Signaling Pathway In Colorectal Cancer Research Articles

Progress in the relationship between P2X7R and colorectal cancer.

Purinergic ligand-gated ion channel 7 receptor (P2X7R) is a nonselective cation channel of the purinergic receptor family. P2X7R is activated by adenosine triphosphate (ATP) and plays a significant role in inflammatory and autoimmune diseases by triggering cellular signal transduction. More importantly, P2X7R is abnormally expressed in many tumor cells and is involved in the progression of various tumor cells. Studies have shown that the irregular expression of P2X7R in colorectal cancer (CRC) can not only indirectly affect the occurrence and development of CRC by promoting inflammatory bowel disease but also directly affect the proliferation and metastasis of CRC cells. P2X7R plays a bidirectional role in cancer induction and inhibition by mediating complex signaling pathways in CRC, and its expression level is closely related to the overall survival of CRC patients. Therefore, P2X7R may be a biomarker and potential therapeutic target for the development and prognosis of CRC. In this paper, we review the research progress on P2X7R in CRC.

Inhibition of colorectal cancer tumorigenesis by ursolic acid and doxorubicin is mediated by targeting the Akt signaling pathway and activating the Hippo signaling pathway.

Colorectal cancer (CRC) is one of the deadliest malignant tumors worldwide and its prevalence is increasing in South Korea. The efficacy of combined treatment with natural product‑derived and chemotherapy agents including curcumin combined with 5‑fluorouracil, resveratrol combined with cisplatin and epigallocatechin‑3‑gallate (EGCG) combined with cisplatin in preventing cancer progression and killing cancer cells has emerged. The Akt and Hippo signaling pathways serve a key role in colorectal tumor growth; however, the exact role of the crosstalk between Akt and Hippo signaling pathways in CRC remains poorly elucidated. The combined effect of UA and DOX on the cell proliferation, apoptosis, migration and cell cycle of CRC cells were investigated by performing Cell proliferation assay, a soft agar colony formation assay, flow cytometry, wound healing assay and western blotting assay. Subsequently, the expression of AKT and Hippo signaling pathway‑associated proteins were also assessed by western blot assay. Moreover, a xenograft nude mouse model was constructed to verify the effects of UA and DOX on the tumorigenesis of HCT116 cell invivo. The present study reported that ursolic acid (UA) strongly enhanced the antitumor action of doxorubicin (DOX) via blocking the Akt/glycogen synthase kinase‑3β (Gsk3β) signaling pathway and activating tumor‑suppressive Hippo signaling (mammalian Ste20‑like kinase 1 and 2, salvador family WW domain containing protein 1 and MOB kinase activator 1), thereby downregulating downstream effector yes‑associated protein 1 (Yap) and connective tissue growth factor (CTGF) protein expression levels in CRC cells. Furthermore, The PI3K inhibitor LY294002 further suppressed Akt activity and enhance the function of Hippo pathway‑associated proteins in DOX + UA treated cells; this effect led to subsequent oncogenic Yap and CTGF inhibition following combined treatment, whereas Akt activator SC79 exerted an opposite effect in CTGF expression. Invivo, treatment with UA combined with DOX markedly suppressed the progression of CRC without any toxic effects on a xenograft mouse model by disrupting Akt signaling and activating the Hippo signaling pathway. These results demonstrated that UA and DOX treatment successfully induced Akt/Gsk3β inactivation via Hippo signaling pathway activation to promote Yap degradation, resulting in the inhibition of colorectal tumorigenesis. In conclusion, these findings suggested that combination therapy with UA and DOX may be more effective than DOX alone. UA may be a novel anticancer strategy and could be considered for investigation as a complementary chemotherapy agent in the future.

Prevalence and patterns of mutations in RAS/RAF/MEK/ERK/MAPK signaling pathway in colorectal cancer in North Africa

BackgroundOur review discuss (i) the findings from analyzed data that have examined KRAS, NRAS and BRAF mutations in patients with colorectal cancer (CRC) in North Africa and to compare its prevalence with that shown in other populations and (ii) the possible role of dietary and lifestyle factors with CRC risk. MethodsUsing electronic databases, a systematic literature search was performed for the KRAS, NRAS, and BRAF mutations in CRC patients from Morocco, Tunisia, Algeria and Lybia. ResultsSeventeen studies were identified through electronic searches with six studies conducted in Morocco, eight in Tunisia, two in Algeria, and one in Libya. A total of 1843 CRC patients were included 576 (31.3%) in Morocco, 641 (34.8%) in Tunisia, 592 (32.1%) in Algeria, and 34 (1.8%) in Libya. Overall, the average age of patients was 52.7 years old. Patients were predominantly male (56.6%). The mutation rates of KRAS, NRAS and BRAF were 46.4%, 3.2% and 3.5% of all patients, respectively. A broad range of reported KRAS mutation frequencies have been reported in North Africa countries. The KRAS mutation frequency was 23.9% to 51% in Morocco, 23.1% to 68.2% in Tunisia, 31.4% to 50% in Algeria, and 38.2% in Libya. The G12D was the most frequently identified KRAS exon 2 mutations (31.6%), followed by G12V (25.4%), G13D (15.5%), G12C (10.2%), G12A (6.9%), and G12S (6.4%). G12R, G13V, G13C and G13R are less than 5%. There are important differences among North Africa countries. In Morocco and Tunisia, there is a higher prevalence of G12D mutation in KRAS exon 2 (≈50%). The most frequently mutation type in KRAS exon 3 was Q61L (40%). A59T and Q61E mutations were also found. In KRAS exon 4, the most common mutation was A146T (50%), followed by K117N (33.3%), A146P (8.3%) and A146V (8.3%).ConclusionKRAS mutated CRC patients in North Africa have been identified with incidence closer to the European figures. Beside established anti-CRC treatment, better understanding of the causality of CRC can be established by combining epidemiology and genetic/epigenetic on CRC etiology. This approach may be able to significantly reduce the burden of CRC in North Africa.

MicroRNAs regulating Wnt signaling pathway in colorectal cancer: biological implications and clinical potentials.

Colorectal cancer (CRC) is one of the most frequent cancers leading to death worldwide. Different signaling pathways such as the canonical Wnt signaling pathway have many effects on the development of CRC. MicroRNAs are small non-coding RNAs and different evidence represent their importance in the development of cancer via regulating the expression of their target genes. miRNAs can affect CRC progression as oncogenes or tumor suppressors. Dysregulation in miRNA expression can occur for various reasons, causes different abnormalities in the Wnt signaling pathway, and contributes to CRC development. Identifying the exact interactions between microRNAs and mRNAs or other non-coding RNAs assists in designing effective therapeutic, diagnostic, and prognostic approaches. In this review, we aim to focus on microRNAs that regulate CRC through modulating the Wnt pathway and then present the perspective outlook on the implication of miRNA in liquid biopsy for the management of patients with CRC.

PARPi treatment enhances radiotherapy-induced ferroptosis and antitumor immune responses via the cGAS signaling pathway in colorectal cancer

In cancer cells, poly (ADP-ribose) polymerase (PARP)-1 and PARP2 initiate and regulate DNA repair pathways to protect against DNA damage and cell death caused by radiotherapy or chemotherapy. Radiotherapy and PARP inhibitors (PARPis) have been combined in clinical trials, but their action mechanisms remain unclear. Here, we show that activated by ionizing radiation (IR) generated dsDNA, cyclic GMP-AMP synthase (cGAS) signaling promoted regulated cell death, specifically ferroptosis, via the activating transcription factor 3 (ATF3)–solute carrier family 7 member 11 axis and the antitumor immune response via the interferon-β-CD8+ T cell pathway. Niraparib, a widely used PARPi, augmented cGAS-mediated ferroptosis and immune activation. In colorectal cancer models, cGAS knockdown (KD) compromised IR-induced ferroptosis via downregulation of ATF3 (key ferroptosis regulator) expression. cGAS depletion reversed IR-induced infiltration of CD8+ T or CD8+GZMB+ T cells in the cGAS KD group. Survival analysis of paired tumor samples before and after standard radiotherapy revealed that high expression levels of cGAS, ATF3, and PTGS2 and high density of CD8+ T cells resulted in a significantly high disease-free survival rate in patients with rectal cancer. Therefore, PARPi treatment increases the cytoplasmic accumulation of dsDNA caused by IR, triggering the cGAS signaling-mediated tumor control in cancer cell lines and mouse xenograft models.

Evacetrapib Elicits Antitumor Effects on Colorectal Cancer by Inhibiting the Wnt/β-Catenin Signaling Pathway and Activating the JNK Signaling Pathway.

Despite advances in colorectal cancer (CRC) treatment, most advanced CRC patients who experience disease progression after chemotherapy, targeted therapy, and immunotherapy face a situation in which there is no available medicine. Thus, new therapeutic drugs for CRC are urgently needed. Studies have shown that cholesteryl ester transfer protein (CETP) has a vital role in tumor development and is a possible target for CRC therapy. We found that Evacetrapib, a CETP inhibitor, suppressed CRC cell growth by inhibiting the Wnt/β-catenin signaling pathway and activating the c-Jun NH2-terminal kinase (JNK) signaling pathway in CRC. Therefore, Evacetrapib displays an anti-cancer effect and is a possible option for treating CRC.

Mechanisms and prospects of circular RNAs and their interacting signaling pathways in colorectal cancer.

Colorectal cancer (CRC) is the leading malignant tumor in terms of morbidity and mortality worldwide, and its pathogenesis involves multiple factors, including environment, lifestyle, and genetics. Continuing evidence suggests that circular RNAs (circRNAs), as a novel non-coding RNA, constitute an important genetic variable in the pathogenesis of CRC. These circRNAs with covalently closed-loop structures exist objectively in organisms. They not only have the biological functions of regulating the expression of target genes, changing the activity of proteins, and translating proteins, but also play a key role in the proliferation, invasion, migration, and apoptosis of tumor cells. CRC is one of the most common cancers in which circRNAs are involved in tumorigenesis, metastasis, and drug resistance, and circRNAs have been demonstrated to function through crosstalk with multiple signaling pathways. Therefore, this review summarizes the biological and carcinogenic functions of circRNAs and their related PI3K/AKT, MAPK, Notch, JAK/STAT, Hippo/YAP, WNT/β-catenin, and VEGF signaling pathways in CRC. We further explore the clinical value of circRNAs and important signaling proteins in the diagnosis, prognosis, and treatment of CRC.

Motile sperm domain containing 1 is upregulated by the Wnt/β-catenin signaling pathway in colorectal cancer.

Aberrant activation of the Wnt/β-catenin signaling pathway plays a crucial role in the development and progression of colorectal cancer. Previously, we identified a set of candidate genes that were regulated by this signaling pathway, and the present study focused on motile sperm domain containing 1 (MOSPD1). Immunohistochemical staining revealed that the expression of MOSPD1 was elevated in tumor cells from colorectal cancer tissues compared with in non-tumor cells. Using ChIP-seq data and the JASPAR database, the regulatory region(s) in the MOSPD1 gene as a target of the Wnt/β-catenin signaling pathway were searched, and a region containing three putative TCF-binding motifs in the 3'-flanking region was identified. Additional analyses using reporter assay and ChIP-quantitative PCR suggested that this region harbors enhancer activity through an interaction with transcription factor 7 like 2 (TCF7L2) and β-catenin. In addition, chromatin conformation capture assay revealed that the 3'-flanking region interacts with the MOSPD1 promoter. These data suggested that MOSPD1 was regulated by the β-catenin/TCF7L2 complex through the enhancer element located in the 3'-flanking region. These findings may be helpful for future studies regarding the precise regulatory mechanisms of MOSPD1.

Abstract 1409: Synergistic antitumorigenic activity of Berberine and oligomeric proanthocyanidins through regulation of PI3-AKt signaling pathway in colorectal cancer

Abstract Background: The development of chemo-resistance against conventional chemotherapeutic drugs presents a major clinical challenge in the management of patients with colorectal cancer (CRC). Accumulating body of data in recent years have shown that active principles within various naturally-occurring dietary botanicals not only offer time-tested safety and anti-cancer efficacy, but a combination of certain compounds can overcome the elusive chemotherapeutic resistance in cancer patients. In this regard, data in recent years have shown that berberine (BBR) and oligomeric proanthocyanidins (OPCs) from the grape-seed extract have significant anti-tumorigenic properties in CRC, and a more recent study reported existence of synergism between these two natural medicines in patients with type 2 diabetes. Accordingly, herein we hypothesized that BBR and OPCs might regulate synergistically multiple oncogenic pathways to exert a superior anti-cancer activity in CRC. Methods: We performed a series of experiment in various cell lines, followed by their interrogation in patient-derived organoids (PDOs) to evaluate the synergistic anti-tumorigenic effects of BBR and OPCs in CRC cells. In addition, using genome-wide RNA sequencing analyses, we identified specific functional determinants and key targeted genes and pathways regulated by the combined therapeutic approach with these compounds. Results: To confirm our hypothesis, we first evaluated the potential of OPCs to increase the cellular uptake of BBR in CRC cells, by measuring the fluorescent signal of BBR in multiple cell lines treated individually or their combination. The synergistic anti-tumorigenic effects of BBR and OPCs were observed in various functional assays including reduced cell viability, colony formation potential, wound healing, and invasion assays. Furthermore, the combined treatment with these compounds potentiated the cell apoptosis in an Annexin V binding assay. It was intriguing to note that we were able to successfully validate all cell culture findings in the PDO models from multiple CRC patients. Whole genome transcriptomic profiling identified oncogene MYB, including in PI3-AKT signaling pathway as one of the key pathways that was critically involved in mediating the anti-tumorigenic properties of this combined therapy. Conclusions: We for the first time demonstrate that a combined treatment with BBR and OPCs synergistically promotes the anti-tumorigenic properties in CRC. This synergism was potentially due to enhanced apoptosis and the regulation of oncogenic MYB in the PI3-Akt signaling pathway; hence, offering an attractive potential for the use of these two compounds as adjuvant treatment options in patients with CRC. Citation Format: Keisuke Okuno, Rachana Garg, Masanori Tokunaga, Yusuke Kinugasa, Ajay Goel. Synergistic antitumorigenic activity of Berberine and oligomeric proanthocyanidins through regulation of PI3-AKt signaling pathway in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1409.

P-289 Study of the hedgehog signaling pathway in colorectal cancer: Association with wild type RAS status

EGFR antibodies are efficient in the treatment of patients with RAS wild type metastatic colorectal cancer (mCRC). However, 25% of those patients resist to this therapy. This could be explained by other genetic alterations. Hedgehog (Hh) signaling pathway was described in the development and transition to metastatic stages. The aim of this study is to investigate the expression of Gli1, transcription factor of Hh signaling pathway, and PDGFRα, target gene of Hh signaling pathway, in colorectal adenocarcinoma as compared to normal mucosa and to assess their correlation with clinicopathological features and molecular RAS status.

Metallothionein 2A (MT2A) controls cell proliferation and liver metastasis by controlling the MST1/LATS2/YAP1 signaling pathway in colorectal cancer

BackgroundColorectal cancer (CRC) is one of the three major cancers in the world and is the cancer with the most liver metastasis. The present study aimed to investigate the role of metallothionein 2A (MT2A) in the modulation of CRC cell proliferation and liver metastasis, as well as its molecular mechanisms.MethodsThe expression profile of metallothionein 2A (MT2A) in colorectal cancer retrieved from TCGA, GEO and Oncomine database. The biological effect of MT2A overexpression was investigated mainly involving cell proliferation and migration in CRC cells as well as growth and metastasis in CRC animal models. To explore the specific mechanism of MT2A metastasis in CRC, transcriptome sequencing was used to compare the overall expression difference between the control group and the MT2A overexpression group.ResultsMetallothionein 2A (MT2A) was downregulated in the tumor tissues of patients with CRC compared to adjacent normal tissues and was related to the tumor M stage of patients. MT2A overexpression inhibited CRC cell proliferation and migration in cells, as well as growth and metastasis in CRC animal models. While knockdown of MT2A had the opposite effect in cells. Western blotting confirmed that MT2A overexpression promoted the phosphorylation of MST1, LAST2 and YAP1, thereby inhibiting the Hippo signaling pathway. Additionally, specific inhibitors of MST1/2 inhibited MT2A overexpression-mediated phosphorylation and relieved the inhibition of the Hippo signaling pathway, thus promoting cell proliferation. Immunohistochemistry in subcutaneous grafts and liver metastases further confirmed this result.ConclusionsOur results suggested that MT2A is involved in CRC growth and liver metastasis. Therefore, MT2A and MST1 may be potential therapeutic targets for patients with CRC, especially those with liver metastases.

Berberine and Oligomeric Proanthocyanidins Exhibit Synergistic Efficacy Through Regulation of PI3K-Akt Signaling Pathway in Colorectal Cancer.

BackgroundNaturally occurring dietary botanicals offer time-tested safety and anti-cancer efficacy, and a combination of certain compounds has shown to overcome the elusive chemotherapeutic resistance, which is of great significance for improving the mortality of patients with colorectal cancer (CRC). Accordingly, herein, we hypothesized that berberine (BBR) and oligomeric proanthocyanidins (OPCs) might regulate synergistically multiple oncogenic pathways to exert a superior anti-cancer activity in CRC.MethodsWe performed a series of cell culture studies, followed by their interrogation in patient-derived organoids to evaluate the synergistic effect of BBR and OPCs against CRC. In addition, by performing whole genome transcriptomic profiling we identified the key targeted genes and pathways regulated by the combined treatment.ResultsWe first demonstrated that OPCs facilitated enhanced cellular uptake of BBR in CRC cells by measuring the fluorescent signal of BBR in cells treated individually or their combination. The synergism between BBR and OPCs were investigated in terms of their anti-tumorigenic effect on cell viability, clonogenicity, migration, and invasion. Furthermore, the combination treatment potentiated the cellular apoptosis in an Annexin V binding assay. Transcriptomic profiling identified oncogene MYB in PI3K-AKT signaling pathway might be critically involved in the anti-tumorigenic properties of the combined treatment. Finally, we successfully validated these findings in patient-derived CRC tumor organoids.ConclusionsCollectively, we for the first time demonstrate that a combined treatment of BBR and OPCs synergistically promote the anti-tumorigenic properties in CRC possibly through the regulation of cellular apoptosis and oncogene MYB in the PI3K-Akt signaling pathway.

Discovery of Small-Molecule Inhibitors of the PTK7/β-Catenin Interaction Targeting the Wnt Signaling Pathway in Colorectal Cancer.

Colorectal cancer (CRC), the second cause of death due to cancer worldwide, is a major public health issue. The discovery of new therapeutic targets is thus essential. Pseudokinase PTK7 intervenes in the regulation of the Wnt/β-catenin pathway signaling, in part, through a kinase domain-dependent interaction with the β-catenin protein. PTK7 is overexpressed in CRC, an event associated with metastatic development and reduced survival of nonmetastatic patients. In addition, numerous alterations have been identified in CRC inducing constitutive activation of the Wnt/β-catenin pathway signaling through β-catenin accumulation. Thus, targeting the PTK7/β-catenin interaction could be of interest for future drug development. We have developed a NanoBRET screening assay recapitulating the interaction between PTK7 and β-catenin to identify compounds able to disrupt this protein-protein interaction. A high-throughput screening allowed us to identify small-molecule inhibitors targeting the Wnt pathway signaling and inducing antiproliferative and antitumor effects in vitro in CRC cells harboring β-catenin or adenomatous polyposis coli (APC) mutations. Thus, inhibition of the PTK7/β-catenin interaction could represent a new therapeutic strategy to inhibit cell growth dependent on the Wnt signaling pathway. Moreover, despite a lack of enzymatic activity of its tyrosine kinase domain, targeting the PTK7 kinase domain-dependent functions appears to be of interest for further therapeutic development.

SNORD1C maintains stemness and 5-FU resistance by activation of Wnt signaling pathway in colorectal cancer

Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs that play indispensable roles in cancers, including colorectal cancer (CRC). However, the role of SNORD1C in CRC is unclear. In the current study, SNORD1C expression was measured in CRC tissues using quantitative real-time PCR. A series of in vivo and in vitro experiments were performed to examine the functional role of SNORD1C in CRC. Quantitative real-time PCR, western blotting, sphere formation assay, and chemotherapy resistance analysis were conducted to illustrate the SNORD1C molecular mechanism. SNORD1C was upregulated in CRC and that high SNORD1C expression was related to poor prognosis. After knocking down SNORD1C in CRC cell lines, cell proliferation, colony formation, cell migration, and invasion were alleviated, while apoptosis was increased. Transcriptional RNA-sequencing analysis revealed that following SNORD1C knockdown, β-catenin was downregulated, as was the transcription factor TCF7, which inhibited the Wnt/β-catenin pathway. Meanwhile, levels of the stem cell-related factors were reduced, diminishing cell stemness and tumorigenesis. Our findings suggest that SNORD1C functions via the Wnt/β-catenin pathway to enhance cancer cell stemness in CRC and could be a predictive biomarker for the prognosis ad aggressiveness of this malignancy. Additionally, targeting SNORD1C may be a novel therapeutic strategy for CRC.

Luteolin impacts deoxyribonucleic acid repair by modulating the mitogen-activated protein kinase pathway in colorectal cancer

ABSTRACT This study aimed to investigate the effects of luteolin on colorectal cancer (CRC) and explore its underlying mechanism. HCT-116 and HT-29 cells were treated with luteolin, cisplatin, or selumetinib. The cell survival, cell proliferation, apoptosis and cell cycle distribution, and DNA damage were detected using Cell Counting Kit-8, colony formation, flow cytometry, and immunofluorescence staining analysis, respectively. Western blotting was used to detect the expression of apoptosis-related, cycle-related, DNA-damage-related, and mitogen-activated protein kinase (MAPK) pathway-related proteins. Luteolin showed inhibitory effects on cellular growth by reducing cell survival and proliferation, inducing apoptosis and DNA damage, and arresting the cell cycle in a concentration-dependent manner in HCT-116 and HT-29 cells. Meanwhile, luteolin increased the expression of pro-apoptotic proteins, p-CHK1 (central to the induction of cell cycle arrest), and DNA excision repair protein and decreased anti-apoptotic proteins, G2-M phase-related proteins, and DNA repair proteins. The combination of cisplatin and luteolin significantly decreased cell survival and increased the apoptosis rate of HCT-116 and HT-29 cells compared with cisplatin alone. Bioinformatic analysis using the Comparative Toxicogenomics Database and STITCH and MalaCards databases showed that the MAPK pathway is involved in the pharmacology of luteolin. Furthermore, western blotting demonstrated that luteolin plays an inhibitory role by suppressing the MAPK signaling pathway in CRC, which is enhanced when combined with selumetinib. Luteolin can also prevent tumourigenesis in CRC in vivo. In conclusion, luteolin suppressed cell proliferation, blocked the cell cycle, and induced DNA damage and apoptosis progression in CRC cells by mediating the MAPK pathway

DOT1L affects colorectal carcinogenesis via altering T cell subsets and oncogenic pathway

ABSTRACT Chronic inflammation and oncogenic pathway activation are key-contributing factors in colorectal cancer pathogenesis. However, colorectal intrinsic mechanisms linking these two factors in cancer development are poorly defined. Here, we show that intestinal epithelial cell (IEC)-specific deletion of Dot1l histone methyltransferase (Dot1lΔIEC ) reduced H3K79 dimethylation (H3K79me2) in IECs and inhibited intestinal tumor formation in ApcMin - and AOM-DSS-induced colorectal cancer models. IEC-Dot1l abrogation was accompanied by alleviative colorectal inflammation and reduced Wnt/β-catenin signaling activation. Mechanistically, Dot1l deficiency resulted in an increase in Foxp3+RORϒ+ regulatory T (Treg) cells and a decrease in inflammatory Th17 and Th22 cells, thereby reducing local inflammation in the intestinal tumor microenvironment. Furthermore, Dot1l deficiency caused a reduction of H3K79me2 occupancies in the promoters of the Wnt/β-catenin signaling genes, thereby diminishing Wnt/β-catenin oncogenic signaling pathway activation in colorectal cancer cells. Clinically, high levels of tumor H3K79me2 were detected in patients with colorectal carcinomas as compared to adenomas, and negatively correlated with RORϒ+FOXP3+ Treg cells. Altogether, we conclude that DOT1L is an intrinsic molecular node connecting chronic immune activation and oncogenic signaling pathways in colorectal cancer. Our work suggests that targeting the DOT1L pathway may control colorectal carcinogenesis. Significance: IEC-intrinsic DOT1L controls T cell subset balance and key oncogenic pathway activation, impacting colorectal carcinogenesis.

The gut microbiota can orchestrate the signaling pathways in colorectal cancer.

Current evidence suggests that bacteria contribute to the development of certain cancers, such as colorectal cancer (CRC), partly by stimulating chronic inflammation. However, little is known about the bacterial impact on molecular pathways in CRC. Recent studies have demonstrated how specific bacteria can influence the major CRC-related pathways, i.e., Wnt, PI3K-Akt, MAPK, TGF-β, EGFR, mTOR, and p53. In order to advance the current understanding and facilitate the choice of pathways to investigate, we have systematically collected and summarized the current knowledge within bacterial altered major pathways in CRC. Several pro-tumorigenic and anti-tumorigenic bacterial species and their respective metabolites interfere with the major signaling pathways addressed in this review. Not surprisingly, some of these studies investigated known CRC drivers, such as Escherichia coli, Fusobacterium nucleatum, and Bacteroides fragilis. Interestingly, some metabolites produced by bacterial species typically considered pathogenic, e.g., Vibrio cholera, displayed anti-tumorigenic activities, emphasizing the caution needed when classifying healthy and unhealthy microorganisms. The results collectively emphasize the complexity of the relationship between the microbiota and the tumorigenesis of CRC, and future studies should verify these findings in more realistic models, such as organoids, which constitute a promising platform. Moreover, future trials should investigate the clinical potential of preventive modulation of the gut microbiota regarding CRC development.

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer.

Simple SummaryColorectal cancer (CRC) is an emerging public health problem and the second leading cause of death worldwide, with a significant socioeconomic impact in several countries. The 5-year survival rate is only 12% due to the lack of early diagnosis and resistance to available treatments, and the canonical Wnt signaling pathway is involved in this process. This review underlines the importance of understanding the fundamental roles of this pathway in physiological and pathological contexts and analyzes the use of naturally occurring small molecules that inhibits the Wnt/β-catenin pathway in experimental models of CRC. We also discuss the progress and challenges of moving these small molecules off the laboratory bench into the clinical platform.Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/β-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/β-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/β-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.

TIMP-2 regulates 5-Fu resistance via the ERK/MAPK signaling pathway in colorectal cancer.

5-Fluorouracil (5-Fu) is the first-line chemotherapeutic option for colorectal cancer. However, its efficacy is inhibited by drug resistance. Cytokines play an important role in tumor drug resistance, even though their mechanisms are largely unknown. Using a cytokine array, we established that tissue inhibitor metalloproteinase 2 (TIMP-2) is highly expressed in 5-Fu resistant colorectal cancer patients. Analysis of samples from 84 patients showed that elevated TIMP-2 expression levels in colorectal patients were correlated with poor prognostic outcomes. In a 5-Fu-resistant patient-derived xenograft (PDX) model, TIMP-2 was also found to be highly expressed. We established an autocrine mechanism through which elevated TIMP-2 protein levels sustained colorectal cancer cell resistance to 5-Fu by constitutively activating the ERK/MAPK signaling pathway. Inhibition of TIMP-2 using an anti-TIMP-2 antibody or ERK/MAPK inhibition by U0126 suppressed TIMP-2 mediated 5-Fu-resistance in CRC patients. In conclusion, a novel TIMP-2-ERK/MAPK mediated 5-Fu resistance mechanism is involved in colorectal cancer. Therefore, targeting TIMP-2 or ERK/MAPK may provide a new strategy to overcome 5-Fu resistance in colorectal cancer chemotherapy.

Tumor-Secreted IFI35 Promotes Proliferation and Cytotoxic Activity of CD8+ T Cells Through PI3K/Akt/mTOR Signaling Pathway in Colorectal Cancer

Tumor-Secreted IFI35 Promotes Proliferation and Cytotoxic Activity of CD8+ T Cells Through PI3K/Akt/mTOR Signaling Pathway in Colorectal Cancer