Therapeutic Target For Colorectal Cancer Research Articles

GNAO1: A Novel Tumor Suppressor Gene in Colorectal Cancer Pathogenesis.

This study examined the role of GNAO1 as a potential tumor suppressor gene in colorectal cancer (CRC). RNA-seq data analysis revealed a significant GNAO1 down-regulation in colon cancer tissues compared to normal colon tissues. GNAO1 over-expression in CRC cell lines inhibited cell proliferation, migration, and tumor formation both in vitro and in vivo. This study suggests that GNAO1 exerts its tumor-suppressive effects by inhibiting the mTOR/S6K signaling pathway. The observed correlation between GNAO1 expression and cancer progression highlights its potential as a prognostic marker and therapeutic target in CRC. This study provides a foundation for further exploration of the molecular mechanisms by which GNAO1 influences CRC pathogenesis, with significant implications for its application in clinical settings.

Innovation in CRC Research: Targeting SPACA6P-AS for Progression.

The purpose of this research was to provide light on the functional role that the long noncoding RNA SPACA6P-AS plays in the biology of colorectal cancer (CRC). The presence of elevated SPACA6P-AS expression in colorectal cancer tissues is linked to advanced stages of the disease as well as a decreased overall survival rate. It has been demonstrated through knockdown tests conducted on CRC cell lines that SPACA6P-AS stimulates cell growth in both in vitro and in vivo settings. By acting as a competing endogenous RNA, SPACA6P-AS is able to modulate the levels of miR-339-5p and promote the proliferation of colorectal cancer cells by way of the miR-339-5p/FAM167AFAM167A signaling axis. Based on these findings, SPACA6P-AS is a promising candidate for both a prognostic marker and a therapeutic target in colorectal cancer.

Reduction of Chemoresistance by Claudin-14-Targeting Peptide in Human Colorectal Cancer Cells.

The expression of claudins (CLDNs), major components of tight junctions (TJs), is abnormal in various solid tumors. CLDN14 is highly expressed in human colorectal cancer (CRC) tissues and confers chemoresistance. CLDN14 may become a novel therapeutic target for CRC, but CLDN14-targeting drugs have not been developed. Here, we searched for a CLDN14-targeting peptide, which can suppress CLDN14 expression and chemoresistance using human CRC-derived DLD-1 and LoVo cells. Among some short peptides which mimic the second extracellular loop structure of CLDN14, PSGMK most strongly suppressed the protein expression of CLDN14. The mRNA expression of other endogenous TJ components was unchanged by PSGMK. The PSGMK-induced reduction of CLDN14 protein was inhibited by chloroquine, a lysosome inhibitor, and monodansylcadaverine, a clathrin-dependent endocytosis inhibitor, indicating that PSGMK may enhance endocytosis and lysosomal degradation of CLDN14. In a three-dimensional culture model, the oxidative stress was significantly reduced by PSGMK, whereas hypoxia stress was not. Furthermore, the expression levels of nuclear factor erythroid 2-related factor 2, an oxidative stress response factor, and its target genes were decreased by PSGMK. These results suggest that PSGMK relieves stress conditions in spheroids. The cell viability of spheroids was decreased by anticancer drugs such as doxorubicin and oxaliplatin, which was exaggerated by the cotreatment with PSGMK. Our data indicate that CLDN14-targeting peptide, PSGMK has an anti-chemoresistance effect in CRC cells.

Knockdown of ribosomal protein L22-like 1 arrests the cell cycle and promotes apoptosis in colorectal cancer

Objective: Colorectal cancer (CRC) remains a remarkable challenge despite considerable advancements in its treatment, due to its high recurrence rate, metastasis, drug resistance, and heterogeneity. Molecular targets that can effectively inhibit CRC growth must be identified to address these challenges. Therefore, we aim to reveal the regulatory effect of ribosomal protein L22-like 1 (RPL22L1) on the proliferation and apoptosis of CRC cells and its potential mechanism. Material and Methods: We detected the expression of RPL22L1 from the Cancer Genome Atlas, Gene Expression Omnibus and UALCAN databases. The effects of RPL22L1 on CRC growth and migration were determined by knocking down RPL22L1 in human CRC cell lines and those on the cell cycle and apoptosis using flow cytometry. The influence of RPL22L1 knockdown on xenograft tumor growth was verified in vivo. The potential RPL22L1 mechanisms in promoting cancer were predicted with RNA sequencing (RNAseq). The molecular mechanism of enhanced apoptosis and cell cycle arrest in RPL22L1 knockdown was revealed using real-time reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Results: The present study reveals a considerable upregulation of RPL22L1 expression in CRC as well as in diverse tumor tissues, and most cells within the CRC tumor microenvironment (TME) demonstrate RPL22L1 expression. Notably, this elevated expression level of RPL22L1 exhibits a strong association with an unfavorable prognosis among patients diagnosed with CRC (P < 0.05). Furthermore, the association between RPL22L1 expression and the CRC TME index did not exhibit statistical significance (P > 0.05). However, RPL22L1 knockdown experiments revealed a substantial suppression of growth and migratory capacities in CRC cells RKO and HCT116 (P < 0.05). Flow cytometry analysis exhibited that on RPL22L1 knockdown, a remarkable arrest of the G1 and S phases of the cell cycle (P < 0.05) occurred. In addition, a remarkable elevation in the level of cell apoptosis was observed (P < 0.001). RNAseq exhibited that cell cycle, DNA replication, and mechanistic target of rapamycin (mTOR) complex 1pathway were inhibited after RPL22L1 knockdown, whereas the apoptosis pathway was activated (P < 0.05). Validation through RT-qPCR and western blot analysis also corroborated the downregulation of P70S6K, MCM3, MCM7, GADD45B, WEE1, and MKI67 expression levels, following RPL22L1 knockdown (P < 0.05). Consequent rescue experiments offered supportive evidence, indicating the involvement of the mTOR pathway in mediating the influence of RPL22L1 on the promotion of cell cycle progression. Moreover, in vivo assays involving tumor-bearing mice exhibited that diminished RPL22L1 levels led to arrested CRC growth (P < 0.05). Conclusion: These findings support RPL22L1 as a possible prognostic and therapeutic target in CRC, providing novel insights into the development of anticancer medications.

The Risk Genes S1PR5, CMC1, and ASAH1 as Potential Targets for the Diagnosis, Immunotherapy, and Treatment of Colon Adenocarcinoma by Single-Cell and Bulk RNA Sequencing Analysis

Globally, one of the main causes of cancer-related mortality is Colon Adenocarcinoma (COAD). In this study, a new special Immune Cell Functions (ICF) risk model was constructed using single-cell and bulk RNA sequencing data to develop a new understanding and clinical applications for COAD. The immune function gene sets were downloaded from a literature reference, and the COAD single-cell dataset GSE146771 was downloaded from the Tumour Immune Single Cell Hub database. Using Lasso analysis, a multiple gene signature was made from the enrichment scores of immune function gene sets that were enriched in different ways. Robust validation of the signature was then performed in multiple independent cohorts. After that, we built the model using a 10-fold cross-test and evaluated its independence for clinical usage using a nomogram. We also investigated the connection between signature and immune function, genetic variation, immunotherapy, and the cancer immunological microenvironment. Lastly, we used qPCR and immunohistochemistry to examine the expression of the unreported model genes. To find the regulatory functions of unreported model genes, an EdU assay was employed. First, 20 differentially enriched immune function gene sets were identified. Ten genes can be used as a risk profile to assess the prognosis of colon cancer, according to Lasso regression analysis. Signature performance was stable in both the training cohort and two independent GEO external cohorts, and risk scores were confirmed as independent prognostic factors. At the same time, our risk model continued to be highly predictive across various clinical clusters and clinical characteristics, such as immune checkpoints, tumour genome mutations, and chemotherapeutic drug resistance. Patients in the low-risk group have exhibited a higher chance of benefiting from immunotherapy, according to immunotherapy response research. qPCR and immunohistochemistry analysis have revealed S1PR5 expression as high in COAD tissues, while CMC1 and ASAH1 expression has been found to be low. According to the findings of the functional experiment, S1PR5, CMC1, and ASAH1 may control the ability of CRC cells to proliferate. In this study, using scRNA-seq and bulk RNA-seq data, we created a risk model to predict the prognosis and effectiveness of immunotherapy in patients with COAD. In addition, we have discovered three model genes (S1PR5, CMC1, and ASAH1) that have not been reported before. These genes have the potential to be novel therapeutic targets in Colorectal Cancer (CRC). These findings suggest that this model could be used to evaluate the prognostic risk and identify potential targets for COAD patient treatment.

Clinical Significance of HHLA2 as a Novel Therapeutic Target for Colorectal Cancer.

Colorectal cancer (CRC) is a high-indence malignance of the digestive system with a high mortality rate in the world. The results are desired to provide an important theoretical basis for discovering new therapeutic targets for CRC. The expression of human endogenous retrovirus-H-long terminal repeat association protein 2 (HHLA2) in human CRC was detected to explore its correlationship with clinicopathological features and prognosis of patients and its potential in treating CRC. Western blot was employed to detect HHLA2 expression in fresh tissues obtained from 6 CRC patients' excisions, including cancer, paracancer, and normal issues. Immunohistochemical staining was employed to determine HHLA2 expression in paraffin-embedded specimens of 139 patients with colorectal cancer, and its relationship with the clinicopathological profiles and survival was analyzed. Small interfering RNA (siRNA) targeting HHLA2 was used to transfect CRC cells to silent HHLA2. MTT, plate colony formation, cell scratch, and Transwell assay were conducted to observe the proliferation, migration, and invasion of CRC cells. HHLA2 protein was expressed in human colorectal cancer tissues, paracancer tissues and normal tissues, which was significantly upregulated in cancer tissues (P<0.01). HHLA2 expression level in CRC tissues showed a close correlationship with the invasion depth of the tumor (P=0.000), metastasis of regional lymph nodes (P=0.018), clinical stage (P=0.010), and patient survival (P=0.011). Correlation with gender (P=0.873), age (P=0.864), location of the tumor (P=0.768), degree of tumor differentiation (P=0.569) and distant metastasis (P=0.494) exhibited no significance. The survival time of CRC patients with high and low HHLA2 expression groups was 43.231 months and 55.649 months, respectively, with a statistical difference between the two groups (P=0.001). Silencing HHLA2 inhibited proliferation, migration and invasion of CRC cells significantly. HHLA2 is overexpressed in CRC tissues which is associated with poor prognosis of patients. HHLA2 might be recognized as a new candidate for adjuvant diagnosis and prognosis of CRC, as well as a promised new target for immunotherapy of CRC.

Circ_0089761 accelerates colorectal cancer metastasis and immune escape via miR-27b-3p/PD-L1 axis.

Circular RNAs have been implicated as critical regulators in the initiation and progression of colorectal cancer (CRC). This study was intended to elucidate the functional significance of the circ_0089761/miR-27b-3p/programmed cell death ligand 1 (PD-L1) axis in CRC. Our findings indicated that circ_0089761 expression was significantly elevated in CRC tissues and cell lines. Furthermore, the high expression of circ_0089761 was correlated with TNM stage and tumor size. Silencing circ_0089761 inhibited CRC cell proliferation, migration, and invasion, and increased apoptosis. Mechanistically, circ_0089761 facilitated its biological function by binding to miR-27b-3p to upregulate PD-L1 expression in CRC. Coculture experiments confirmed that low expression of circ_0089761 impeded CD8 + T cell apoptosis and depletion, activated CD8 + T cell function, and increased secretion of the immune effector cytokines IFN-γ, TNF-α, perforin, and granzyme-B. MiR-27b-3p inhibition or PD-L1 overexpression partially impeded CD8 + T cell function. The circ_0089761/miR-27b-3p/PD-L1 axis is postulated to exert pivotal functions in the mechanistic progression of CRC. Furthermore, it holds promising prospects as a feasible biomarker and therapeutic target for CRC.

Copper and Colorectal Cancer.

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30-40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is crucial for mitochondrial respiration, pigmentation, iron transport, antioxidant defense, hormone production, and extracellular matrix biosynthesis. Copper deficiency, often caused by mutations in the ATP7A gene, results in Menkes disease, an X-linked recessive disorder. On the contrary, Wilson disease is characterized by toxic copper accumulation. Cuproptosis, a unique form of cell death regulated by copper, is a subtype of necrosis induced by enhanced mitochondrial metabolism and intracellular copper accumulation. This process can reduce the malignant potential of tumor cells by inhibiting glucose metabolism. Therapeutically, copper and its complexes have shown efficacy in malignancy treatments. The disruption of copper homeostasis and excessive cuproplasia are significant in colorectal cancer development and metastasis. Therefore, manipulating copper status presents a potential therapeutic target for colorectal cancer, using copper chelators to inhibit copper formation or copper ion carriers to promote cuproptosis. This review highlights the role of copper in human physiology and pathology, emphasizing its impact on colorectal cancer and potential therapeutic strategies. Future AI-based approaches are anticipated to accelerate the development of new compounds targeting cuproptosis and copper disruption in colorectal cancer.

Circular RNA circWBSCR22 facilitates colorectal cancer metastasis by enhancing CHD4's protein stability

Widespread metastases continue to be a massive challenge for colorectal cancer (CRC) therapy and contribute to the high mortality rate in patients with CRC. Circular RNAs (circRNAs) are a novel group of endogenous RNAs identified as agents modulating tumorigenesis and aggressiveness with tissue heterogeneity. However, the biological functions of circRNAs in CRC metastasis remain largely unknown. Here, we identified that circWBSCR22, a novel circRNA back-spliced from the WBSCR22 pre-mRNA, was significantly elevated in CRC tissue compared with adjacent normal tissue. Further gain- and loss-of-function assays manifested that circWBSCR22 promotes epithelial-mesenchymal transition (EMT) and metastasis in vitro and in vivo, which are mediated by the chromodomain helicase-DNA-binding protein 4 (CHD4) protein. Mechanically, circWBSCR22 binds directly to up-frameshift protein 1 (UPF1), an RNA binding protein recognized for its function in RNA surveillance, and hinders its role in directing CHD4 protein ubiquitination for degradation. Consequently, by stabilizing the CHD4 protein, circWBSCR22 hastens the development and metastasis of CRC. Therefore, our findings first delineate the oncogenic role and mechanism of circWBSCR22 in CRC growth and metastasis and its potential to serve as a therapeutic target for CRC.

Neutrophil Extracellular Traps: Potential Thrombotic Markers and Therapeutic Targets in Colorectal Cancer.

Neutrophil extracellular traps (NETs) are promising promoters in venous thromboembolism (VTE). In the present study, we have investigated the potential thrombogenic role of NETs in colorectal cancer (CRC). A total of 583 patients with gastrointestinal malignancies who were diagnosed with or without VTE by extremities arteriovenous ultrasound and computed tomography were enrolled. The incidence of VTE in CRC was as high as 17.53%. In serological ELISA experiments, Cit-H3, MPO and cfDNA were significantly overexpressed in CRC patients with VTE compared to CRC patients without VTE and healthy individuals. Neutrophils from CRC patients with VTE produced appreciable amounts of NETs after stimulation with phorbol-12-myristate-13-acetate, which were lacking in CRC patients without VTE and healthy individuals. CfDNA was positively correlated with plasmin-α2-antiplasmin complex and tissue plasmin activator inhibitor-1 complex, and Cit-H3 was positively correlated with plasmin-α2-antiplasmin complex, suggesting that NETs are associated with increased fibrinolytic activity. We screened some NETs-related genes by analysing several high-throughput sequencing datasets of VTE and NETs. FCGR1A was identified as the optimal target gene by pan-cancer expression analysis and survival analysis. FCGR1A was significantly overexpressed in the peripheral blood of CRC patients without VTE compared to healthy individuals and showed a positive correlation with cfDNA. Neutrophil-derived NETs were significantly reduced by FCGR1A inhibitor exposure. These findings indicate that NETs are actively involved in VTE in CRC. NETs are promising thrombotic marker and therapeutic target in CRC to prevent the thrombotic consequences of cancer.

Glycyrrhizin ameliorates colorectal cancer progression by regulating NHEJ pathway through inhibiting HMGB1-induced DNA damage response

As one of the most common malignancies, colorectal cancer (CRC) usually starts with a benign lesion and accumulates DNA damage as it progresses to full-fledged cancer. Glycyrrhizin (GL) has been found to alleviate tumor growth and inflammation, while the role of GL influences DNA damage response (DDR) in colorectal cancer remains unclear. GL exposure significantly reduced cell colony formation and viability with a concomitant increase in DNA fragmentation in CRC, meanwhile GL induced apoptosis by activating caspase-3. Moreover, GL induced cell cycle arrest in CRC cells at S phase, which was associated with decreased cyclin D1 in vitro. GL treatment significantly ameliorated tumor growth and promoted DDR in vivo. Mechanism analysis revealed that GL significantly downregulated the NHEJ pathway via inhibiting HMGB1. Finally, the expression of HMGB1 was abnormal regulated in CRC tissue than in adjacent normal tissues and associated with TNM stage and overall survival. Our findings indicate that HMGB1 may be a novel therapeutic target in CRC, a result that GL may serve as a promising drug for CRC treatment.

RNA Binding Proteins as Potential Therapeutic Targets in Colorectal Cancer

RNA-binding proteins (RBPs) play critical roles in regulating post-transcriptional gene expression, managing processes such as mRNA splicing, stability, and translation. In normal intestine, RBPs maintain the tissue homeostasis, but when dysregulated, they can drive colorectal cancer (CRC) development and progression. Understanding the molecular mechanisms behind CRC is vital for developing novel therapeutic strategies, and RBPs are emerging as key players in this area. This review highlights the roles of several RBPs, including LIN28, IGF2BP1–3, Musashi, HuR, and CELF1, in CRC. These RBPs regulate key oncogenes and tumor suppressor genes by influencing mRNA stability and translation. While targeting RBPs poses challenges due to their complex interactions with mRNAs, recent advances in drug discovery have identified small molecule inhibitors that disrupt these interactions. These inhibitors, which target LIN28, IGF2BPs, Musashi, CELF1, and HuR, have shown promising results in preclinical studies. Their ability to modulate RBP activity presents a new therapeutic avenue for treating CRC. In conclusion, RBPs offer significant potential as therapeutic targets in CRC. Although technical challenges remain, ongoing research into the molecular mechanisms of RBPs and the development of selective, potent, and bioavailable inhibitors should lead to more effective treatments and improved outcomes in CRC.

Analysis of SLC genes alternative splicing identifies the SLC7A6 RI isoform as a therapeutic target for colorectal cancer.

Alternative splicing (AS), a crucial mechanism in post-transcriptional regulation, has been implicated in diverse cancer processes. Several splicing variants of solute carrier (SLC) transporters reportedly play pivotal roles in tumorigenesis and tumor development. However, an in-depth analysis of AS landscapes of SLCs in colon adenocarcinoma (COAD) is lacking. Herein, we analyzed data from The Cancer Genome Atlas and identified 1215 AS events across 243 SLC genes, including 109 differentially expressed AS (DEAS) events involving 62 SLC genes in COAD. Differentially spliced SLCs were enriched in biological processes, including transmembrane transporter activity, transporter activity, ferroptosis, and choline metabolism. In patients with COAD, tumor tissues exhibited higher expression of longer mitochondrial carrier SLC25A16 isoforms than adjacent normal tissues, consistent with bioinformatics analysis. Protein-coding sequences and transmembrane helices of survival-related DEAS were predicted, revealing that shifts in splicing sites altered the number and structure of their transmembrane proteins. We developed a prognostic risk model based on the screened 6-SLC-AS (SLC7A6_RI_37208 (SLC7A6-RI), SLC11A2_AP_21724, SLC2A8_ES_87631, SLC35B1_AA_42317, SLC39A11_AD_43204, and SLC7A8_AP_26712). Knockdown of the intronic region of SLC7A6-RI isoform enhanced colon cancer cell proliferation. Invivo, knockdown of the intronic region of SLC7A6-RI isoform enhanced tumor growth in colon cancer. Mechanistically, si-SLC7A6-RI isoform exerted oncogenic effects by activating the PI3K-Akt-mTOR signaling pathway and promoting cell proliferation, evidenced by increased expression of key regulators Phosphorylated Mammalian Target of Rapamycin (p-mTOR) and a cell proliferation marker Proliferating Cell Nuclear Antigen (PCNA) using western blotting. Our study elucidated SLC-AS in COAD, highlighting its potential as a prognostic and therapeutic target and emphasizing the suppressive influence of SLC7A6-RI in colon cancer progression.

Identification of Novel Target DCTPP1 for Colorectal Cancer Therapy with the Natural Small-Molecule Inhibitors Regulating Metabolic Reprogramming.

Colorectal cancer (CRC) is one of the most common malignant tumors. Identification of new effective drug targets for CRC and exploration of bioactive small-molecules are clinically urgent. The human dCTP pyrophosphatase 1 (DCTPP1) is a newly identified pyrophosphatase regulating the cellular nucleotide pool but remains unexplored as potential target for CRC treatment. Here, twelve unprecedented chemical architectures terpene-nonadride heterodimers (1-12) and their monomers (13-20) were isolated from endophyte Bipolaris victoriae S27. Compounds 1-12 represented the first example of terpene-nonadride heterodimers, in which nonadride monomers of 1 and 2 were also first example of 5/6 bicyclic nonadrides. A series of assays showed that 2 could repress proliferation and induce cell cycle arrest, apoptotic and autophagic CRC cell death in vitro and in vivo. Clinical cancer samples data revealed that DCTPP1 was a novel target associated with poor survival in CRC. DCTPP1 was also identified as a new target protein of 2. Mechanically, compound 2 bound to DCTPP1, inhibited its enzymatic activity, intervened with amino acid metabolic reprogramming, and exerted anti-CRC activity. Our study demonstrates that DCTPP1 was a novel potential biomarker and therapeutic target for CRC, and 2 was the first natural anti-CRC drug candidate targeting DCTPP1.

Ubiquitin-specific protease 10 determines colorectal cancer outcome by modulating epidermal growth factor signaling via inositol polyphosphate-4-phosphatase type IIB

Although there have been advances in understanding colorectal cancer (CRC) pathogenesis, significant gaps still exist, highlighting the need for deeper insights. Dysregulated protein homeostasis, including perturbations in the epidermal growth factor receptor (EGFR) pathway, remains a focal point in CRC pathogenesis. Within this context, the roles of ubiquitin ligases and deubiquitinases have attracted attention, but exploration of their precise contributions is still in its early stages. To address this gap, we investigated the involvement of the deubiquitinase USP10 in CRC. Our in vitro and in vivo study reveals a new paradigm in CRC biology and unravels a novel mechanistic axis, demonstrating for the first time the involvement of inositol polyphosphate 4-phosphatase type II B (INPP4B) in USP10-mediated CRC modulation. Specifically, our study demonstrates that the loss of USP10 results in reduced sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and osimertinib. This is accompanied by a decrease in the activation of the AKT1/PKB pathway upon EGF stimulation, which is mediated by INPP4B. Importantly, in vivo xenograft experiments validate these findings and highlight the crucial role of USP10, particularly in conjunction with INPP4B, in driving CRC progression. The findings enhance our understanding of CRC pathobiology and reveal a new regulatory axis involving USP10 and INPP4B in CRC progression. This unique insight identifies USP10 and INPP4B as potential therapeutic targets in CRC.

Targeting PARP-1 and DNA Damage Response Defects in Colorectal Cancer Chemotherapy with Established and Novel PARP Inhibitors.

The DNA repair protein PARP-1 emerged as a valuable target in the treatment of tumor entities with deficiencies of BRCA1/2, such as breast cancer. More recently, the application of PARP inhibitors (PARPi) such as olaparib has been expanded to other cancer entities including colorectal cancer (CRC). We previously demonstrated that PARP-1 is overexpressed in human CRC and promotes CRC progression in a mouse model. However, acquired resistance to PARPi and cytotoxicity-mediated adverse effects limit their clinical applicability. Here, we detailed the role of PARP-1 as a therapeutic target in CRC and studied the efficacy of novel PARPi compounds in wildtype (WT) and DNA repair-deficient CRC cell lines together with the chemotherapeutics irinotecan (IT), 5-fluorouracil (5-FU), and oxaliplatin (OXA). Based on the ComPlat molecule archive, we identified novel PARPi candidates by molecular docking experiments in silico, which were then confirmed by in vitro PARP activity measurements. Two promising candidates (X17613 and X17618) also showed potent PARP-1 inhibition in a CRC cell-based assay. In contrast to olaparib, the PARPi candidates caused no PARP-1 trapping and, consistently, were not or only weakly cytotoxic in WT CRC cells and their BRCA2- or ATR-deficient counterparts. Importantly, both PARPi candidates did not affect the viability of nonmalignant human colonic epithelial cells. While both olaparib and veliparib increased the sensitivity of WT CRC cells towards IT, no synergism was observed for X17613 and X17618. Finally, we provided evidence that all PARPi (olaparib > veliparib > X17613 > X17618) synergize with chemotherapeutic drugs (IT > OXA) in a BRCA2-dependent manner in CRC cells, whereas ATR deficiency had only a minor impact. Collectively, our study identified novel lead structures with potent PARP-1 inhibitory activity in CRC cells but low cytotoxicity due to the lack of PARP-1 trapping, which synergized with IT in homologous recombination deficiency.

Shengqiyichang decoction regulates antitumor immunity in colorectal cancer by downregulating lymphocyte antigen 6 family member G6D via the protein kinase B/p38 mitogen-activated protein kinase signaling pathway

The traditional Chinese medicine (TCM) formulation Shengqiyichang Decoction (SQYCD) has been reported to stimulate host immunity, and it has been administered for the treatment of colorectal cancer (CRC). Here, we applied network and bioinformatics analyses to elucidate the mechanisms by which SQYCD ameliorates CRC and validated its modes of action via in vivo and in vitro experiments. We identified 46 active compounds in SQYCD and selected 237 proteins as potential therapeutic targets in CRC, most notably p38 mitogen-activated protein kinase (p38⍺). Bioinformatics analyses demonstrated differential expression in CRC tissues and prognostic value of the genes encoding TNFα, MAPK14, CASP-3, MAPK1, AKT1, PRKACA, VEGF, IL-6, EGFR and ESR1. We then plotted receiver operating curves (ROC) and time-ROC for the differentially expressed genes (DEGs) ESR1 and AKT1 to predict the progress of CRC. We speculated that the AKT/p38α-MAPK signaling pathway is associated with the clinical prognosis of CRC. In a mouse model, we found that SQYCD inhibits CRC tumor growth by increasing CD4+ and CD8+ T cell abundance and decreasing the ratio of T-regulatory cells (Tregs) in the tumor microenvironment. In cultured mouse CRC cells, SQYCD selectively upregulated levels of the CRC-associated protein lymphocyte antigen 6 family member G6D, while the AKT activator SC-79 reversed this effect. The discoveries made herein suggest that SQYCD exerts a therapeutic effect in CRC by inhibiting Treg recruitment via inhibition of the AKT/p38α/LY6G6D signaling axis.

Upregulation of Fatty Acid Synthase Increases Activity of β-Catenin and Expression of NOTUM to Enhance Stem-like Properties of Colorectal Cancer Cells.

Dysregulated fatty acid metabolism is an attractive therapeutic target for colorectal cancer (CRC). We previously reported that fatty acid synthase (FASN), a key enzyme of de novo synthesis, promotes the initiation and progression of CRC. However, the mechanisms of how upregulation of FASN promotes the initiation and progression of CRC are not completely understood. Here, using Apc/VillinCre and ApcMin mouse models, we show that upregulation of FASN is associated with an increase in activity of β-catenin and expression of multiple stem cell markers, including Notum. Genetic and pharmacological downregulation of FASN in mouse adenoma organoids decreases the activation of β-catenin and expression of Notum and significantly inhibits organoid formation and growth. Consistently, we demonstrate that NOTUM is highly expressed in human CRC and its expression positively correlates with the expression of FASN in tumor tissues. Utilizing overexpression and shRNA-mediated knockdown of FASN, we demonstrate that upregulation of FASN increases β-catenin transcriptional activity, NOTUM expression and secretion, and enhances stem-like properties of human CRC cells. Pharmacological inhibition of NOTUM decreases adenoma organoids growth and proliferation of cancer cells. In summary, upregulation of FASN enhances β-catenin signaling, increases NOTUM expression and stem-like properties of CRC cells, thus suggesting that targeting FASN upstream of the β-catenin/NOTUM axis may be an effective preventative therapeutic strategy for CRC.

ATF6 Promotes Colorectal Cancer Growth and Stemness by Regulating the Wnt Pathway.

ATF6 intervention reduces colorectal cancer cell and organoid viability by interrupting dysregulated Wnt signaling, identifying a novel facilitator and potential therapeutic target in colorectal cancer.

Exploring the Potential of Epiregulin and Amphiregulin as Prognostic, Predictive, and Therapeutic Targets in Colorectal Cancer

Exploring the Potential of Epiregulin and Amphiregulin as Prognostic, Predictive, and Therapeutic Targets in Colorectal Cancer