Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Окт. 7, 2024

Abstract Colorectal cancer (CRC) remains one of the leading causes cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis CRC a testament to dysregulation these signaling cascades, which culminates in malignant transformation colonic epithelium. This review aims dissect foundational mechanisms implicated CRC, elucidate generalized principles underpinning neoplastic evolution progression. We discuss molecular hallmarks including genomic, epigenomic microbial features highlight role orchestration tumorigenic process. Concurrently, we advent targeted immune therapies assessing their impact on current clinical landscape. development has been informed deepening understanding oncogenic signaling, identification key nodes within can be exploited pharmacologically. Furthermore, explore potential integrating AI enhance precision therapeutic targeting patient stratification, emphasizing personalized medicine. In summary, our captures dynamic interplay between aberrant concerted efforts counteract changes through strategies, ultimately aiming pave way for improved prognosis treatment modalities colorectal cancer.

Язык: Английский

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The role of RNA methylation in tumor immunity and its potential in immunotherapy

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Июнь 20, 2024

Abstract RNA methylation, a prevalent post-transcriptional modification, has garnered considerable attention in research circles. It exerts regulatory control over diverse biological functions by modulating splicing, translation, transport, and stability. Notably, studies have illuminated the substantial impact of methylation on tumor immunity. The primary types encompass N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), 3-methylcytidine (m3C). Compelling evidence underscores involvement regulating microenvironment (TME). By affecting translation stability through "writers", "erasers" "readers", influence dysregulation immune cells factors. Consequently, plays pivotal role immunity mediating various behaviors, encompassing proliferation, invasion, metastasis, etc. In this review, we discussed mechanisms several methylations, providing comprehensive overview their roles underlying within among immunocytes. exploring how these modifications mediate evasion, also examine potential applications immunotherapy. This review aims to provide novel insights strategies for identifying targets advancing cancer immunotherapy efficacy.

Язык: Английский

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Wnt/β-catenin signalling, epithelial-mesenchymal transition and crosslink signalling in colorectal cancer cells

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 175, С. 116685 - 116685

Опубликована: Май 5, 2024

Colorectal cancer (CRC), with its significant incidence and metastatic rates, profoundly affects human health. A common oncogenic event in CRC is the aberrant activation of Wnt/β-catenin signalling pathway, which drives both initiation progression disease. Persistent facilitates epithelial-mesenchymal transition (EMT), accelerates invasion metastasis. This review provides a summary recent molecular studies on role axis regulating EMT cells, triggers pathogenesis. We present comprehensive examination process transcriptional controllers, an emphasis crucial functions β-catenin, transcription factors (EMT-TFs). also evidences showing that hyperactive phenotypes via "Destruction complex" β-catenin mechanisms. Potential therapeutic challenges approache to suppress prevent cells metastasis by targeting are discussed. These include direct inhibitors novel targets Wnt finally highlight potential combinational treatment options based inhibition pathway.

Язык: Английский

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Helicobacter pylori CagA elevates FTO to induce gastric cancer progression via a “hit‐and‐run” paradigm

Cancer Communications, Год журнала: 2025, Номер unknown

Опубликована: Фев. 17, 2025

Abstract Background Helicobacter pylori ( H. ) infection contributes significantly to gastric cancer (GC) progression. The intrinsic mechanisms of ‐host interactions and their role in promoting GC progression need further investigation. In this study, we explored the potential fat mass obesity‐associated protein (FTO) mediating Cytotoxin‐associated gene A (CagA)‐induced Methods effects on N 6 ‐methyladenosine (m A) modification were evaluated both human samples cell lines. function FTO was elucidated through vitro vivo studies. series techniques, including methylated RNA immunoprecipitation sequencing, binding immunoprecipitation, chromatin assays, utilized investigate mechanism by which mediates capacity cagA ‐positive promote Furthermore, therapeutic inhibitor meclofenamic acid (MA) impeding across cells, animal models, organoids. Results Infection with upregulated expression , essential for CagA‐mediated metastasis associated a poor prognosis patients. Mechanistically, CagA delivered enhanced transcription via Jun proto‐oncogene. Elevated induced demethylation m inhibited degradation heparin‐binding EGF‐like growth factor (HBEGF), thereby facilitating epithelial‐mesenchymal transition (EMT) process cells. Interestingly, eradication did not fully reverse increases HBEGF levels . However, treatment combination antibiotics MA substantially ‐induced EMT prevented metastasis. Conclusion Our study revealed that “hit‐and‐run” CagA‐induced progression, suggests targeting could offer promising approach prevention

Язык: Английский

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Single-Cell Chromatin Accessibility Analysis Reveals the Epigenetic Basis and Signature Transcription Factors for the Molecular Subtypes of Colorectal Cancers

Cancer Discovery, Год журнала: 2024, Номер 14(6), С. 1082 - 1105

Опубликована: Март 5, 2024

Abstract Colorectal cancer is a highly heterogeneous disease, with well-characterized subtypes based on genome, DNA methylome, and transcriptome signatures. To chart the epigenetic landscape of colorectal cancers, we generated high-quality single-cell chromatin accessibility atlas epithelial cells for 29 patients. Abnormal states acquired in adenomas were largely retained which tightly accompanied by opposite changes methylation. Unsupervised analysis malignant revealed two subtypes, exactly matching iCMS classification, key iCMS-specific transcription factors (TFs) identified, including HNF4A PPARA iCMS2 tumors FOXA3 MAFK iCMS3 tumors. Notably, subtype-specific TFs bind to distinct target gene sets contribute both interpatient similarities diversities accessibilities RNA expressions. Moreover, identified CpG-island methylator phenotypes pinpointed state signatures TF regulators CIMP-high subtype. Our work systematically basis well-known CIMP classifications cancers. Significance: minor major genes can faithfully explain corresponding expression respectively. This article featured Selected Articles from Issue, p. 897

Язык: Английский

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ALKBH5-mediated upregulation of CPT1A promotes macrophage fatty acid metabolism and M2 macrophage polarization, facilitating malignant progression of colorectal cancer

Experimental Cell Research, Год журнала: 2024, Номер 437(1), С. 113994 - 113994

Опубликована: Март 12, 2024

m6A modification has been studied in tumors, but its role host anti-tumor immune response and TAMs polarization remains unclear. The fatty acid oxidation (FAO) process of is also attracting attention. A co-culture model colorectal cancer (CRC) cells macrophages was used to simulate the tumor microenvironment. Expression changes demethylase genes FTO ALKBH5 were screened. further investigated. Gain-of-function experiments conducted study ALKBH5's effects on macrophage M2 polarization, CRC cell viability, proliferation, migration, more. Me-RIP Actinomycin D assays performed influence CPT1A, FAO rate-limiting enzyme. AMP, ADP, ATP content detection, OCR measurement, ECAR measurement explore impact level. Rescue validated mechanistic malignant development. In co-culture, enhance suppress macrophages. selected as gene for investigation. mediates CPT1A upregulation by removing modification, promoting facilitating These findings indicate that enhances metabolism upregulating thereby

Язык: Английский

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Myeloid‑derived suppressor cells: Key immunosuppressive regulators and therapeutic targets in colorectal cancer (Review)

International Journal of Oncology, Год журнала: 2024, Номер 65(3)

Опубликована: Июль 25, 2024

Globally, colorectal cancer (CRC) is the third most common type of cancer. CRC has no apparent symptoms in early stages disease, and patients receive a confirmed diagnosis middle or late disease stages. The incidence continues to increase, affected population tends be younger. Therefore, determining how achieve an treatment become top priority for prolonging patient survival. Myeloid‑derived suppressor cells (MDSCs) are group bone marrow‑derived immuno‑negative regulatory that divided into two subpopulations, polymorphonuclear‑MDSCs monocytic‑MDSCs, based on their phenotypic similarities neutrophils monocytes, respectively. These can inhibit immune response promote cell metastasis tumour microenvironment (TME). A large aggregation MDSCs TME often marker poor prognosis inflammatory diseases intestine (such as colonic adenoma ulcerative colitis). In present review, classification first discussed. Then, amplification, role metastatic mechanism described, focusing genes, gene modifications, proteins intestinal microenvironment. Finally, progress CRC‑targeted therapies aim modulate quantity, function structure summarized hope identifying potential screening markers improving therapeutic options.

Язык: Английский

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ALKBH5 acts a tumor-suppressive biomarker and is associated with immunotherapy response in hepatocellular carcinoma

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 2, 2025

As immune-checkpoint inhibitors (ICIs) therapy has made great strides in hepatocellular carcinoma (HCC) treatment, improving patient response to this strategy become the main focus of research. Accumulating evidence shown that m6A methylation plays a crucial role tumorigenesis and progression HCC, while precise impact demethylase ALKBH5 on tumor immune microenvironment (TIME) HCC remains poorly defined. The clinical significance TIM3 were evaluated human tissues. biological function was analyzed vitro vivo. molecular subtypes identified based key ALKBH5-regulated methylation-related genes (MRGs). differences survival, features, TIME immunotherapy between these two then evaluated. regulation detected by qPCR, western blotting MeRIP. downregulated associated with worse prognosis. inhibited proliferation migration activities cells subtype high expression MRGs characterized immunosuppression phenotypes ICIs. Moreover, as target ALKBH5. Upregulated level negatively correlated survival HCC. results study suggest is an important regulator progression. exerts its influence targeting This work provides new insight into correlation modification ICI response, which may help provide therapeutic benefits patients.

Язык: Английский

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Breaking the Barrier: Epigenetic Strategies to Combat Platinum Resistance in Colorectal Cancer

Drug Resistance Updates, Год журнала: 2024, Номер 77, С. 101152 - 101152

Опубликована: Сен. 28, 2024

Язык: Английский

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Epigenetic regulation of tumor immunity

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(12)

Опубликована: Июнь 16, 2024

Although cancer has long been considered a genetic disease, increasing evidence shows that epigenetic aberrations play crucial role in affecting tumor biology and therapeutic response. The dysregulated epigenome cells reprograms the immune landscape within microenvironment, thereby hindering antitumor immunity, promoting progression, inducing immunotherapy resistance. Targeting epigenetically mediated tumor-immune crosstalk is an emerging strategy to inhibit progression circumvent limitations of current immunotherapies, including checkpoint inhibitors. In this Review, we discuss mechanisms by which regulate interactions how targeted therapies synergize with immunotherapy.

Язык: Английский

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