RESUMO
Metastasis is the primary cause of cancer-related deaths, and colorectal cancer (CRC) liver metastasis is a major poor prognostic factor in CRC. NAT1 (N-acetyltransferase 1) plays a crucial role in the invasive and metastatic processes of colorectal cancer. The role and molecular mechanism of NAT1 on tumor cells were verified by establishing a cell model of overexpression and knockdown of NAT1, and further verified by establishing a liver metastasis model of colorectal cancer for animal experiments. In vivo and in vitro experiments have demonstrated that overexpression of NAT1 reduces the ability of metastasis and invasion of colorectal cancer cells. NAT1 overexpression inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing the EMT (epithelial-mesenchymal transition) process and glycolytic ability of tumor cells. Additionally, decreased glycolytic ability results in reduced VEGF (Vascular endothelial growth factor) expression in colorectal cancer cells. The decreased VEGF expression leads to decreased angiogenesis and vascular permeability in liver metastases, ultimately reducing the occurrence of liver metastasis. Our findings highlight that overexpression of NAT1 significantly inhibits the PI3K/AKT/mTOR signaling pathway, thereby suppressing EMT, glycolytic ability, and VEGF expression in colorectal cancer cells, collectively preventing the development of liver metastasis.
Assuntos
Arilamina N-Acetiltransferase , Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Glicólise , Neoplasias Hepáticas , Transdução de Sinais , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Transição Epitelial-Mesenquimal/genética , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Animais , Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/metabolismo , Linhagem Celular Tumoral , Camundongos , Serina-Treonina Quinases TOR/metabolismo , Isoenzimas/metabolismo , Isoenzimas/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação Neoplásica da Expressão Gênica , Camundongos NusRESUMO
BACKGROUND AND OBJECTIVES: Intraoperative bile duct injury is a significant complication in laparoscopic cholecystectomy (LC). Near-infrared fluorescence cholangiography (NIFC) can reduce this complication. Therefore, determining the optimal indocyanine green (ICG) dosage for effective NIFC is crucial. This study aimed to determine the optimal ICG dosage for NIFC. METHODS: This was a prospective, randomized, double-blind clinical trial at a single tertiary referral center, including 195 patients randomly assigned to three groups: lower dose (0.01 mg/BMI) ICG (n = 63), medium dose (0.02 mg/BMI) ICG (n = 68), and higher dose (0.04 mg/BMI) ICG (n = 64). Surgeon satisfaction and detection rates for seven biliary structures were compared among the three dose groups. RESULTS: Demographic parameters did not significantly differ among the groups. The medium dose (72.1%) and higher dose ICG groups (70.3%) exhibited superior visualization of the common hepatic duct compared to the lower dose group (41.3%) (p < 0.001). No differences existed between the medium and higher dose groups. Similar trends were observed for the common bile duct and cystic common bile duct junction. CONCLUSIONS: In patients undergoing fluorescent laparoscopic cholecystectomy, the 0.02 mg/BMI dose of indocyanine green demonstrated better biliary structure detection rates than the 0.01 mg/BMI dose and was non-inferior to the 0.04 mg/BMI dose.
Assuntos
Colecistectomia Laparoscópica , Verde de Indocianina , Humanos , Verde de Indocianina/administração & dosagem , Colecistectomia Laparoscópica/métodos , Método Duplo-Cego , Feminino , Masculino , Estudos Prospectivos , Pessoa de Meia-Idade , Colangiografia/métodos , Adulto , Idoso , Corantes/administração & dosagem , Ductos BiliaresRESUMO
Ubiquitin A-52 residue ribosomal protein fusion product 1 (UBA52) has a role in the occurrence and development of tumours. However, the mechanism by which UBA52 regulates hepatocellular carcinoma (HCC) tumorigenesis and progression remains poorly understood. By using the Cell Counting Kit (CCK-8), colony formation, wound healing and Transwell assays, we assessed the effects of UBA52 knockdown and overexpression on the proliferation and migration of HCC cells in vitro. By establishing subcutaneous and metastatic tumour models in nude mice, we evaluated the effects of UBA52 on HCC cell proliferation and migration in vivo. Through bioinformatic analysis of data from the Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) databases, we discovered that UBA52 is associated with autophagy. In addition, we discovered that HCC tissues with high UBA52 expression had a poor prognosis in patients. Moreover, knockdown of UBA52 reduced HCC cell growth and metastasis both in vitro and in vivo. Mechanistically, knockdown of UBA52 induced autophagy through EMC6 in HCC cells. These findings suggest that UBA52 promoted the proliferation and migration of HCC cells through autophagy regulation via EMC6 and imply that UBA52 may be a viable novel treatment target for HCC patients.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Autofagia/genética , Carcinogênese/genética , Carcinoma Hepatocelular/genética , Transformação Celular Neoplásica , Neoplasias Hepáticas/genética , Proteínas de Membrana , Camundongos NusRESUMO
BACKGROUND: Ferroptosis, is characterized by lipid peroxidation of fatty acids in the presence of iron ions, which leads to cell apoptosis. This leads to the disruption of metabolic pathways, ultimately resulting in liver dysfunction. Although ferroptosis is linked to nonalcoholic steatohepatitis (NASH), understanding the key ferroptosis-related genes (FRGs) involved in NASH remains incomplete. NASH may be targeted therapeutically by identifying the genes responsible for ferroptosis. METHODS: To identify ferroptosis-related genes and develop a ferroptosis-related signature (FeRS), 113 machine-learning algorithm combinations were used. RESULTS: The FeRS constructed using the Generalized Linear Model Boosting algorithm and Gradient Boosting Machine algorithms exhibited the best prediction performance for NASH. Eight FRGs, with ZFP36 identified by the algorithms as the most crucial, were incorporated into in FeRS. ZFP36 is significantly enriched in various immune cell types and exhibits significant positive correlations with most immune signatures. CONCLUSION: ZFP36 is a key FRG involved in NASH pathogenesis.
Assuntos
Ferroptose , Hepatopatia Gordurosa não Alcoólica , Humanos , Algoritmos , Apoptose , Aprendizado de MáquinaRESUMO
BACKGROUND: Tertiary lymphoid structures (TLSs) have been proposed to assess the prognosis of patients with cancer. Here, we investigated the prognostic value and relevant mechanisms of TLSs in colorectal cancer liver metastases (CRCLM). METHODS: 603 patients with CRCLM treated by surgical resection from three cancer centers were included. The TLSs were categorized according to their anatomic subregions and quantified, and a TLS scoring system was established for intratumor region (T score) and peritumor region (P score). Differences in relapse-free survival (RFS) and overall survival (OS) between groups were determined. Multiplex immunohistochemical staining (mIHC) was used to determine the cellular composition of TLSs in 40 CRCLM patients. RESULTS: T score positively correlated with superior prognosis, while P score negatively associated with poor survival (all p<0.05). Meanwhile, T score was positively associated with specific mutation subtype of KRAS. Furthermore, TLSs enrichment gene expression was significantly associated with survival and transcriptomic subtypes of CRCLM. Subsequently, mIHC showed that the densities of Treg cells, M2 macrophages and Tfh cells were significantly higher in intratumor TLSs than in peritumor TLSs (p=0.029, p=0.047 and p=0.041, respectively), and the frequencies of Treg cells and M2 macrophages were positively correlated with P score, while the frequencies of Tfh cells were positively associated with T scores in intratumor TLSs (all p<0.05). Next, based on the distribution and abundance of TLSs, an Immune Score combining T score and P score was established which categorized CRCLM patients into four immune classes with different prognosis (all p<0.05). Among them, patients with higher immune class have more favorable prognoses. The C-index of Immune Class for RFS and OS was higher than Clinical Risk Score statistically. These results were also confirmed by the other two validation cohorts. CONCLUSIONS: The distribution and abundance of TLSs is significantly associated with RFS and OS of CRCLM patients, and a novel immune class was proposed for predicting the prognosis of CRCLM patients.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Estruturas Linfoides Terciárias , Humanos , Linfócitos do Interstício Tumoral , Recidiva Local de Neoplasia/patologia , Neoplasias Hepáticas/patologia , Neoplasias Colorretais/patologiaRESUMO
BACKGROUND: Selenium-binding protein 1 (SELENBP1), a member of the selenium-containing protein family, plays an important role in malignant tumorigenesis and progression. However, it is currently lacking research about relationship between SELENBP1 and immunotherapy in colorectal cancer (CRC). METHODS: We first analyzed the expression levels of SELENBP1 based on the Cancer Genome Atlas (TCGA), Oncomine andUALCAN. Chisq.test, Fisher.test, Wilcoxon-Mann-Whitney test and logistic regression were used to analyze the relationship of clinical characteristics with SELENBP1 expression. Then Gene ontology/ Kyoto encyclopedia of genes and genomes (GO/KEGG), Gene set enrichment analysis (GSEA) enrichment analysis to clarify bio-processes and signaling pathways. The cBioPortal was used to perform analysis of mutation sites, types, etc. of SELENBP1. In addition, the correlation of SELENBP1 gene with tumor immune infiltration and prognosis was analyzed using ssGSEA, ESTIMATE, tumor immune dysfunction and rejection (TIDE) algorithm and Kaplan-Meier (KM) Plotter database. Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were used to validate the expression of SELENBP1 in CRC samples and matched normal tissues. Immunohistochemistry (IHC) was further performed to detect the expression of SELENBP1 in CRC samples and matched normal tissues. RESULTS: We found that SELENBP1 expression was lower in CRC compared to normal colorectal tissue and was associated with poor prognosis. The aggressiveness of CRC increased with decreased SELENBP1 expression. Enrichment analysis showed that the SELENBP1 gene was significantly enriched in several pathways, such as programmed death 1 (PD-1) signaling, signaling by interleukins, TCR signaling, collagen degradation, costimulation by the CD28 family. Decreased expression of SELENBP1 was associated with DNA methylation and mutation. Immune infiltration analysis identified that SELENBP1 expression was closely related to various immune cells and immune chemokines/receptors. With increasing SELENBP1 expression, immune and stromal components in the tumor microenvironment were significantly decreased. SELENBP1 expression in CRC patients affects patient prognosis by influencing tumor immune infiltration. Beside this, SELENBP1 expression is closely related to the sensitivity of chemotherapy and immunotherapy. CONCLUSIONS: Survival analysis as well as enrichment and immunoassay results suggest that SELENBP1 can be considered as a promising prognostic biomarker for CRC. SELENBP1 expression is closely associated with immune infiltration and immunotherapy. Collectively, our study provided useful information on the oncogenic role of SELENBP1, contributing to further exploring the underlying mechanisms.
Assuntos
Neoplasias Colorretais , Selênio , Antígenos CD28 , Colágeno , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Humanos , Fatores Imunológicos , Imunoterapia , Prognóstico , Receptor de Morte Celular Programada 1 , Receptores de Antígenos de Linfócitos T , Proteínas de Ligação a Selênio/genética , Proteínas de Ligação a Selênio/metabolismo , Microambiente TumoralRESUMO
Evidence shows that the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (Lnc-MALAT1) is associated with activation of hepatic stellate cells (HSCs) and liver fibrosis in animal and in vitro studies. However, its roles in human liver fibrosis and the underlying mechanism in HSC activation are not yet defined. In our current study, the expression of Lnc-MALAT1 in the fibrotic liver tissues and in the plasma extracelllar vesicles (EVs) of liver fibrosis patients was detected by FISH and qRT-PCR. The results revealed that enhanced expression of Lnc-MALAT1 was co-localized with increased expression of the fibrotic markers (collagen I and α-SMA) and the Wnt/ß-catenin signaling proteins (ß-catenin, cyclinD1 and c-myc) in the fibrotic liver tissues. The level of Lnc-MALAT1 in the plasma EVs isolated from 60 liver fibrosis patients was significantly increased compared with that of the 46 control patients, and area under receiver operating curve (AUROC) analysis showed that plasma EVs-Lnc-MALAT1 was a potential diagnostic marker for liver fibrosis, especially for high liver fibrosis. Plasma EVs with highly expressed Lnc-MALAT1 derived from high liver fibrosis patients up-regulated the expression of the fibrotic markers and enhanced the Wnt/ß-catenin signaling in human hepatic stellate cells LX-2, and the fibrogenic effects in LX-2 were inhibited by Lnc-MALAT1 knock-down. Interestingly, TGF-ß1, a potent pro-fibrotic cytokine, promoted the expression of Lnc-MALAT1 in LX-2 and its pro-fibrotic effects were also abolished by siRNA for Lnc-MALAT1, suggesting that Lnc-MALAT1 probably functions as a common mediator in the activation and fibrogenesis of HSCs. Our results indicate that enhanced expression of Lnc-MALAT1 in the fibrotic liver stimulate the activation of HSCs and thus promote their fibrogenic activity. These results also provide evidences that Lnc-MALAT1 is a potential therapeutic target and plasma EVs-Lnc-MALAT1 is a potential diagnostic biomarker for liver fibrosis.