Colorectal Cancer Cell Migration Research Articles

Investigating the Effects of HMGB1 Overexpression on Colorectal Cancer Cell Migration via Oncolytic Herpes simplex Virus Type 1 (oHSV-1).

Colorectal Cancer (CRC) represents a significant global health challenge, and its progression, resistance to therapy, and metastasis are strongly influenced by the tumor microenvironment, including factors like hypoxia. This study explores the impact of High Mobility Group Box 1 (HMGB1) overexpression on CRC cell migration, while identifying potential genes associated with this process. To explore this, we developed oncolytic virotherapy, resulting in HSVHMGB1, an oncolytic Herpes simplex virus that expresses HMGB1. HMGB1 is known its role in cancer progression, particularly in the context of cancer cell migration. Contrary to expectations, our scratch assays indicated that HSV-HMGB1 did not significantly induce migration in CRC cells, suggesting that HMGB1 might not directly contribute to this process. Employing microarray analysis, we investigated gene expression changes linked to CRC cell migration, leading to construction of a Protein-Protein Interaction (PPI) network. This network revealed the presence of hub proteins, including as NDRG1, LGALS1, and ANGPTL4, which are recognized for their roles in cancer cell migration. The differential expression of these genes under hypoxic conditions was further validated using quantitative RT-PCR, aligning with the findings from our microarray data. Our findings emphasize the complex regulation of CRC cell migration, and provides valuable insights into potential molecular mechanisms and pathways. These findings have implications for further research into cancer progression and the development of therapeutic strategies.

TRIM3 inhibits colorectal cancer cell migration and lipid droplet formation by promoting FABP4 degradation.

This study is to investigate the regulation of TRIM3/FABP4 on colorectal cancer (CRC) cell migration and lipid metabolism. After transfection of HCT116, LoVo, or SW480 cells, the expression of FABP4, TRIM3, N-cadherin, Vimentin, E-cadherin, and lipid droplet (LD) formation-related genes was measured by qRT-PCR or western blot assays. Wound healing and Transwell assays were applied to detect CRC cell migration and invasion abilities. The levels of triglyceride (TG) and total cholesterol (TC) were measured and the formation of LDs was observed. Additionally, the relationship between FABP4 and TRIM3 was confirmed by Co-IP and ubiquitination assays. Furthermore, a liver metastasis model of CRC was established to explore the effect of FABP4 on CRC tumor metastasis in vivo. FABP4 was upregulated in CRC cells. Downregulation of FABP4 or upregulation of TRIM3 resulted in repressed cell migration and invasion, decreased TG and TC levels, and reduced numbers of LDs. In nude mice, knockdown of FABP4 reduced metastatic nodules in the liver. Mechanistically, TRIM3 combined FABP4 and decreased its protein expression by ubiquitination. Overexpressed FABP4 reversed the influence of TRIM3 upregulation on CRC cell migration and LD formation. In conclusion, underexpressed TRIM3 suppressed FABP4 ubiquitination and accelerated CRC cell migration and LD formation.

TiO2-Ti3C2 Nanocomposites Utilize Their Photothermal Activity for Targeted Treatment of Colorectal Cancer.

The search for effective and low-risk treatment methods for colorectal cancer (CRC) is a pressing concern, given the inherent risks and adverse reactions associated with traditional therapies. Photothermal therapy (PTT) has emerged as a promising approach for cancer treatment, offering advantages such as non-radiation, non-invasiveness, and targeted treatment. Consequently, the development of nanoparticles with high stability, biocompatibility, and photothermal effects has become a significant research focus within the field of PTT. In this study, TiO2-Ti3C2 nanocomposites were synthesized and characterized, and their photothermal conversion efficiency in the near-infrared region II (NIR-II) was determined. Then studied the in vivo and in vitro photothermal activity and anti-tumor effect of TiO2-Ti3C2 in human colorectal cancer cell lines and nude mice subcutaneous tumor model. The results showed that TiO2-Ti3C2 nanocomposites have strong absorption ability in the NIR-II, and have high photothermal conversion efficiency under 1064 nm (0.5 W/cm2, 6 min) laser stimulation. In addition, in vitro experiments showed that TiO2-Ti3C2 nanocomposites significantly inhibited the invasion, migration, and proliferation of colorectal cancer cells, and induced cell apoptosis; in vivo, experiments showed that TiO2-Ti3C2 nanocomposites-mediated PTT had good biocompatibility and efficient targeted inhibition of tumor growth. In conclusion, TiO2-Ti3C2 nanocomposites can be used as NIR-II absorption materials in PTT to suppress the invasion, migration, and proliferation of colorectal cancer cells, induce colorectal cancer cell apoptosis, and thus inhibit the development of CRC. Therefore, TiO2-Ti3C2 nanocomposites can be used as potential anti-tumor drugs for photothermal ablation of colorectal cancer cells.

Mechanism of miR-7 mediating TLR4/TRAF6/NF-κB inflammatory pathway in colorectal cancer

This study is aimed at investigating the roles of Toll-like receptor 4 (TLR4) and microRNA-7 (miR-7) in colorectal cancer (CRC) development and progression. We assessed TLR4 and miR-7 expression in CRC cells and tissues using reverse transcription-quantitative polymerase chain reaction. The relationship between miR-7 and TLR4 was analyzed through dual luciferase reporter assays. MTT, wound healing, and cell invasion assays were conducted to examine the effects of TLR4 and miR-7 on CRC cell proliferation, migration, and invasion. Western blotting was used to explore the involvement of the TRAF6/NF-κB signaling pathway. miR-7 was underexpressed in CRC, while TLR4 levels were increased. miR-7 negatively regulated TLR4 expression and its knockdown enhanced CRC cell proliferation, migration, and invasion. TLR4 knockdown had the opposite effects. The TRAF6/NF-κB pathway was linked to TLR4’s role in tumor progression. miR-7 might inhibit TRAF6/NF-κB target a signaling pathway of TLR4 and promote CRC occurrence. miR-7 may therefore be used as a sensitive biomarker in CRC patients.

Effect of Paxillin Expression and Phosphorylation on Colorectal Cancer Prognosis and Metastasis.

Colorectal cancer (CRC) is the third most common cancer worldwide, and metastasis is strongly associated with poor prognosis in patients with CRC. We have previously found that the expression and phosphorylation of paxillin (PXN) play an important role in the metastatic potential of breast cancer. This study examined the potential role of PXN in CRC metastasis. Resected tumor specimens from 92 patients with CRC were subjected to immunohistochemical analysis of PXN levels. Three human CRC cell lines, HCT116, LoVo, and SW480 were used for scratch and transwell invasion assays to examine the effects of PXN over-expression. RNA sequencing was performed to obtain the expression profiles under PXN over-expression. High levels of PXN were significantly correlated with advanced stage, higher carcinoembryonic antigen and carbohydrate antigen 19-9 levels, and poorer overall survival. The migration ability of CRC cells was enhanced by exogenous PXN over-expression, but this enhancement was not observed in cells harboring exogenously mutated PXN at Tyr31 or Tyr88 phosphorylation sites. In PXN-over-expressing cells, TNF-α signaling via NF-[Formula: see text]B was positively enriched. PXN expression and phosphorylation at Tyr31 or Tyr88 may influence the migration and invasion of CRC cells. PXN expression and phosphorylation at Tyr31 or Tyr88 are promising targets for evaluating prognosis and treating CRC.

O-GlcNAcylation of CSNK2A1 by OGT is Involved in the Progression of Colorectal Cancer.

Colorectal cancer (CRC) metastasis is challenging for improved clinical outcomes. The casein kinase 2 alpha 1 (CSNK2A1) is an oncogene involved in several cancers. This study aimed to investigate the influence of CSNK2A1 on CRC progression and the related molecular mechanism. The CSNK2A1 levels were predicted using bioinformatic analysis and were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Cell phenotypes were analyzed using cell-counting kit-8, colony formation, transwell assay, and western blot. Tumor growth was evaluated in a tumor-bearing mouse model in vivo. Similarly, O-GlcNAc modification of CSNK2A1 was assessed by immunoprecipitation, western blot, and immunofluorescence. Results indicated that CSNK2A1 was upregulated in CRC and was related to poor prognosis. Interference with CSNK2A1 suppressed CRC cell proliferation, migration, invasion, and epithelial-mesenchymal transition, inhibiting tumor growth. Moreover, OGT promoted the glycosylation modification of CSNK2A1, enhanced its protein stability, and reversed tumor progression when CSNK2A1 was knocked down. The CSNK2A1 might also affect CRC progression via the PI3K/AKT pathway. In conclusion, the OGT-O-GlcNAcylation-CSNK2A1 axis accelerated the malignant advancement of CRC, suggesting potential CRC therapeutic targets.

Sodium Butyrate Inhibits the Expression of Thymidylate Synthase and Induces Cell Death in Colorectal Cancer Cells.

The most commonly used chemotherapy for colorectal cancer (CRC) is the application of 5-fluorouracil (5-FU). Inhibition of thymidylate synthase (TYMS) expression appears to be a promising strategy to overcome the decreased sensitivity to 5-FU caused by high expression of TYMS, which can be induced by 5-FU treatment. Several compounds have been shown to potentially inhibit the expression of TYMS, but it is unclear whether short-chain fatty acids (SCFAs), which are naturally produced by bacteria in the human intestine, can regulate the expression of TYMS. Sodium butyrate (NaB) is the most widely known SCFA for its beneficial effects. Therefore, we investigated the enhancing effects on inhibition of cell viability and induction of apoptosis after co-treatment of NaB with 5-FU in two CRC cell lines, HCT116 and LoVo. This study suggests that the effect of NaB in improving therapeutic sensitivity to 5-FU in CRC cells may result from a mechanism that strongly inhibits the expression of TYMS. This study also shows that NaB inhibits the migration of CRC cells and can cause cell cycle arrest in the G2/M phase. These results suggest that NaB could be developed as a potential therapeutic adjuvant to improve the therapeutic effect of 5-FU in CRC.

P1212 Effects of Enterococcus faecalis-derived Gelatinase E on HCT116 colorectal cancer cells

Abstract Background The leading cause of death in colorectal cancer (CRC) patients is metastasis to crucial organs, such as the lung, brain and liver. The tumour microenvironment (TME) influences metastasis heavily. One important component in the TME of CRC is the microbiota. Microbiota can affect several pathways related to the origin of metastasis and reorganization of the extracellular matrix. One of the possible contributors to early CRC metastasis is Enterococcus faecalis. E. faecalis produces Gelatinase E (GelE), a quorum-sensing protein with collagenolytic properties. The primary goal of our study was to determine the effect of GelE on CRC behaviour, and especially on migration and invasion in HCT-116 human CRC cells. Moreover, we aimed to uncover the underlying pathways by which GelE influences CRC cells. Methods Extracellular GelE was purified from E. faecalis strain V583 from the culture medium. HCT-116 cells were cultured and exposed to different concentrations of GelE. We performed a viability assay using CCK-8 to assess potential toxicity of GelE. To test effects of GelE on collagen structure, we measured stiffness of collagen-I. A transwell assay was used to assess the influence of GelE on invasive capacity of cells through a collagen-I matrix. GelE exposed cells were assessed for shape and motility markers using immunofluorescent staining for β-catenin (cell shape) and loss of E-cadherin (cell motility marker). For mechanistic insight of GelE exposure on HCT116, we performed proteomics analysis on the cells. Results GelE treatment did not affect relative cell viability of HCT116 cells up to a concentration of 100 μg/ml. Exposure to GelE caused a concentration-dependent increase in HCT-116 cell invasion through collagen-I. The immunostainings showed a downregulation of E-cadherin, indicating an induction of cell motility. Immunostaining for β-catenin showed a statistically significant effect on cell shape, becoming more elongated, an additional indication of cell motility. Proteomics showed possible mechanistic pathways that explain the increased motility including activation of the SMAD pathway, RhoGTPAse activation and activation the urokinase-plasminogen system. Reactome database analysis on the proteomics data also revealed an increase in cell-cycle related pathways. Conclusion Our results indicate that E. faecalis-derived GelE drives HCT-116 invasion with an elongated motility. Therefore, drugs inhibiting the activity of GelE could decrease the risk of metastasis in patients with a high E. faecalis V583 abundance in the TME.

Anti‐tumor efficacy of emodin on colorectal cancer cells via targeting lncRNA HLA complex P5

AbstractEmodin is a naturally occurring anthraquinone derivative with a variety of pharmacologic effects, but its role and regulatory mechanism in colorectal cancer (CRC) remain to be investigated. Thus, the aim of this study is to explore the effect of emodin on CRC cells. A gradient of emodin and long noncoding RNA HCP5 overexpression plasmid/small interfering RNA targeting HCP5 (siHCP5) were used for treating CRC cells. Expression levels of RNAs and proteins were detected by utilizing quantitative real‐time polymerase chain reaction and Western blot. The viability, migration, and invasion of CRC cells were tested via cell counting kit‐8, wound healing, and Transwell assays. In HT29 and HCT116 cells, the viability, migration, and invasion, along with HCP5 expression, were suppressed by emodin in a dose‐dependent manner. HCP5 overexpression elevated the viability, migration as well as invasion, and up‐regulated N‐cadherin, MMP‐2, and MMP‐9 levels, while reducing E‐cadherin expression. Nevertheless, silencing of HCP5 inhibited the viability, migration as well as invasion, and down‐regulated N‐cadherin, MMP‐2 and MMP‐9 expression levels, while increasing E‐cadherin expression. Additionally, the promoting role of HCP5 overexpression in CRC cells was reversed by emodin, while the suppressive role of siHCP5 was enhanced by emodin in CRC cells. Our study indicates that emodin is a promising agent to inhibit CRC progression through suppression of HCP5 expression.

Lysine acetyltransferase KAT2A modulates ferroptosis during colorectal cancer development

Background Histone modifications, especially the lysine acetylation, have drawn increasing attention in cancer research area. The aim of this research is to explore the molecular mechanisms underlying the regulation of lysine acetyltransferase 2 A (KAT2A) on colorectal cancer (CRC). Methods Clinical samples were collected from patients with CRC. The expression and correlation between KAT2A and ferroptosis suppressor SLC7A11 and glutathione peroxidase 4 (GPX4) were measured by qPCR and Pearson correlation analysis. NCP cells were transfected with KAT2A overexpression vectors or siRNAs. The proliferation of cells was measured by CCK-8 and colony formation assay. Cell migration and invasion was analyzed by Transwell. The accumulation of lipid peroxidation, ferrous iron, and malondialdehyde (MDA) were analyzed to determine cell ferroptosis. The expression of cell metastasis biomarkers was measured by western blotting assay. Interaction between KAT2A with GPX4 gene was measured by chromatin immunoprecipitation (ChIP). Results The KAT2A, GPX4, and SLC7A11 expression was notably elevated in tumor tissues compared with the paired non-tumor tissues from CRC patients. The expression of KAT2A showed positive correlation with GPX4 and SLC7A11. Overexpression of KAT2A recovered the cell proliferation, migration, and invasion of CRC cells that suppressed by ferroptosis inducer erastin, along with deceased levels of ROS, iron, Fe2+, and MDA. Overexpression of KAT2A suppressed E-cadherin level and increased N-cadherin, Snail, and Vimentin expression in CRC cells. KAT2A interacted with GPX4 promoter region. Conclusions In conclusion, our findings demonstrated that KAT2A modulates the histone acetylation of GPX4 to regulate proliferation, metastasis, and ferroptosis of CRC cells.

Enterotoxigenic Bacteroides fragilis (ETBF) Enhances Colorectal Cancer Cell Proliferation and Metastasis Through HDAC3/miR-139-3p Pathway.

Enterotoxigenic Bacteroides fragilis (ETBF) is believed to promote the malignant process of colorectal cancer (CRC), but the underlying molecular mechanism still needs to be revealed. CRC cells (SW480 and HCT-116) were treated with ETBF strain. Cell proliferation, invasion and, migration were evaluated by cell counting kit 8 assay, EdU assay, colony formation assay, transwell assay, and wound healing assay. Protein expression was analyzed by western blot. MicroRNA (miR)-139-3p and histone deacetylase 3 (HDAC3) expression levels in tissues and cells were determined by qRT-PCR. Xenograft tumor model was conducted to evaluate the effect of miR-139-3p on CRC tumor growth. ETBF treatment could promote CRC cell proliferation, invasion and migration. MiR-139-3p expression was decreased by ETBF, and its overexpression reversed the effect of ETBF on CRC cell progression. HDAC3 negatively regulated miR-139-3p expression, and its overexpression facilitated CRC cell behaviors via reducing miR-139-3p expression. Moreover, HDAC3 expression was increased by ETBF, and its knockdown also abolished ETBF-mediated CRC cell progression. Additionally, miR-139-3p overexpression could reduce CRC tumor growth in vivo. ETBF aggravated CRC proliferation and metastasis via the regulation of HDAC3/miR-139-3p axis. The discovery of ETBF/HDAC3/miR-139-3p axis may provide a new direction for CRC treatment.

Leukotriene B4 receptor knockdown affects PI3K/AKT/mTOR signaling and apoptotic responses in colorectal cancer.

Colorectal cancer (CRC) presents a landscape of intricate molecular dynamics. In this study, we focused on the role of the leukotriene B4 receptor (LTB4R) in CRC, exploring its significance in the disease's progression and potential therapeutic approaches. Using bioinformatics analysis of the GSE164191 and the Cancer Genome Atlas-colorectal adenocarcinoma (TCGA-COAD) datasets, we identified LTB4R as a hub gene influencing CRC prognosis. Subsequently, we examined the relationship between LTB4R expression, apoptosis, and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway through cellular and mice experiments. Our findings revealed that LTB4R is highly expressed in CRC samples and is pivotal for determining prognosis. In vitro experiments demonstrated that silencing LTB4R significantly impeded CRC cell viability, migration, invasion, and colony formation. Correspondingly, in vivo tests indicated that LTB4R knockdown led to markedly slower tumor growth in mice models. Further in-depth investigation revealed that LTB4R knockdown significantly amplified the apoptosis in CRC cells and upregulated the expression of apoptosis-related proteins, such as caspase-3 and caspase-9, while diminishing p53 expression. Interestingly, silencing LTB4R also resulted in a significant downregulation of the PI3K/AKT/mTOR signaling pathway. Moreover, pretreatment with the PI3K activator 740Y-P only partially attenuated the effects of LTB4R knockdown on CRC cell behavior, emphasizing LTB4R's dominant influence in CRC cell dynamics and signaling pathways. LTB4R stands out as a critical factor in CRC progression, profoundly affecting cellular behavior, apoptotic responses, and the PI3K/AKT/mTOR signaling pathway. These findings not only shed light on LTB4R's role in CRC but also establish it as a potential diagnostic biomarker and a promising target for therapeutic intervention.

BVES-AS1 suppresses the colorectal cancer progression via the miR-1269a/b-SVEP1-PI3K/AKT axis.

Numerous studies have indicated the engagement of long non-coding RNA (lncRNA) in various cancer types, including colorectal cancer (CRC). However, the functional and mechanistic roles of lncRNAs in CRC remain largely elusive. The aim of this study was to explore the function and mechanism of lncRNA BVES-AS1 in CRC. The expression levels of BVES-AS1 were validated in CRC tissues and paired normal samples using quantitative real-time polymerase chain reaction (qPCR) Subsequently, the biological functions of BVES-AS1 in CRC cells were investigated both in vitro and in vivo. Various experimental techniques such as western blot, fluorescence in situ hybridization, RNA-sequencing (RNA-seq), biotin-labeled miRNA pulldown assay, dual-luciferase reporter gene assay, and RNA-protein immunoprecipitation (RIP) assay were employed to elucidate the potential mechanism of BVES-AS1. The findings of this study demonstrated that BVES-AS1 expression was downregulated in CRC tissues compared to normal tissues, and its expression level was associated with tumor infiltration and tumor-nodule-metastasis (TNM) stage. Furthermore, BVES-AS1 was found to suppress CRC cell proliferation, migration and metastasis both in vitro and in vivo. Mechanistically, BVES-AS1 acted as a sponge for miR-1269a and miR-1269b, thereby regulating SVEP1. Additionally, the silencing of SVEP1 activated the PI3K/AKT pathway. These results suggest that BVES-AS1 plays a crucial role in the progression of CRC through the miR-1269a/b-SVEP1-PI3K/AKT axis, providing new insights into the therapeutic strategies for CRC.

Unraveling a novel hippo-associated immunological prognostic signature: The contribution of SERPINE1 in facilitating colorectal cancer progression via the notch signaling pathway

BackgroundAccumulating evidence demonstrated that Hippo signaling pathway is implicated in tumor initiation and progression. However, there have been limited studies on establishing signatures utilizing genes related to the Hippo pathway to evaluate prognosis and clinical efficacy in colorectal cancer (CRC) patients. MethodsHippo pathway-associated genes with prognostic significance were identified in the TCGA database. Subsequently, a prognostic signature associated with the Hippo pathway was constructed using Cox and LASSO regression analyses. Survival analysis, ROC analysis, and stratified analyses were conducted to appraise the performance effect of our prognostic model. We also explored the relationship between the risk score and tumor immune microenvironment. Furthermore, GO analyses and GSEA were performed for SERPINE1. Additional experiments were conducted to illuminate the underlying function and possible mechanism of SERPINE1 in CRC cell proliferation and migration. ResultsWe identified 58 differentially expressed genes associated with Hippo pathway that have prognostic significance in CRC. Among them, five genes (PPP2CB, SERPINE1, WNT5A, TCF7L1, and LEF1) were selected to establish a prognostic signature for CRC. Multivariate analysis demonstrated that this signature exhibited excellent diagnostic and prognostic performance, providing maximum benefits for CRC patients. In accordance with the prognostic signatures, the cases were divided into low-risk and high-risk groups. Remarkably, the high-risk group displayed lower immune scores, reduced immune cell infiltration, and decreased expression of immune checkpoints. Low-risk group could more possibly benefit from conventional chemotherapeutic and targeted therapies. CRC exhibited significantly elevated expression of SERPINE1, which was linked to worst overall survival. Moreover, inhibition of SERPINE1 suppressed proliferation, invasion, and migration of CRC cells via Notch pathway. ConclusionsTo sum up, we established a novel immunological prognostic signature utilizing genes associated with the Hippo pathway. This signature offers accurate prognostic prediction and can guide individualized therapy for patients with CRC.

Exosomes derived from cancer-associated fibroblasts promote tumorigenesis, metastasis and chemoresistance of colorectal cancer by upregulating circ_0067557 to target Lin28

BackgroundCancer associated fibroblasts (CAFs) can remodel tumor microenvironment by secreting exosomes. This study aimed to investigate the role of exosomes derived from cancer-associated fibroblasts in colorectal cancer (CRC) progression.MethodsCircular RNA (circRNA) array was used to identify differentially expressed circRNAs in exosomes from normal fibroblasts (NFs) and CAFs, and confirmed one differentially expressed circRNA circ_0067557 by real-time PCR. The effect of circ_0067557 on proliferation, metastasis, chemoresistance and apoptosis was verified by wound heal, tranwell, CCK8, sphere-forming and flow cytometry assay.ResultsCirc_0067557 expression in exosomes from CAFs was higher than those from NFs. CAF-derived exosomes promoted the proliferation, migration, invasion and chemoresistance of CRC cells while suppressed apoptosis. Silencing of circ_0067557 inhibited malignant phenotypes of CRC cells by targeting Lin28A and Lin28B. Moreover, CAF-derived exosomes enhanced the growth of CRC xenograft tumors.ConclusionCirc_0067557/Lin28A and Lin28B signal axis may be a potential therapy target for CRC.

ETV7 promotes colorectal cancer progression through upregulation of IFIT3

Members of the E26 transformation-specific (ETS) variant transcription factor family act as either tumor suppressors or oncogenic factors in numerous types of cancer. ETS variant transcription factor 7 (ETV7) participates in the development of malignant tumors, whereas its involvement in colorectal cancer (CRC) is less clear. In this study, The Cancer Genome Atlas (TCGA) and immunochemistry staining were applied to check the clinical relevance of ETV7 and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) in CRC patients. Overexpression and knockdown of ETV7 and IFIT3 were conducted by transfecting the cells with pCDNA3.1 plasmids and siRNAs, respectively. Western blotting was used to detect the protein expression of ETV7 in CRC cells. Cell Counting Kit-8, cell colony formation, and Transwell assays, as well as flow cytometry, were used to evaluate the proliferation, migration, cell cycle, and apoptosis of CRC cells. Furthermore, western blotting, RT-qPCR, and luciferase assay were used to explore the regulation of ETV7 on IFIT3. Rescue assay was used to investigate the significance of ETV7/IFIT3 axis on CRC progression. We found that ETV7 was upregulated in CRC tissues and cells. Overexpression of ETV7 stimulated the proliferation, migration, and cell cycle amplification, and reduced the apoptosis of CRC cells. Downregulation of ETV7 exerted the opposite effect on CRC cell progression. Moreover, we demonstrated that ETV7 stimulated the transcription activity, the mRNA and protein expression of IFIT3 in CRC cells. There was a positive correlation between ETV7 and IFIT3 in CRC patients. IFIT3 knockdown reversed the promotive effect exerted by overexpression of ETV7 on the amplification and migration of CRC cells. By contrast, overexpression of IFIT3 blocked the inhibitory effect of ETV7-targeting siRNA. In summary, ETV7 induces progression of CRC by activating the transcriptional expression of IFIT3. The EVT7/IFIT3 axis may be a novel target for CRC therapy.

ABHD6 suppresses colorectal cancer progression via AKT signaling pathway.

Colorectal cancer (CRC) continues to be a prevalent malignancy, posing a significant risk to human health. The involvement of alpha/beta hydrolase domain 6 (ABHD6), a serine hydrolase family member, in CRC development was suggested by our analysis of clinical data. However, the role of ABHD6 in CRC remains unclear. This study seeks to elucidate the clinical relevance, biological function, and potential molecular mechanisms of ABHD6 in CRC. We investigated the role of ABHD6 in clinical settings, conducting proliferation, migration, and cell cycle assays. To determine the influence of ABHD6 expression levels on Oxaliplatin sensitivity, we also performed apoptosis assays. RNA sequencing and KEGG analysis were utilized to uncover the potential molecular mechanisms of ABHD6. Furthermore, we validated its expression levels using Western blot and reactive oxygen species (ROS) detection assays. Our results demonstrated that ABHD6 expression in CRC tissues was notably lower compared to adjacent normal tissues. This low expression correlated with a poorer prognosis for CRC patients. Moreover, ABHD6 overexpression impeded CRC cell proliferation and migration while inducing G0/G1 cell cycle arrest. In vivo experiments revealed that downregulation of ABHD6 resulted in an increase in tumor weight and volume. Mechanistically, ABHD6 overexpression inhibited the activation of the AKT signaling pathway and decreased ROS levels in CRC cells, suggesting the role of ABHD6 in CRC progression via the AKT signaling pathway. Our findings demonstrate that ABHD6 functions as a tumor suppressor, primarily by inhibiting the AKT signaling pathway. This role establishes ABHD6 as a promising prognostic biomarker and a potential therapeutic target for CRC patients.

Circular RNA FMN2 motivates colorectal cancer development by mediating tumor-associated macrophage polarization by controlling the microRNA-150-5p/PIK3R3 axis

BackgroundIt has been reported that circular RNA formin 2 (circFMN2) can motivate colorectal cancer (CRC) proliferation. However, the effect of circFMN2 on the polarization of tumor-associated macrophages (TAMs) in the CRC tumor microenvironment remains unclear. The study was to figure out the latent mechanism by which circFMN2 impacts TAM polarization to motivate the malignant behavior of CRC cells. ResultscircFMN2 and PIK3R3 levels were reduced in M1 macrophages but elevated in M2 macrophages, whereas miR-150-5p level was the opposite. circFMN2 knockdown downregulated M2 macrophage markers CD163, CCL22 and CD206 and upregulated M1 macrophage markers CD86, TNF-α and IL-1β in M2 macrophages. Co-culture with M2 macrophage-conditioned medium with circFMN2 knockdown reduced CRC proliferation, invasion, and migration, while knockdown of miR-150-5p had the opposite effect. CircFMN2 adsorbed miR-150-5p to mediate PIK3R3 in M2 macrophages. Overexpression of miR-150-5p can reverse the promoting effects of overexpression of circFMN2 on M2 polarization, CRC cell proliferation, invasion, and migration. Elevation of PIK3R3 could turn around the repressive effect of circFMN2 knockdown on M2 polarization and CRC cell proliferation, invasion, and migration. In an in vivo model, M2 macrophages expressing low or high circFMN2 were co-transplanted with CRC cells into nude mice, resulting in inhibition and promotion of tumor growth, respectively. ConclusionsAll in all, circFMN2 mediates TAM polarization to M2 type by controlling the miR-150-5p/PIK3R3 axis to motivate CRC development and may offer a latent molecular target for CRC treatment.How to cite: Cao Y, Cao D, Zhu T. Circular RNA FMN2 motivates colorectal cancer development by mediating tumor-associated macrophage polarization by controlling the microRNA-150-5p/PIK3R3 axis. Electron J Biotechnol 2024;68. https://doi.org/10.1016/j.ejbt.2023.12.002.

E3 ubiquitin ligase RNF148 functions as an oncogene in colorectal cancer by ubiquitination-mediated degradation of CHAC2.

We previously reported that RNF148 was involved in the ubiquitination-mediated degradation of CHAC2. However, its molecular mechanism was not determined. In this study, we investigated the role and mechanism of RNF148 in the progression of colorectal cancer (CRC), especially in the process of ubiquitination-mediated degradation of CHAC2. Our results revealed that RNF148 was upregulated in most CRC tissues, and its expression significantly correlated with the 3-year overall survival rate and most clinicopathological parameters of CRC patients. Furthermore, RNF148 served as an independent prognostic biomarker of CRC and promoted CRC cell proliferation and migration while inhibiting cell apoptosis and sensitivity to 5-FU. Mechanistically, RNF148 used its protease-associated domain to bind to the CHAC domain of CHAC2 and target it for degradation. In addition, we identified two phosphorylation and three ubiquitination residues of CHAC2 and identified Y118 and K102 as the critical phosphorylation and ubiquitination residues, respectively. We also identified CHAC2's and RNF148's interacting proteins and discovered their potential interaction network. In conclusion, our current study unveiled the role of RNF148 in CRC and the mechanism of RNF148 in the ubiquitination-mediated degradation of CHAC2, which shed light on providing potential prognostic biomarkers and molecular targets for CRC patients.

β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K

Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC50 value of 4.28 µM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.Graphical