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Colorectal cancer is the third most common cancer in the world with increasing incidence and mortality rates globally. Standard treatments for colorectal cancer have always been surgery, chemotherapy and radiotherapy which may be used in combination to treat patients. However, these treatments have many side effects due to their non-specificity and...
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Citations
... These approaches often lead to several side-effects such as postoperative infectious complications, diarrhea, vomiting, nausea, etc. (4)(5)(6). More recently, immunotherapy and targeted therapy have emerged as viable options in select cases (5,7). ...
... Although this systematic review also aimed to study the impact of microbiota modulation in immunotherapy, no studies meeting our inclusion criteria, specifically focusing on CRC patients undergoing immunotherapy were found. This treatment is a relatively new approach for CRC patients so it's possible that research may still be ongoing, and results will be published upcoming years regarding the role of pre-, pro-, and synbiotic supplementation in CRC patients undergoing immunotherapy (7,78). Nevertheless, a recent meta-analysis, that included 6 studies, reported that probiotics improved the efficacy of immune checkpoint inhibitors in non-small cell lung cancer patients with the intervention group having better overall survival and higher objective response rate and disease control rate (79). ...
Introduction
The effectiveness of the supplementation of prebiotics, probiotics and synbiotics as a therapeutic approach in colorectal cancer (CRC) remains unclear. The aim of this systematic review is to critically examine the current scientific evidence on the impact of modulating the microbiota, through the use of prebiotics, probiotics and synbiotics, in patients diagnosed with CRC undergoing treatment, to determine the potential therapeutic use of this approach.
Methods
This systematic review was made according to the PRISMA 2020 guidelines. Inclusion criteria were randomized controlled trials (RCT) comparing the impact of pre-, pro-, or synbiotic supplementation with placebo or standard care in patients with CRC undergoing treatment. Exclusion criteria were non-human studies, non-RCTs, and studies in languages other than English or Portuguese. Six databases were consulted, namely, Cochrane Library, Pubmed, Scopus, Cinahl, MedicLatina and Web of Science until May of 2023. RAYYAN software was used to manage the search results and risk of bias was assessed according to the guidelines of the Cochrane Collaboration using the Rob 2.0 tool.
Results
Twenty-four RCTs met the inclusion criteria and were included in this review. Administration of pre-, pro-, or synbiotics improved surgical outcomes such as the incidence of infectious and non-infectious postoperative complications, return to normal gut function, hospital length of stay, and antibiotic usage. The supplementation of these microorganisms also alleviated some symptoms from chemotherapy and radiotherapy, mainly diarrhea. Evidence on the best approach in terms of types of strains, dosage and duration of intervention is still scarce.
Conclusions
Pre-, pro-, and synbiotics supplementation appears to be a beneficial therapeutic approach in CRC treatment to improve surgical outcomes and to alleviate side-effects such as treatment toxicity. More RCTs with larger sample sizes and less heterogeneity are needed to confirm these potential benefits and to determine the best strains, dosage, and duration of administration in each situation.
Systematic review registration
https://www.crd.york.ac.uk/prospero, identifier CRD42023413958.
... Ulcerative colitis and dysbacteriosis of the intestinal flora have also been shown to be associated with colorectal tumorigenesis [3,4]. Current mainstream treatments for CRC include surgical resection, chemotherapy, radiotherapy, and immunotherapy [5,6]. Despite the significant achievements of CRC treatments, particularly immunotherapy, over the last decade, the prognosis of CRC patients remains unsatisfactory [7][8][9]. ...
This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired from UCSC Xena, GTEx, Gene Expression Omnibus, and TCGA. Pooled analysis of the mRNA expression of LACTB2 in CRC was performed using Stata software. The protein expression of LACTB2 in CRC tissues was evaluated by immunohistochemistry. The relationship between immune cell infiltration and LACTB2 expression was investigated using CIBERSORT. The potential signaling pathways and biological mechanisms of LACTB2 were explored using GSEA, KEGG, and GO. Subsequently, further screening of small molecular compounds with potential therapeutic effects on CRC was conducted through the HERB database, followed by molecular docking studies of these compounds with the LACTB2 protein. The integration and analysis of expression data obtained from 2294 CRC samples and 1286 noncancerous colorectal samples showed that LACTB2 was highly expressed in CRC. Immunohistochemistry performed on in-house tissue samples confirmed that LACTB2 protein expression was upregulated in CRC. CIBERSORT revealed lower B cell infiltration levels in the high LACTB2 expression group than in the low expression group. GO, KEGG, and GSEA analyses showed that LACTB2 expression and genes positively correlating with it were mainly related to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tumor progression.
... There is a tendency for colon cancer to be more common than rectal cancer [15]. The standard treatments for colorectal cancer include surgery, chemotherapy, radiotherapy, or a combination of several methods, but many patients relapse despite a series of treatments [16]. In this study, hBD-1 inhibited the viability and proliferation of SW620 cells. ...
BACKGROUND
Colorectal cancer has a low 5-year survival rate and high mortality. Human β-defensin-1 (hBD-1) may play an integral function in the innate immune system, contributing to the recognition and destruction of cancer cells. Long non-coding RNAs (lncRNAs) are involved in the process of cell differentiation and growth.
AIM
To investigate the effect of hBD-1 on the mammalian target of rapamycin (mTOR) pathway and autophagy in human colon cancer SW620 cells.
METHODS
CCK8 assay was utilized for the detection of cell proliferation and determination of the optimal drug concentration. Colony formation assay was employed to assess the effect of hBD-1 on SW620 cell proliferation. Bioinformatics was used to screen potentially biologically significant lncRNAs related to the mTOR pathway. Additionally, p-mTOR (Ser2448), Beclin1, and LC3II/I expression levels in SW620 cells were assessed through Western blot analysis.
RESULTS
hBD-1 inhibited the proliferative ability of SW620 cells, as evidenced by the reduction in the colony formation capacity of SW620 cells upon exposure to hBD-1. hBD-1 decreased the expression of p-mTOR (Ser2448) protein and increased the expression of Beclin1 and LC3II/I protein. Furthermore, bioinformatics analysis identified seven lncRNAs (2 upregulated and 5 downregulated) related to the mTOR pathway. The lncRNA TCONS_00014506 was ultimately selected. Following the inhibition of the lncRNA TCONS_00014506, exposure to hBD-1 inhibited p-mTOR (Ser2448) and promoted Beclin1 and LC3II/I protein expression.
CONCLUSION
hBD-1 inhibits the mTOR pathway and promotes autophagy by upregulating the expression of the lncRNA TCONS_00014506 in SW620 cells.
... In recent years, the clinical efficacy of immune checkpoint inhibitors, such as PD-1, PD-L1, and CTLA-4, has been demonstrated in COAD treatment (Le et al., 2017;Cantero-Cid et al., 2018;Johdi et al., 2020). Noteworthy drugs in this category, including Opdivo (nivolumab), Keytruda (pembrolizumab), and Yervoy (ipilimumab), have been employed in clinical trials (Boland et al., 2017). ...
Background
Despite the recognized roles of Sialic acid-binding Ig-like lectins (SIGLECs) in endocytosis and immune regulation across cancers, their molecular intricacies in colon adenocarcinoma (COAD) are underexplored. Meanwhile, the complicated interactions between different SIGLECs are also crucial but open questions.
Methods
We investigate the correlation between SIGLECs and various properties, including cancer status, prognosis, clinical features, functional enrichment, immune cell abundances, immune checkpoints, pathways, etc. To fully understand the behavior of multiple SIGLECs’ co-evolution and subtract its leading effect, we additionally apply three unsupervised machine learning algorithms, namely, Principal Component Analysis (PCA), Self-Organizing Maps (SOM), K-means, and two supervised learning algorithms, Least Absolute Shrinkage and Selection Operator (LASSO) and neural network (NN).
Results
We find significantly lower expression levels in COAD samples, together with a systematic enhancement in the correlations between distinct SIGLECs. We demonstrate SIGLEC14 significantly affects the Overall Survival (OS) according to the Hazzard ratio, while using PCA further enhances the sensitivity to both OS and Disease Free Interval (DFI). We find any single SIGLEC is uncorrelated to the cancer stages, which can be significantly improved by using PCA. We further identify SIGLEC-1,15 and CD22 as hub genes in COAD through Differentially Expressed Genes (DEGs), which is consistent with our PCA-identified key components PC-1,2,5 considering both the correlation with cancer status and immune cell abundance. As an extension, we use SOM for the visualization of the SIGLECs and show the similarities and differences between COAD patients. SOM can also help us define subsamples according to the SIGLECs status, with corresponding changes in both immune cells and cancer T-stage, for instance.
Conclusion
We conclude SIGLEC-1,15 and CD22 as the most promising hub genes in the SIGLECs family in treating COAD. PCA offers significant enhancement in the prognosis and clinical analyses, while using SOM further unveils the transition phases or potential subtypes of COAD.
... Given that the majority of CRC patients are diagnosed at middle to advanced stages, missing the optimal surgical window, and facing limited treatment options with radiotherapy and chemotherapy, which frequently result in limited efficacy and severe side effects [25,26], there is an urgent need for the development and optimization of new drugs targeting biological targets. Given that a significant suppression of growth and migration was observed upon HSP90AB1 knockdown in vitro, we sought to investigate whether HSP90AB1 knockdown could impede tumor growth in a CRC mouse model, thereby evaluating its potential as an anti-CRC drug target. ...
Objectives
Colorectal cancer (CRC) is a global challenge, and heat shock protein 90 (HSP90) is identified as a key driver in cancer progression. However, the tumor-promoting mechanism of HSP90 in CRC, particularly HSP90AB1, remains unclear. This study aims to explore and analyze the oncogenic mechanism of HSP90AB1 in CRC and identify potential therapeutic targets.
Materials and methods
HSP90AB1 expression underwent analysis in CRC cell lines and tissues at mRNA and protein levels. Through the use of shRNA, targeted suppression of HSP90AB1 was achieved in CRC cell lines, enabling analysis of its influence on cell proliferation, invasion, apoptosis, and cell cycle progression. Subsequent investigation focused on elucidating the regulatory relationship between HSP90AB1 and IDO1, employing a combination of bioinformatics approaches and in vitro/vivo experiments. These efforts confirmed IDO1 as a downstream target of HSP90AB1 and provided insight into its role in driving CRC progression.
Results
HSP90AB1 exhibits overexpression in both CRC cell lines and tumor tissues (p<0.05). Its downregulation impedes cell proliferation and invasion (p<0.01), promotes apoptosis and cell cycle arrest (p<0.05). Investigation reveals that decreased HSP90AB1 leads to the inhibition of IDO1 (p<0.01), suggesting that IDO1 regulation plays a crucial role in mediating the pro-tumorigenic effects of HSP90AB1. In vivo experiments confirm the substantial reduction in tumor growth upon HSP90AB1 knockdown in xenograft models (p<0.01). However, this tumor-suppressive effect is reversed upon IDO1 overexpression (p<0.01), highlighting IDO1 as a downstream target of HSP90AB1 in CRC progression.
Conclusions
HSP90AB1 exerts a regulatory role in the progression of CRC by upregulating IDO1.
... Following lung and breast cancer, CRC is the third most prevalent cancer globally and has the second highest cancer fatality rate [2]. Currently, the treatment methods for CRC include chemotherapy, radiotherapy, immunotherapy, targeted therapy, and traditional Chinese medicine (TCM) [3]. Surgical resection in conjunction with chemotherapy is the mainstream comprehensive approach for CRC treatment; however, these treatments have not reduced the morbidity, mortality, or recurrence rate of CRC in patients [4]. ...
Natural chemicals derived from herbal plants have recently been recognized as potentially useful treatment alternatives owing to their ability to target a wide range of important biological molecules. Cynaroside is one of these natural compounds with promising anticancer activity for numerous tumor types. Nevertheless, the anticancer effects and molecular mechanisms of action of cynaroside on colorectal cancer (CRC) remain unclear. In this study, cynaroside was found to markedly inhibit CRC cell proliferation and colony formation in vitro. Cynaroside also inhibited cell proliferation in vivo and decreased the expression of KI67, a cell nuclear antigen. RNA sequencing revealed 144 differentially expressed genes (DEGs) in HCT116 cells and 493 DEGs in RKO cells that were enriched in the cell cycle signaling pathway. Cell division cycle 25A (CDC25A), a DEG widely enriched in the cell cycle signaling pathway, is considered a key target of cynaroside in CRC cells. Cynaroside also inhibited DNA replication and arrested cells in the G1/S phase in vitro. The expression levels of CDC25A and related G1-phase proteins were significantly elevated after CDC25A overexpression in CRC cells, which partially reversed the inhibitory effect of cynaroside on CRC cell proliferation and G1/S-phase arrest. In summary, cynaroside may be used to treat CRC as it inhibits CDC25A expression.
... It is the third most common carcinoma and the second most fatal malignant cancer [1]. Although surgical resection, chemoradiotherapy, and immunotherapy are applied for CRC treatment in clinical practice, their effectiveness is frequently limited by poor survival improvement, along with drug resistance, unbearable side effects, and high costs [3,19]. Consequently, it is crucial to develop novel potential drugs for CRC treatment with higher effectiveness and lower toxicity. ...
This study aimed to explore the mechanism through which Tibetan medicine Liuwei Muxiang (LWMX) pills acts against colorectal cancer (CRC). We firstly retrieved the active ingredients and the correlated targets of LWMX pills from public databases. The CRC-related targets were determined through bioinformatic analysis of a public CRC dataset. By computing the intersection of the drug-specific and disease-related targets, LWMX pill–CRC interaction networks were constructed using the protein–protein interaction (PPI) method and functional enrichment analysis. Subsequently, we determined the hub genes using machine learning tools and further verified their critical roles in CRC treatment via immune infiltration analysis and molecular docking studies. We identified 81 active ingredients in LWMX pills with 614 correlated targets, 1877 differentially expressed genes, and 9534 coexpression module genes related to CRC. A total of 5 target hub genes were identified among the 108 intersecting genes using machine learning algorithms. The immune infiltration analysis results suggested that LWMX pills could affect the CRC immune infiltration microenvironment by regulating the expression of the target hub genes. Finally, the molecular docking outcomes revealed stable binding affinity between all target hub proteins and the primary active ingredients of LWMX pills. Our findings illustrate the anti-CRC potential and the mechanism of action of LWMX pills and provide novel insights into multitarget medication for CRC treatment.
... Despite the success of ICIs in recent years, their benefit in metastatic CRC is limited to 3-7% of cases with microsatellite instability [3]. Additionally, the side effects of this therapy can be very risky for patients if they occur [34]. Fluorouracil and oxaliplatin remain the most commonly used baseline chemotherapeutic agents for patients with CRC. ...
Background
A large number of Fusobacterium nucleatum (Fn) are present in colorectal cancer (CRC) tissues of patients who relapse after chemotherapy, and Fn has been reported to promote oxaliplatin and 5-FU chemoresistance in CRC. Pathogens such as bacteria and parasites stimulate exosome production in tumor cells, and the regulatory mechanism of exosomal circRNA in the transmission of oxaliplatin and 5-FU chemotherapy resistance in Fn-infected CRC remains unclear.
Methods
Hsa_circ_0004085 was screened by second-generation sequencing of CRC tissues. The correlation between hsa_circ_0004085 and patient clinical response to oxaliplatin/5-FU was analyzed. Exosome tracing experiments and live imaging systems were used to test the effect of Fn infection in CRC on the distribution of hsa_circ_0004085. Colony formation, ER tracking analysis and immunofluorescence were carried out to verify the regulatory effect of exosomes produced by Fn-infected CRC cells on chemotherapeutic resistance and ER stress. RNA pulldown, LC–MS/MS analysis and RIP were used to explore the regulatory mechanism of downstream target genes by hsa_circ_0004085.
Results
First, we screened out hsa_circ_0004085 with abnormally high expression in CRC clinical samples infected with Fn and found that patients with high expression of hsa_circ_0004085 in plasma had a poor clinical response to oxaliplatin/5-FU. Subsequently, the circular structure of hsa_circ_0004085 was identified. Fn infection promoted hsa_circ_0004085 formation by hnRNP L and packaged hsa_circ_0004085 into exosomes by hnRNP A1. Exosomes produced by Fn-infected CRC cells transferred hsa_circ_0004085 between cells and delivered oxaliplatin/5-FU resistance to recipient cells by relieving ER stress. Hsa_circ_0004085 enhanced the stability of GRP78 mRNA by binding to RRBP1 and promoted the nuclear translocation of ATF6p50 to relieve ER stress.
Conclusions
Plasma levels of hsa_circ_0004085 are increased in colon cancer patients with intracellular Fn and are associated with a poor response to oxaliplatin/5-FU. Fn infection promoted hsa_circ_0004085 formation by hnRNP L and packaged hsa_circ_0004085 into exosomes by hnRNP A1. Exosomes secreted by Fn-infected CRC cells deliver hsa_circ_0004085 between cells. Hsa_circ_0004085 relieves ER stress in recipient cells by regulating GRP78 and ATF6p50, thereby delivering resistance to oxaliplatin and 5-FU.
Graphical Abstract
... Currently, conventional treatments for colorectal cancer include surgery, chemotherapy and radiotherapy. Furthermore, these treatments can be used in combination depending on the location and progression of the disease [3] . However, more effective treatments for treating CRC patients are needed. ...
Background: CD8+ T cells in the tumor microenvironment are crucial for antitumor effects. Boosting their infiltration can significantly enhance the efficacy of antitumor immunotherapy. However, the precise contribution of the epigenetic regulator lysine-specific demethylase 6B (KDM6B) to colorectal cancer (CRC) immunity remains elusive.
Methods: KDM6B expression was detected in adjacent and CRC tissues or normal and cancer cells. Mouse models of CRC were established to assess the impact of KDM6B on tumor progression. The infiltration of CD8⁺ T cells was detected by IHC and a transwell assay. RT-qPCR, western blotting or flow cytometry were used to detect the effect of KDM6B on PD-L1, CD8+ T-cell-attracting chemokines and p-STAT3 expression. ChIP-qPCR was performed to determine the H3K27me3 enrichment in the promoter regions of target genes PD-L1 and CD8+ T-cell-attracting chemokines. Finally, paricalcitol was combined with anti-PD-L1 antibodies to evaluate their anti-CRC effects.
Results: KDM6B was downregulated in CRC tissues and cells, but its overexpression successfully hindered CRC growth and liver metastasis. Mechanistically, the activation of demethylase activity and STAT3 signaling, leading to increased expression of CD8+ T-cell-attracting chemokines CCL5, CXCL9, and CXCL10, as well as enhanced PD-L1 expression in CRC cells. This ultimately resulted in increased infiltration of CD8+ T cells. Paricalcitol and anti-PD-L1 antibody therapy work together to achieve superior tumor elimination efficiency. Paricalcitol, combined with anti-PD-L1 antibodies, offered superior tumor elimination efficiency.
Conclusion: These findings suggest that KDM6B plays a positive role in regulating the immune microenvironment in CRC, potentially offering a theoretical basis for CRC immunotherapy.
... Globally, an estimated 1.8 million new cases of CRC occur annually, the incidence rate and mortality rate of which respectively account for 10 and 9.4% of all cancers (2,3). The outcome of patients with CRC remains negative due to metastasis and recurrence in spite of the great advances that have been witnessed in the therapeutic modalities of CRC including surgery, chemotherapy, radiotherapy, immunotherapy and targeted therapy (4)(5)(6). Moreover, epidemiological studies have consistently displayed the obvious interaction between the risk of CRC and other human diseases, such as inflammatory bowel disease, obesity and diabetes (7,8). ...
Colorectal cancer (CRC) is one of the most prevailing and lethal forms of cancer globally. α-enolase (ENO1) has been well documented to be involved in the progression and drug resistance of CRC. The present study was designed to specify the role of ENO1 in major events during the process of CRC and to introduce its latent functional mechanism. ENO1 expression was determined by western blot analysis. Extracellular acidification rates were assessed using an XF96 extracellular flux analyzer. Glucose uptake, lactic acid production, total iron levels and ferroptosis-related markers were examined with corresponding kits. A dichlorodihydrofluorescein diacetate probe measured intracellular reactive oxygen species content. Western blotting detected the expression of glycolysis- and ferroptosis-related proteins. CCK-8 and EdU staining assays assessed cell proliferation. In the current study, ENO1 was highly expressed in CRC cells. Knockdown of ENO1 markedly reduced the glycolysis and accelerated the ferroptosis in CRC cells. Moreover, the inhibitory effects of WZB117, a specific inhibitor of glycolysis-related glucose transporter type 1, on CRC cell proliferation were further enhanced by ENO1 interference. In addition, silencing of ENO1 inactivated the AKT/STAT3 signaling. The AKT activator SC79 partially reversed the effects of ENO1 deficiency on the AKT/STAT3 signaling, glycolysis, proliferation as well as ferroptosis in CRC cells. In summary, inactivation of AKT/STAT3 signaling mediated by ENO1 inhibition might boost the ferroptosis and suppress the glycolysis in CRC cells.
