GEO databases. There was no significant correlation between the TNM stage and tumor stage of CRC and any of the five miRNAs. Plasma expression of the miRNAs differed significantly between CRC and non-cancer patients, and each miRNA had moderate diagnostic value for CRC. Combining the five miRNAs provided better diagnostic potential for CRC than a single miRNA. CONCLUSIONS: This study demonstrated that five miRNAs were related to the pathogenesis of CRC, but independent of the stage of CRC; Plasma expression of these miRNAs have moderate diagnostic value, and combination of these miRNAs showed better diagnostic ability in CRC.
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Neoplasias Colorretais , MicroRNAs , MicroRNAs/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , IdosoRESUMO
BACKGROUND: The detection rate of methylated Septin9 (mSEPT9) in colorectal cancer (CRC) is varied greatly across the studies. This study aimed to evaluate the diagnostic ability of mSEPT9 in CRC, and compare the diagnostic efficacy with fecal immunochemical test (FIT). METHODS: 326 subjects from four centers were prospectively recruited, including 179 CRC and 147 non-CRC subjects. The plasma was collected for mSEPT9 and CEA, AFP, CA125, CA153 and CA199 test, and fecal samples for FIT tests. Sensitivity, specificity and area under the curve (AUC) of receiver operating characteristic curve were calculated to evaluate the diagnostic value of each biomarker. RESULTS: The positive rate in mSEPT9 and FIT, and the level of CEA, CA125 and CA199 were significantly higher in CRC compared with non-CRC subjects. The mSEPT9 positive rate was not associated with TNM stage and tumor stage. The sensitivity, specificity and AUC of mSEPT9 in diagnostic CRC were 0.77, 0.88 and 0.82, respectively, while the value in FIT was 0.88, 0.80 and 0.83, respectively. mSEPT9 and FIT have higher AUC value than that of CEA, CA125 and CA199. Combination of both mSEPT9 and FIT positive increased sensitivity and AUC to 0.98 and 0.83, respectively, but the specificity was declined. mSEPT9 has a slightly low sensitivity in diagnosis of colon cancer (0.87) compared with rectal cancer (0.93). CONCLUSION: mSEPT9 demonstrated moderate diagnostic value in CRC detection, which was similar to the FIT but superior to the CEA, CA125 and CA199. Combination of mSEPT9 and FIT further improved diagnostic sensitivity in CRC. TRIAL REGISTRATION: ChiCTR2000038319.
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Neoplasias Colorretais , Septinas , Biomarcadores Tumorais , Antígeno Carcinoembrionário , China , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Detecção Precoce de Câncer , Humanos , Septinas/genética , Septinas/metabolismoRESUMO
Patients with advanced-stage or treatment-resistant colorectal cancer (CRC) benefit less from traditional therapies; hence, new therapeutic strategies may help improve the treatment response and prognosis of these patients. Ferroptosis is an iron-dependent type of regulated cell death characterized by the accumulation of lipid reactive oxygen species (ROS), distinct from other types of regulated cell death. CRC cells, especially those with drug-resistant properties, are characterized by high iron levels and ROS. This indicates that the induction of ferroptosis in these cells may become a new therapeutic approach for CRC, particularly for eradicating CRC resistant to traditional therapies. Recent studies have demonstrated the mechanisms and pathways that trigger or inhibit ferroptosis in CRC, and many regulatory molecules and pathways have been identified. Here, we review the current research progress on the mechanism of ferroptosis, new molecules that mediate ferroptosis, including coding and non-coding RNA; novel inducers and inhibitors of ferroptosis, which are mainly small-molecule compounds; and newly designed nanoparticles that increase the sensitivity of cells to ferroptosis. Finally, the gene signatures and clusters that have predictive value on CRC are summarized.
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Neoplasias Colorretais , Ferroptose , Humanos , Espécies Reativas de Oxigênio , Ferro , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genéticaRESUMO
BACKGROUND: Cancers located on the right and left sides of the colon have distinct clinical and molecular characteristics. This study aimed to explore the regulatory mechanisms of location-specific long noncoding RNAs (lncRNAs) as competing endogenous RNAs (ceRNAs) in colon cancer and identify potential prognostic biomarkers. METHOD: Differentially expressed lncRNAs (DELs), miRNAs (DEMs), and genes (DEGs) between right- and left-side colon cancers were identified by comparing RNA sequencing profiles. Functional enrichment analysis was performed for the DEGs, and a ceRNA network was constructed. Associations between DELs and patient survival were examined, and a DEL-based signature was constructed to examine the prognostic value of these differences. Clinical colon cancer tissues and Gene Expression Omnibus (GEO) datasets were used to validate the results. RESULTS: We identified 376 DELs, 35 DEMs, and 805 DEGs between right- and left-side colon cancers. The functional enrichment analysis revealed the functions and pathway involvement of DEGs. A ceRNA network was constructed based on 95 DEL-DEM-DEG interactions. Three DELs (LINC01555, AC015712, and FZD10-AS1) were associated with the overall survival of patients with colon cancer, and a prognostic signature was established based on these three DELs. High risk scores for this signature indicated poor survival, suggesting that the signature has prognostic value for colon cancer. Examination of clinical colon cancer tissues and GEO dataset analysis confirmed the results. CONCLUSION: The ceRNA regulatory network suggests roles for location-specific lncRNAs in colon cancer and allowed the development of an lncRNA-based prognostic signature, which could be used to assess prognosis and determine treatment strategies in patients with colon cancer.
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BACKGROUND Natural killer (NK) cells are important for the prognosis of multiple cancers, but their prognostic value remains to be evaluated in patients with gastric cancer. Thus, this retrospective study was conducted at a single center to investigate the association between percentage of NK cells in the peripheral blood and prognosis in patients with gastric cancer. MATERIAL AND METHODS The data of 180 gastric cancer patients were collected. Univariate and multivariate Cox regression models were applied to screen candidate prognostic factors. A time-dependent receiver operating characteristic curve was employed to evaluate the ability of NK cells as a prognostic marker. Furthermore, we determined the correlation between the NK cells percentage and other parameters and their clinical significance. RESULTS Patients with a higher percentage of NK cells survived longer than those with a lower percentage of NK cells. Cox analysis revealed that NK cells could be used as an independent indicator for patients with gastric cancer. The percentage of NK cells was positively correlated with lymphocyte count and albumin, but was negatively correlated with CA125 and neutrophil-lymphocyte ratio. The area under the curve for NK cells in predicting the 5-year survival rate for gastric cancer was 0.792. This increased to 0.830 upon combining NK cells with neutrophil-lymphocyte ratio. Patients at early T, N, and clinical stages possessed a significantly higher percentage of NK cells compared to those at advanced T, N, and clinical stages of gastric cancer. CONCLUSIONS Our results suggest that a higher percentage of NK cells predicts is associated with longer survival of gastric cancer patients and could serve as an independent prognostic biomarker.
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Células Matadoras Naturais/imunologia , Neoplasias Gástricas/sangue , Adulto , Idoso , Biomarcadores Tumorais/sangue , Antígeno Ca-125/sangue , Antígeno Ca-125/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/patologia , Contagem de Linfócitos , Linfócitos/imunologia , Masculino , Proteínas de Membrana/sangue , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Neutrófilos/imunologia , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Estudos Retrospectivos , Albumina Sérica/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: The association between natural killer (NK) cells and survival in colorectal cancer (CRC) patients remains controversial. This study aimed to clarify the prognostic value of peripheral blood NK cells in CRC patients. METHODS: A total of 447 CRC patients who underwent radical surgery and chemotherapy were retrospectively analyzed. Cox regression analyses were used to identify independent prognostic indicators. Correlation between NK cell percentage and other clinicopathological features (gender, age, histological grade, tumor stage, immune cells, and inflammatory indicators) was analyzed. The prognostic values of the combinations of NK cell percentage and other clinicopathological features were also determined. RESULTS: Multivariate Cox regression analysis revealed that NK cell percentage in the peripheral blood was an independent prognostic indicator in CRC patients. A higher percentage of NK cells indicated a longer survival time than a lower percentage. NK cell percentage was positively correlated to the T and B lymphocyte counts and negatively correlated to the patients' age and albumin levels. With an area of 0.741 under a receiver operating characteristic curve, NK cells have a moderate predictive value for 3rd-year survival in CRC. This area increased to 0.851 by combining NK cell percentage with the B lymphocyte count. Elderly patients and those at an advanced clinical stage presented a lower percentage of NK cells than younger patients and those at an early clinical stage. CONCLUSIONS: This study demonstrated that NK cells in the blood were an independent predictor of survival in CRC patients, and the combined count of NK cells and B lymphocytes could increase the prognostic value.
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Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/terapia , Células Matadoras Naturais/imunologia , Idoso , Linfócitos B/imunologia , Quimioterapia Adjuvante , Neoplasias Colorretais/sangue , Neoplasias Colorretais/cirurgia , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Linfócitos T/imunologiaRESUMO
BACKGROUND: Colorectal cancer (CRC) originating from the right-sided or left-sided colon is distinct clinicopathological entity. The KRAS status and its prognostic value in CRC remain controversial. This study aimed to investigate the association of KRAS status with clinicopathological features and prognostic value in CRC. METHODS: 178 colon cancer and 145 rectal cancer patients were enrolled. KRAS mutation test was performed on paraffin-embedded tumor samples using PCR methods. The colon cancer was divided into right-sided colon cancer (RCC) and left-sided colon cancer (LCC). Studies that reported the association of KRAS mutation with CRC clinical features and prognosis in databases were searched prior to 2018. The data of the present study was combined with the data of published studies using meta-analysis methods. RESULTS: No significant difference between colon cancer and rectal cancer regarding the KRAS status. The KRAS mutation was much frequent in RCC than in LCC (p = 0.010). 17 studies with 11,385 colon cancer patients were selected, the pooled results of our data and previous published data showed that KRAS mutation was more frequent in RCC compared with in LCC (p < 0.01); KRAS mutation was not associated with the prognosis in RCC patient; however, KRAS mutation indicated a poor prognosis in LCC patients compared with KRAS wild type (p < 0.01). CONCLUSION: KRAS status has no difference between colon cancer and rectal cancer. KRAS mutation was more frequent in RCC than in LCC, and associated with a poor prognosis in LCC patients, but not in RCC patients.
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Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND This meta-analysis aimed to clarify the diagnostic role of plasma methylated SEPT9 (mSEPT9) in colorectal cancer (CRC) and examined its association with CRC. MATERIAL AND METHODS A systematic review was conducted prior to July 2018. Summary sensitivity, specificity, and positive and negative likelihood ratio (PLR/NLR) were calculated for the diagnostic value of mSEPT9 for CRC. The areas under the receiver operating curves (AUCs) were used to summarize the overall test performance. RESULTS Twenty-two studies with 2271 CRC patients were enrolled. The summary sensitivity, specificity, PLR, NLR, DOR, and AUC of the overall analysis of mSEPT9 were 0.69, 0.92, 8.1, 0.34, 24, and 0.89, respectively. Subgroup and meta-regression analyses demonstrated that the diagnostic value was higher for the Epi proColon 2.0 assay, Asian ethnicity, and mSEPT9 test combined with fecal occult blood test (FOBT) or fecal immunochemical test (FIT) than for other test methods, white ethnicity, and mSEPT9 test alone. The rate of mSEPT9 positivity was higher in advanced CRC cases compared with early-stage CRC cases, and was higher in CRC cases than in adenoma cases. No significant difference in mSEPT9 positivity rate was found between left- and right-sided CRC. CONCLUSIONS Plasma mSEPT9 has a high diagnostic value for CRC, especially on the newly developed Epi proColon test 2.0 method. The diagnostic sensitivity is superior among Asians compared to whites, and the combination of mSEPT9 and FOBT/FIT has a better performance than mSEPT9 alone. Finally, the expression of mSEPT9 is associated with CRC stage but not with location.
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Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Septinas/genética , Adenoma/patologia , Área Sob a Curva , Biomarcadores Tumorais/sangue , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Metilação de DNA , Detecção Precoce de Câncer/métodos , Humanos , Estadiamento de Neoplasias , Prognóstico , Sensibilidade e Especificidade , Septinas/sangue , Septinas/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: The association between smoking and clinical outcomes after coronary stenting is controversial. The aim of this meta-analysis was to assess the association between smoking and in stent restenosis (ISR), major adverse cardiac events (MACE), or major adverse cardiac and cerebrovascular events (MACCE) after coronary stenting. METHODS: A search for studies published before December 2014 was conducted in PubMed, Embase, and Cochrane library. An inverse random weighted meta-analysis was conducted using logarithm of the odds ratio (OR) and its standard error for each study. RESULTS: Ten studies investigated the association between smoking and ISR. Overall, smoking was not associated with ISR (OR: 1.05, 95% CI: 0.79-1.41; I(2) = 47.8%). Subgroup analysis also failed to show a significant association between smoking and ISR risk regardless of bare metal stent (BMS) and drug-eluting stent (DES) implantation. Eight studies explored the association between smoking and MACE, but no association was found (OR: 0.92, 95% CI: 0.77-1.10; I(2) = 25.5%), and subgroup analysis revealed that no distinct difference was found between BMS and DES implantation. Three studies investigated the association between smoking and MACCE and significant association was found (OR: 2.09, 95% CI: 1.43-3.06; I(2) = 21.6%). CONCLUSIONS: Our results suggest that in patients undergoing percutaneous coronary intervention with stent implantation, smoking is not associated with ISR and MACE; however, smoking is an independent risk factor for MACCE.
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Calcium overload can lead to tumor cell death. However, because of the powerful calcium channel excretory system within tumor cells, simplistic calcium overloads do not allow for an effective antitumor therapy. Hence, the nanoparticles are created with polyethylene glycol (PEG) donor-modified calcium phosphate (CaP)-coated, manganese-doped hollow mesopores Prussian blue (MMPB) encapsulating glucose oxidase (GOx), called GOx@MMPB@CaP-PEG (GMCP). GMCP with a three-mode enhancement of intratumor reactive oxygen species (ROS) levels is designed to increase the efficiency of the intracellular calcium overload in tumor cells to enhance its anticancer efficacy. The released exogenous Ca2+ and the production of cytotoxic ROS resulting from the perfect circulation of the three-mode ROS outbreak generation that Fenton/Fenton-like reaction and consumption of glutathione from Fe2+/Fe3+and Mn2+/Mn3+ circle, and amelioration of hypoxia from MMPB-guided and GOx-mediated starvation therapy. Photothermal efficacy-induced heat generation owing to MMPB accelerates the above reactions. Furthermore, abundant ROS contribute to damage to mitochondria, and the calcium channels of efflux Ca2+ are inhibited, resulting in a calcium overload. Calcium overload further increases ROS levels and promotes apoptosis of tumor cells to achieve excellent therapy.
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LncRNAs have shown to regulate ferroptosis in colorectal cancer (CRC), but the mechanism remains largely unknown. This study unveiled the mechanism of SNHG4 underlying ferroptosis in CRC. RNA-seq and RT-PCR assay confirmed SNHG4 was decreased after Erastin treatment in CRC cells. Overexpression of SNHG4 inhibited and silence promoted CRC cells ferroptosis. SNHG4 was positively correlated to c-Myb in CRC tissues and both located in cytoplasm of CRC cells. RIP and RNA pull-down assays verified the interaction between SNHG4 and c-Myb. Silence of c-Myb alleviated the suppressing effect on ferroptosis by SNHG4 in CRC cells. Dual-luciferase reporter assay revealed that SNHG4 sponging miR-150-5p in CRC cells. Overexpression of SNHG4 decreased the miR-150-5p and increased c-Myb expression. c-Myb was a direct target gene of miR-150-5p in CRC cells. Moreover, effect of CDO1 on ferroptosis was regulated transcriptionally by c-Myb, overexpression of c-Myb reduce CDO1 expression and enhance the GPX4 levels. The animal models confirmed that regulatory effect of SNHG4 on miR-150-5p and c-Myb after inducing ferroptosis. We concluded that SNHG4 inhibited Erastin-induce ferroptosis in CRC, this effect is via sponging miR-150-5p to regulate c-Myb expression, and activated CDO1/GPX4 axis. These findings provide insights into the regulatory mechanism of SNHG4 on ferroptosis.
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Neoplasias Colorretais , Ferroptose , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Proteínas Proto-Oncogênicas c-myb , RNA Longo não Codificante , Ferroptose/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Humanos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/metabolismo , Animais , Camundongos , Linhagem Celular Tumoral , Masculino , Camundongos NusRESUMO
Background: Angiogenesis plays a pivotal role in colorectal cancer (CRC), yet its underlying mechanisms demand further exploration. This study aimed to elucidate the significance of angiogenesis-related genes (ARGs) in CRC through comprehensive multi-omics analysis. Methods: CRC patients were categorized according to ARGs expression to form angiogenesis-related clusters (ARCs). We investigated the correlation between ARCs and patient survival, clinical features, consensus molecular subtypes (CMS), cancer stem cell (CSC) index, tumor microenvironment (TME), gene mutations, and response to immunotherapy. Utilizing three machine learning algorithms (LASSO, Xgboost, and Decision Tree), we screen key ARGs associated with ARCs, further validated in independent cohorts. A prognostic signature based on key ARGs was developed and analyzed at the scRNA-seq level. Validation of gene expression in external cohorts, clinical tissues, and blood samples was conducted via RT-PCR assay. Results: Two distinct ARC subtypes were identified and were significantly associated with patient survival, clinical features, CMS, CSC index, and TME, but not with gene mutations. Four genes (S100A4, COL3A1, TIMP1, and APP) were identified as key ARCs, capable of distinguishing ARC subtypes. The prognostic signature based on these genes effectively stratified patients into high- or low-risk categories. scRNA-seq analysis showed that these genes were predominantly expressed in immune cells rather than in cancer cells. Validation in two external cohorts and through clinical samples confirmed significant expression differences between CRC and controls. Conclusion: This study identified two ARG subtypes in CRC and highlighted four key genes associated with these subtypes, offering new insights into personalized CRC treatment strategies.
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BACKGROUND: Anastomotic leakage (AL) is a severe complication of colorectal cancer (CRC) surgery and is associated with the immune and nutritional status. OBJECTIVES: This study aimed to investigate the role of the prognostic nutritional index (PNI) in AL in CRC patients after surgery. MATERIAL AND METHODS: A retrospective case-control study was designed in a single center. The clinicopathological features and preoperative laboratory data of 124 CRC patients and 120 non-cancer patients who underwent surgery were collected and examined. Among the CRC patients, 24 had AL. RESULTS: Nutritional indicators were lower in CRC patients than in non-cancer patients (p < 0.05), but the clinical parameters analysis showed that only metastasis (M) stage, albumin, carcinoembryonic antigen (CEA), CA153, and PNI were associated with AL in CRC after surgery (p < 0.05). Prognostic nutritional index had a moderate predictive value for AL, with an area under the curve (AUC) of 0.625. Using the median value as a cutoff point, a high PNI was associated with a longer survival time in CRC patients (p = 0.033), and AL showed marginal significance (p = 0.048). The nomogram showed that PNI has a better prognostic value than tumor-node-metastasis (TNM) staging in CRC patients who underwent surgery. CONCLUSIONS: Prognostic nutritional index is a useful supplement for predicting AL in CRC patients after colorectal surgery. It also helps predict the prognosis of CRC patients.
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BACKGROUND/AIMS: The effect of Helicobacter pylori (H. pylori) eradication on blood ammonia levels in cirrhotic patients is still controversial. We aimed to clarify this effect by performing a quantitative meta-analysis of published studies. METHODOLOGY: We searched PubMed, EMBASE and Cochrane library for studies which explored the effect of H. pylori eradication on blood ammonia levels in cirrhotic patients before March 2012. A random-effects meta-analysis was performed. RESULTS: Nine studies (five non-randomized control studies and four before-after studies) involved in 699 cirrhotic patients who were given H. pylori eradication eligible to our analysis. The before-after studies suggested that H. pylori eradication can significantly reduce the blood ammonia levels in cirrhotic patients (SMD=0.32, 95%CI=0.11-0.53, 12=39.6%). After included five non-randomized control studies,the overall results suggested that H. pylori eradication can not reduce the blood ammonia levels in cirrhotic patients (SMD=-0.36, 95% CI=-0.83-0.11) and with significant heterogeneity (1=89.3%). Subgroup analysis suggested that the no effect was found between Caucasian and Asian ethnicity and between cirrhotic patients with Child-Pugh class B/C <70% and >70%. CONCLUSIONS: The effect of eradication of H. pylori on blood ammonia levels in cirrhotic patients is mainly caused by the non-specific effect of antibiotics regardless of patients' ethnicity and impairment of liver function. However, due to limited studies available and low methodological quality that marked by high risks of bias, our study should be interpreted cautiously.
Assuntos
Amônia/sangue , Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Cirrose Hepática/sangue , Viés , Biomarcadores/sangue , Regulação para Baixo , Medicina Baseada em Evidências , Infecções por Helicobacter/complicações , Infecções por Helicobacter/etnologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/isolamento & purificação , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/etnologia , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Aberrant expression of genes contributes to the chemoresistance of colorectal cancer (CRC) treatment. This study aimed to identify genes associated with the chemoresistance of oxaliplatin-based chemotherapy in CRC patients and to construct a signature. Oxaliplatin resistance-related genes were screened by analyzing the gene profiles of cell lines and tissue samples that underwent oxaliplatin-based treatment. Oxaliplatin resistance-related genes were used to establish a signature. The association of the signature had clinical significance, so the prognostic value of the signature was analyzed. Independent cohorts and CRC cell lines were used to validate the value of the gene signature and the oxaliplatin-resistant genes. There were 64 oxaliplatin resistance-related genes identified after overlapping the genes from the dataset of oxaliplatin-treated CRC cells and the dataset of patients treated with oxaliplatin-based chemotherapy. A gene signature based on five oxaliplatin resistance-related genes was established. This gene signature effectively predicted the prognosis of CRC patients who underwent chemotherapy. No significant associations were found between the gene mutations and survival of the patients; however, two genes were associated with microsatellite instability status. Two external independent cohorts and CRC cell line experiments validated the prognostic values of the signature and expression of the genes after oxaliplatin treatment. In conclusion, the oxaliplatin resistance-related gene signature involving five genes was a novel biomarker for the prediction of the chemotherapy response and prognosis of CRC patients who underwent oxaliplatin-based chemotherapy.