Colorectal Cancer Progression Research Articles

CEBPB-mediated upregulation of SERPINA1 promotes colorectal cancer progression by enhancing STAT3 signaling

Colorectal cancer (CRC) is a highly malignant carcinoma associated with poor prognosis, and metastasis is one of the most common causes of death in CRC. Serpin Family A Member 1 (SERPINA1) is a serine protease inhibitor from the Serpin family. Till now, the function and mechanism of SERPINA1 in CRC progression have not been fully illustrated. We established highly metastatic colorectal cancer cells named as RKO-H and Caco2-H by mice liver metastasis model. By integrative bioinformatic approaches, we analyzed the prognostic value and clinical significance of SERPINA1 in CRC, and predicted potential transcription factors. Colony formation, EDU, MTS, Transwell and wound healing assay were performed to evaluate the biological functions of SERPINA1 in CRC in vitro. Experiments in vivo were conducted to explore the effects of SERPINA1 on liver metastasis of CRC. ChIP and luciferase reporter gene assays were performed to identify the transcriptional regulatory mechanism of SERPINA1 by CEBPB. Our results show that SERPINA1 is highly expressed in CRC and correlated with poor clinical outcomes. SERPINA1 promotes the proliferation, migration by activating STAT3 pathway. Mechanistically, CEBPB binds SERPINA1 gene promoter sequence and promotes the transcription of SERPINA1. SERPINA1 drives CEBPB-induced tumor cell growth and migration via augmenting STAT3 signaling. Our results suggest that SERPINA1 is a potential prognostic marker and may serve as a novel treatment target for CRC.

Correlation of gasdermin B staining patterns with prognosis, progression, and immune response in colorectal cancer

BackgroundPyroptosis is a type of programmed cell death mediated by the gasdermin family. Gasdermin B (GSDMB), as a member of gasdermin family, can promote the occurrence of cell pyroptosis. However, the correlations of the GSDMB expression in colorectal cancer with clinicopathological predictors, immune microenvironment, and prognosis are unclear.MethodsSpecimens from 267 colorectal cancer cases were analyzed by immunohistochemistry to determine GSDMB expression, CD3+, CD4+, and CD8+ T lymphocytes, CD20+ B lymphocytes, CD68+ macrophages, and S100A8+ immune cells. GSDMB expression in cancer cells was scored in the membrane, cytoplasm, and nucleus respectively. GSDMB+ immune cell density was calculated. Univariate and multivariate survival analyses were performed. The association of GSDMB expression with other clinicopathological variables and immune cells were also analyzed. Double immunofluorescence was used to identify the nature of GSDMB+ immune cells. Cytotoxicity assays and sensitivity assays were performed to detect the sensitivity of cells to 5-fluorouracil.ResultsMultivariate survival analysis showed that cytoplasmic GSDMB expression was an independent favorable prognostic indicator. Patients with positive cytoplasmic or nuclear GSDMB expression would benefit from 5-fluorouracil based chemotherapy. The assays in vitro showed that high GSDMB expression enhanced the sensitivity of colorectal cancer cells to 5-fluorouracil. Patients with positive membranous or nuclear GSDMB expression had more abundant S100A8+ immune cells in the tumor invasive front. Positive nuclear GSDMB expression indicated more CD68+ macrophages in the tumor microenvironment. Moreover, GSDMB+ immune cell density in the stroma was associated with a higher neutrophil percentage but a lower lymphocyte counts and monocyte percentage in peripheral blood. Furthermore, the results of double immunofluorescence showed that GSDMB co-expressed with CD68 or S100A8 in stroma cells.ConclusionThe GSDMB staining patterns are linked to its role in cancer progression, the immune microenvironment, systemic inflammatory response, chemotherapeutic efficacy, and prognosis. Colorectal cancer cells with high GSDMB expression are more sensitive to 5-fluorouracil. However, GSDMB expression in immune cells has different effects on cancer progression from that in cancer cells.

Metagenome of Tibetan kefir grains and its alleviating effect on dysfunction of gut microbiome and depressive colorectal cancer comorbidity induced by chronic stress and AOM/DSS

The prevalence of major depression in cancer patients ranges from 5% to 26%. The research on the screening of neurotrophic and anticancer psychoprobiotics is way of important. The aim of this work was to demonstrate the interventional effect of Tibetan kefir fermented goat milk on colorectal cancer and a co-morbidity model established by chronic unpredictable stress (CUMS). The results showed that the Tibetan kefir fermented milk significantly alleviated the manifestations of depressive behavior and altered the level of corticotropin-releasing factor (CRF), serum corticosterone, and inflammatory factors (IL-6, IL-17, TNF-α and IL-1β) in serum, hippocampus and colon Moreover, the Tibetan kefir fermented milk could alleviate the inflammatory response and the hyperactivity of the HPA axis and inhibite the disturbance of 5-hydroxytryptamine system caused by colorectal cancer and CUMS to prevent the progress of depressive colorectal cancer. These results interpreted the potential mechanism of Tibetan kefir on antidepressant and anticancer. It provided a theoretical basis for the exploitation of psychotropic probiotic dairy products and enriched patients' dietary supplement.

AURKB promotes colorectal cancer progression by triggering the phosphorylation of histone H3 at serine 10 to activate CCNE1 expression.

Aurora kinase B (AURKB) initiates the phosphorylation of serine 10 on histone H3 (pH3S10), a crucial process for chromosome condensation and cytokinesis in mammalian mitosis. Nonetheless, the precise mechanisms through which AURKB regulates the cell cycle and contributes to tumorigenesis as an oncogenic factor in colorectal cancer (CRC) remain unclear. Here, we report that AURKB was highly expressed and positively correlated with Ki-67 expression in CRC. The abundant expression of AURKB promotes the growth of CRC cells and xenograft tumors in animal model. AURKB knockdown substantially suppressed CRC proliferation and triggered cell cycle arrest in G2/M phase. Interestingly, cyclin E1 (CCNE1) was discovered as a direct downstream target of AURKB and functioned synergistically with AURKB to promote CRC cell proliferation. Mechanically, AURKB activated CCNE1 expression by triggering pH3S10 in the promoter region of CCNE1. Furthermore, it was showed that the inhibitor specific for AURKB (AZD1152) can suppress CCNE1 expression in CRC cells and inhibit tumor cell growth. To conclude, this research demonstrates that AURKB accelerated the tumorigenesis of CRC through its potential to epigenetically activate CCNE1 expression, suggesting AURKB as a promising therapeutic target in CRC.

Curcumin and its anti-colorectal cancer potential: From mechanisms of action to autophagy.

Colorectal cancer (CRC) development and progression, one of the most common cancers globally, is supported by specific mechanisms to escape cell death despite chemotherapy, including cellular autophagy. Autophagy is an evolutionarily highly conserved degradation pathway involved in a variety of cellular processes, such as the maintenance of cellular homeostasis and clearance of foreign bodies, and its imbalance is associated with many diseases. However, the role of autophagy in CRC progression remains controversial, as it has a dual function, affecting either cell death or survival, and is associated with cellular senescence in tumor therapy. Indeed, numerous data have been presented that autophagy in cancers serves as an alternative to cell apoptosis when the latter is ineffective or in apoptosis-resistant cells, which is why it is also referred to as programmed cell death type II. Curcumin, one of the active constituents of Curcuma longa, has great potential to combat CRC by influencing various cellular signaling pathways and epigenetic regulation in a safe and cost-effective approach. This review discusses the efficacy of curcumin against CRC in vitro and in vivo, particularly its modulation of autophagy and apoptosis in various cellular pathways. While clinical studies have assessed the potential of curcumin in cancer prevention and treatment, none have specifically examined its role in autophagy. Nonetheless, we offer an overview of potential correlations to support the use of this polyphenol as a prophylactic or co-therapeutic agent in CRC.

SLC38A3 Promotes the Proliferation and Migration of Tumor Cells and Predicts Poor Prognosis in Colorectal Cancer.

Previous studies have revealed that abnormal expressions of membrane transporters were associated with colorectal cancer (CRC). We herein performed a comprehensive bioinformatics analysis to identify the key transporter protein-related genes involved in CRC and potential mechanisms. Differentially expressed transporter protein-related genes (DE-TPRGs) were identified from CRC and normal samples using The Cancer Genome Atlas database. SLC38A3 expression was validated by immunohistochemistry and RT-qPCR, and the potential mechanism was explored. A total of 63 DE-TPRGs (29 up-regulated and 34 down-regulated) were screened. Inside, ABCC2, ABCG2, SLC4A4, SLC9A3, SLC15A1, and SLC38A3 were identified as hub genes. SLC38A3 is indeed upregulated in colorectal cancer patients. Furthermore, we found that knockdown of SLC38A3 inhibited the proliferation and migration of HCT116 cells, and Hsp70 ATPase activator could rescue it. Overall, SLC38A3 is a novel potential biomarker involved in CRC progression and promotes the proliferation and migration of tumor cells by positively regulating the function of Hsp70.

“Unravelling Colorectal Cancer: From Origin to Treatment”

The colon and rectum are the primary organs affected by colorectal cancer (CRC), which is the primary cause of cancer-related morbidity and mortality. Inflammation, particularly in disorders like inflammatory bowel diseases, increases the risk of colorectal cancer, with environmental factors playing a crucial role. The majority of adenocarcinomas typically develop from the epithelial cells that line the colon and rectum as a result of a complex series of genetic and epigenetic modifications. Benign precursor lesions such as adenomatous polyps trigger the slow progression of CRC over a period of ten years or longer. Its etiology is influenced by sporadic, familial, and hereditary forms; prominent hereditary syndromes include Lynch syndrome and familial adenomatous polyposis. Chromosome instability and microsatellite instability are the two main tumorigenic pathways that underpin the pathophysiology of CRC, exhibiting regional differences in the global epidemiology. Approaches: TNM classification is the basis for diagnosis, and various treatment modalities, such as surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and gene therapy, are employed during treatment. Surgical treatments, from minimally invasive procedures to colectomy, are essential and highlight the importance of total excision of the mesocolic region. The standard therapeutic approach consists of chemotherapy and targeted agents; however, newer like gene therapy and immunotherapy show promise. In order to improve outcomes and lessen the burden of the disease, combating CRC requires comprehensive strategies that include early detection, prevention, and innovative therapeutic interventions.

Chondroitin polymerizing factor promotes development and progression of colorectal cancer via facilitating transcription of VEGFB.

Colorectal cancer (CRC) is a highly prevalent malignancy affecting the digestive system on a global scale. This study aimed to explore the previously unexplored role of CHPF in the progression of CRC. Our results revealed a significant upregulation of CHPF expression in CRC tumour tissues compared to normal tissues, with its levels correlating with tumour malignancy. Invitro experiments using CRC cell lines demonstrated that inhibiting CHPF expression suppressed cell proliferation, colony formation and cell migration, while promoting apoptosis. Conversely, overexpressing CHPF had the opposite effect. Additionally, our xenograft models in mice confirmed the inhibitory impact of CHPF knockdown on CRC progression using various cell models. Mechanistic investigations unveiled that CHPF may enhance VEGFB expression through E2F1-mediated transcription. Functionally, suppressing VEGFB expression successfully mitigated the oncogenic effects induced by CHPF overexpression. Collectively, these findings suggest that CHPF may act as a tumour promoter in CRC, operating in a VEGFB-dependent manner and could be a potential target for therapeutic interventions in CRC treatment.

The role of the natural compound naringenin in AMPK-mitochondria modulation and colorectal cancer inhibition

BackgroundAlthough AMP-activated protein kinase (AMPK) has been extensively studied in cellular processes, the understanding of its substrates, downstream functions, contributions to cell fate and colorectal cancer (CRC) progression remains incomplete. PurposeThe aim of this study was to investigate the effects and mechanisms of naringenin on CRC. MethodsThe biological and cellular properties of naringenin and its anticancer activity were evaluated in CRC. In addition, the effect of combined treatment with naringenin and 5-fluorouracil on tumor growth in vitro and in vivo was evaluated. ResultsThe present study found that naringenin inhibits the proliferation of CRC and promote its apoptosis. Compared with the naringenin group, naringenin combined with 5-fluorouracil had significant effect on inhibiting cell proliferation and promoting its apoptosis. It is showed that naringenin activates AMPK phosphorylation and mitochondrial fusion in CRC. Naringenin combined with 5-fluorouracil significantly reduces cardiotoxicity and liver damage induced by 5-fluorouracil in nude mice bearing subcutaneous CRC tumors, and attenuates colorectal injuries in azoxymethane/DSS dextran sulfate (AOM/DSS)-induced CRC. The combination of these two drugs alters mitochondrial function by increasing reactive oxygen species (ROS) levels and decreasing the mitochondrial membrane potential (MMP), thereby stimulating AMPK/mTOR signaling. Mitochondrial dynamics are thereby regulated by activating the AMPK/p-AMPK pathway, and mitochondrial homeostasis is coordinated through increased mitochondrial fusion and reduced fission to activate apoptosis in cancer cells. ConclusionsOur data suggest that naringenin is important for inhibiting CRC proliferation, possibly through the AMPK pathway, to regulate mitochondrial function and induce apoptosis in CRC.

LINC02257 regulates colorectal cancer liver metastases through JNK pathway

BackgroundLong noncoding RNAs (lncRNAs) have emerged as critical regulators of colorectal cancer (CRC) progression, but their roles and underlying mechanisms in colorectal cancer liver metastases (CRLMs) remain poorly understood. MethodsTo explore the expression patterns and functions of lncRNAs in CRLMs, we analyzed the expression profiles of lncRNAs in CRC tissues using the TCGA database and examined the expression patterns of lncRNAs in matched normal, CRC, and CRLM tissues using clinical samples. We further investigated the biological roles of LINC02257 in CRLM using in vitro and in vivo assays, and verified its therapeutic potential in a mouse model of CRLM. ResultsOur findings showed that LINC02257 was highly expressed in metastatic CRC tissues and its expression was negatively associated with overall survival. Functionally, LINC02257 promoted CRC cell growth, migration, metastasis, and inhibited cell apoptosis in vitro, and enhanced liver metastasis in vivo. Mechanistically, LINC02257 up-regulated phosphorylated c-Jun N-terminal kinase (JNK) to promote CRLM. ConclusionsOur study revealed that LINC02257 played a key role in the proliferation and metastasis of CRC cells through the LINC02257/JNK axis. Targeting this axis may represent a promising therapeutic strategy for the treatment of liver metastases in patients with CRC.

Lncrna CASC15 Activated By TCF12 Promote Colorectal Cancer Progression via EMT.

Colorectal cancer (CRC) is one of the most common gastrointestinal malignancies. LncRNA CASC15 has also been found to play a vital role in malignant tumors. Our objective is to explore the role of CASC15 in colorectal cancer and its regulation of EMT and to clarify the reasons for its up-regulated expression in CRC. Quantitative real-time PCR was performed to evaluate the expression of CASC15 in CRC. The biology function of CASC15 on CRC was assessed by in vitro experiments, including CCK8, colony formation, transwell assays and flow cytometry. Luciferase reporter assays were used to confirm the regulation between TCF12 and CASC15. Quantitative real-time PCR and western blot analysis were used to evaluate the biomarkers associated with epithelial-mesenchymal transition (EMT). We found that CASC15 was remarkably upregulated in CRC and positively correlated with poorer relapse-free survival. CASC15 knockdown significantly suppressed the proliferation and migration of CRC. Furthermore, CASC15 downregulation mediated apoptosis of CRC. Mechanistically, TCF12 activates CASC15 transcription to mediate its up-regulation, which activates EMT and promotes CRC progression. Our study identified TCF12/CASC15/EMT as a new regulatory signal axis of CRC. CASC15 may be a new molecular marker and target for CRC.

Astragaloside IV inhibits colorectal cancer metastasis by reducing extracellular vesicles release and suppressing M2-type TAMs activation

Ethnopharmacological relevanceTumour-derived extracellular vesicles (TEVs) have been confirmed to facilitate colorectal cancer (CRC) metastasis by remodelling the tumour microenvironment (TME). Drugs targeted TEVs is considered as a promising therapeutic strategy for cancer treatment. Traditional Chinese medicine (TCM) plays a vital role in improving the prognosis of CRC patients and eventually CRC patients with distant metastasis. Although the anti-tumour effects of active compounds from TCM prescriptions are observed widely, the molecular mechanisms remain unknown. Aim of the studyThis study aims to investigate the effects of active compounds in our library of TCM on preventing CRC metastasis, and also explore the potential mechanisms from the perspective of TEVs. Materials and methods: The effects of active compounds on the proliferation of CRC cells were determined by CCK-8 assay. TEVs were extracted from MC38 cells by ultracentrifugation and characterized by electron microscopy, Nanosight NS300 and western blotting. The TEV particles were quantified by Nanosight NS300. The potential mechanism by which astragaloside IV (ASIV) reduced TEV secretion was determined by western blotting. RAW264.7 cells were cocultured with the conditioned medium (CM) of MC38 cells treated with or without ASIV, and the activation of tumour-associated macrophages (TAMs) was assessed by immunofluorescence and quantitative polymerase chain reaction (qPCR). The migration of CRC cells was measured by wound healing and Transwell assay. A spleen-to-liver metastasis model of colorectal cancer was used to confirm the efficiency of ASIV in vivo. Liver metastatic tumours of the mice were used for liver weight measures and H&E staining. Immunofluorescence was applied to observe the infiltration of TAMs, the expression of neutral sphingomyelinase 2 (nSMase2) and Rab27a. ResultsBy screening our TCM monomer library, we found that ASIV, which is mainly extracted from Radix Astragali, reduced the release of TEVs from CRC cells in a time- and concentration-dependent manner. Mechanistically, ASIV inhibited the production and secretion of TEVs by downregulating nSMase2 and Rab27a expression in CRC cells. CM from ASIV-treated CRC cells reshaped the polarization of TAMs by decreasing M2-type polarization, increasing M1-type polarization. Consequently, the repolarization of M2-type to M1-type macrophages led to reduced invasion and migration of CRC cells. Moreover, we confirmed that ASIV inhibited the liver metastasis of CRC, reduced M2-type macrophage infiltration and decreased the expression of nSMase2 and Rab27a in liver metastases. ConclusionsASIV inhibited CRC metastasis by reducing EVs release and suppressing M2-type TAMs activation. All these findings reveal a new insight into the mechanisms of ASIV in preventing CRC progression and provide a promising approach for anti-tumour therapy.

RNA polymerase I subunit D activated by Yin Yang 1 transcription promote cell proliferation and angiogenesis of colorectal cancer cells.

This study aims to explore possible effect of RNA polymerase I subunit D (POLR1D) on proliferation and angiogenesis ability of colorectal cancer (CRC) cells and mechanism herein. The correlation of POLR1D and Yin Yang 1 (YY1) expressions with prognosis of CRC patients in TCGA database was analyzed. Quantitative realtime polymerase chain reaction (qRT-PCR) and Western blot were applied to detect expression levels of POLR1D and YY1 in CRC cell lines and CRC tissues. SW480 and HT- 29 cells were transfected with si-POLR1D or pcDNA3.1-POLR1D to achieve POLR1D suppression or overexpression before cell migration, angiogenesis of human umbilical vein endothelial cells were assessed. Western blot was used to detect expressions of p38 MAPK signal pathway related proteins and interaction of YY1 with POLR1D was confirmed by dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP). TCGA data showed that both POLR1D and YY1 expressions were up-regulated in CRC patients. High expression of POLR1D was associated with poor prognosis of CRC patients. The results showed that POLR1D and YY1 were highly expressed in CRC cell lines. Inhibition or overexpression of POLR1D can respectively suppress or enhance proliferation and angiogenesis of CRC cells. YY1 inhibition can suppress CRC progression and deactivate p38 MAPK signal pathway, which can be counteracted by POLR1D overexpression. JASPAR predicted YY1 can bind with POLR1D promoter, which was confirmed by dual luciferase reporter gene assay and ChIP. YY1 transcription can up-regulate POLR1D expression to activate p38 MAPK signal pathway, thus promoting proliferation and angiogenesis ability of CRC cells.

Serum adenosine deaminase as breast and colorectal cancer progression biomarker

Serum adenosine deaminase as breast and colorectal cancer progression biomarker

CXCL1/IGHG1 signaling enhances crosstalk between tumor cells and tumor-associated macrophages to promote MC-LR-induced colorectal cancer progression

Microcystin-leucine arginine (MC-LR) is a common cyantotoxin produced by hazardous cyanobacterial blooms, and eutrophication is increasing the contamination level of MC-LR in drinking water supplies and aquatic foods. MC-LR has been linked to colorectal cancer (CRC) progression associated with tumor microenvironment, however, the underlying mechanism is not clearly understood. In present study, by using GEO, KEGG, GESA and ImmPort database, MC-LR related differentially expressed genes (DEGs) and pathway- and gene set-enrichment analysis were performed. Of the three identified DEGs (CXCL1, GUCA2A and GDF15), CXCL1 was shown a positive association with tumor infiltration, and was validated to have a dominantly higher upregulation in MC-LR-treated tumor-associated macrophages (TAMs) rather than in MC-LR-treated CRC cells. Both CRC cell/macrophage co-culture and xenograft mouse models indicated that MC-LR stimulated TAMs to secrete CXCL1 resulting in promoted proliferation, migration, and invasion capability of CRC cells. Furtherly, IP-MS assay found that interaction between TAMs-derived CXCL1 and CRC cell-derived IGHG1 may enhance CRC cell proliferation and migration after MC-LR treatment, and this effect can be attenuated by silencing IGHG1 in CRC cell. In addition, molecular docking analysis, co-immunoprecipitation and immunofluorescence further proved the interactions between CXCL1 and IGHG1. In conclusion, CXCL1 secreted by TAMs can trigger IGHG1 expression in CRC cells, which provides a new clue in elucidating the mechanism of MC-LR-mediated CRC progression.

MAPKAP1 orchestrates macrophage polarization and lipid metabolism in fatty liver-enhanced colorectal cancer

Various factors, including fatty liver and macrophage alterations, influence colorectal cancer (CRC). This study explores the mechanistic role of fatty liver in CRC progression, focusing on macrophage polarization and lipid metabolism. A murine fatty liver model was created with a high-fat diet (HFD), and CRC was induced using AOM and DSS. Single-cell transcriptome sequencing (scRNA-seq) identified MAPKAP1 as a critical gene promoting CRC via M2 macrophage polarization and lipid metabolism reprogramming. Prognosis analysis on the TCGA-CRC dataset confirmed MAPKAP1′s significance. In vitro and in vivo experiments demonstrated that EVs from fatty liver cells enhanced MAPKAP1 expression, accelerating CRC development and metastasis. HFD exacerbated CRC, but fatty acid inhibitors delayed progression. Fatty liver upregulates MAPKAP1, driving M2 macrophage polarization and lipid metabolism changes, worsening CRC. These findings suggest potential therapeutic strategies for CRC, particularly targeting lipid metabolism and macrophage-mediated tumor promotion.

Exposure to Microcystin-LR Promotes Colorectal Cancer Progression by Altering Gut Microbiota and Associated Metabolites in APCmin/+ Mice.

Microcystins (MCs), toxins generated by cyanobacteria, feature microcystin-LR (MC-LR) as one of the most prevalent and toxic variants in aquatic environments. MC-LR not only causes environmental problems but also presents a substantial risk to human health. This study aimed to investigate the impact of MC-LR on APCmin/+ mice, considered as an ideal animal model for intestinal tumors. We administered 40 µg/kg MC-LR to mice by gavage for 8 weeks, followed by histopathological examination, microbial diversity and metabolomics analysis. The mice exposed to MC-LR exhibited a significant promotion in colorectal cancer progression and impaired intestinal barrier function in the APCmin/+ mice compared with the control. Gut microbial dysbiosis was observed in the MC-LR-exposed mice, manifesting a notable alteration in the structure of the gut microbiota. This included the enrichment of Marvinbryantia, Gordonibacter and Family_XIII_AD3011_group and reductions in Faecalibaculum and Lachnoclostridium. Metabolomics analysis revealed increased bile acid (BA) metabolites in the intestinal contents of the mice exposed to MC-LR, particularly taurocholic acid (TCA), alpha-muricholic acid (α-MCA), 3-dehydrocholic acid (3-DHCA), 7-ketodeoxycholic acid (7-KDCA) and 12-ketodeoxycholic acid (12-KDCA). Moreover, we found that Marvinbryantia and Family_XIII_AD3011_group showed the strongest positive correlation with taurocholic acid (TCA) in the mice exposed to MC-LR. These findings provide new insights into the roles and mechanisms of MC-LR in susceptible populations, providing a basis for guiding values of MC-LR in drinking water.

Overexpression of Fatty Acid Synthase Upregulates Glutamine-Fructose-6-Phosphate Transaminase 1 and O-Linked N-Acetylglucosamine Transferase to Increase O-GlcNAc Protein Glycosylation and Promote Colorectal Cancer Growth.

Fatty acid synthesis has been extensively investigated as a therapeutic target in cancers, including colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in CRC, and therapeutic approaches of targeting this enzyme are currently being tested in multiple clinical trials. However, the mechanisms behind the pro-oncogenic action of FASN are still not completely understood. Here, for the first time, we show that overexpression of FASN increases the expression of glutamine-fructose-6-phosphate transaminase 1 (GFPT1) and O-linked N-acetylglucosamine transferase (OGT), enzymes involved in hexosamine metabolism, and the level of O-GlcNAcylation in vitro and in vivo. Consistently, expression of FASN significantly correlates with expression of GFPT1 and OGT in human CRC tissues. shRNA-mediated downregulation of GFPT1 and OGT inhibits cellular proliferation and the level of protein O-GlcNAcylation in vitro, and knockdown of GFPT1 leads to a significant decrease in tumor growth and metastasis in vivo. Pharmacological inhibition of GFPT1 and OGT leads to significant inhibition of cellular proliferation and colony formation in CRC cells. In summary, our results show that overexpression of FASN increases the expression of GFPT1 and OGT as well as the level of protein O-GlcNAcylation to promote progression of CRC; targeting the hexosamine biosynthesis pathway could be a therapeutic approach for this disease.

Resveratrol triggers autophagy-related apoptosis to inhibit the progression of colorectal cancer via inhibition of FOXQ1.

Colorectal cancer (CRC) is a significant health problem with elevated mortality rates, prompting intense exploration of its complex molecular mechanisms and innovative therapeutic avenues. Resveratrol (RSV), recognised for its anticancer effects through SIRT1 activation, is a promising candidate for CRC treatment. This study focuses on elucidating RSV's role in CRC progression, particularly its effect on autophagy-related apoptosis. Using bioinformatics, protein imprinting and immunohistochemistry, we established a direct correlation between FOXQ1 and adverse CRC prognosis. Comprehensive in vitro experiments confirmed RSV's ability to promote autophagy-related apoptosis in CRC cells. Plasmids for SIRT1 modulation were used to investigate underlying mechanisms. Molecular docking, glutathione-S-transferase pull-down experiments and immunoprecipitation highlighted RSV's direct activation of SIRT1, resulting in the inhibition of FOXQ1 expression. Downstream interventions identified ATG16L as a crucial autophagic target. In vivo and in vitro studies validated RSV's potential for CRC therapy through the SIRT1/FOXQ1/ATG16L pathway. This study establishes RSV's capacity to enhance autophagy-related cell apoptosis in CRC, positioning RSV as a prospective therapeutic agent for CRC within the SIRT1/FOXQ1/ATG16L pathway.

NLRX1: a key regulator in mitochondrial respiration and colorectal cancer progression.

Colorectal cancer (CRC) is a prevalent and aggressive malignancy with high mortality rates and significant risks to human well-being. Population-wide screening for tumor suppressor genes and oncogenes shows promise for reducing the incidence and fatality of CRC. Recent studies have suggested that NLRX1, an innate immunity suppressor, may play a role in regulating chronic inflammation and tumorigenesis. However, further investigation is needed to understand the specific role of NLRX1 in CRC. To evaluate the impact of NLRX1 on migration, invasion, and metastasis, two human colon cancer cell lines were studied in vitro. Additionally, a knockout mouse tumor-bearing model was used to validate the inhibitory effect of NLRX1 on tumor emergence and progression. The Seahorse XF96 technology was employed to assess mitochondrial function and glycolysis in colorectal cancer cells overexpressing NLRX1. Moreover, public databases were consulted to analyze gene and protein expression levels of NLRX1. Finally, the results were validated using a series of CRC patient samples. Our findings demonstrate that downregulation of NLRX1 enhances proliferation, colony formation, and tumor-forming capacity in HCT116 and LoVo cells. Conversely, overexpression of NLRX1 negatively impacts basal respiration and mitochondrial ATP-linked respiration in both cell lines, resulting in a notable decrease in maximal respiration during the standard mitochondrial stress test. Furthermore, analysis of data from the TCGA database reveals a significant reduction in NLRX1 expression in colon and rectal cancer tissues compared to normal tissues. This result was validated using clinical samples, where immunohistochemistry staining and western blotting demonstrated a notable reduction in NLRX1 protein levels in CRC compared to adjacent normal tissues. The decreased expression of NLRX1 may serve as a significant prognostic indicator and diagnostic biomarker for CRC patients.