Exosomes are extracellular vesicles that carry various biological substances and have potential as functional mediators in cancers. However, little is known about special molecules in colorectal cancer (CRC) exosomes and their immunological functions.

Using genomic data from the TCGA-CRC cohort, we constructed a prognostic model based on exosome-related lncRNA for the first time, and the biological role of MIR4713HG in CRC was deeply analyzed.

In this study, we downloaded the gene expression data and clinical data of CRC from the TCGA database. The limma package, SVM-REF and univariate Cox analysis were used to screen out core ERG (CERG) in CRC. LASSO and multivariate Cox regression analyses were used to filter out CERG-related LncRNA and construct a risk score. We explored the distribution and expression levels of ERG in immune cell types by scRNA-seq data. xCell was used to calculate the infiltration levels of stromal cells and immune cells in CRC. KM plotter was used for immunotherapy evaluation of core ERG. Next, we further provide colony formation assay, Transwell assay and xenograft models to understand the carcinogenic effect of MIR4713HG.

First, 43 differentially expressed ERG and 7 CERG were obtained. We explored the expression and distribution levels of CERG in 9 types of cells by scRNA-seq data. In addition, two key exosome-associated LncRNA (MIR4713HG and ZEB1-AS1) were obtained, and a risk score (EALncRI) was constructed. EALncRI could accurately predict the prognosis of CRC. Based on the EALncRI, we constructed a nomogram that is easy to use in clinical practice, which can more accurately and stably predict the prognosis of CRC patients. Furthermore, EALncRI was significantly correlated with the expression of 5 HLA molecules and 13 immune checkpoint molecules. MIR4713HG showed a good predictive effect in the overall survival of patients with immunotherapy evaluation. Knocking down the expression of MIR4713HG significantly inhibited proliferation and migration, and also impaired subcutaneous tumor growth in nude mice.

In this study, a variety of machine learning algorithms were used to construct the EALncRI based on ERG, which can effectively predict the prognosis and distinguish the immune landscape of CRC. More importantly, we conducted an in-depth study on MIR4713HG, which may become an important therapeutic target in CRC.

Senescent and cancer cells share common inflammatory characteristics, including factors of the senescence-associated secretory phenotype (SASP) and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Inflammation in the tumor microenvironment not only provides an opportunity for immune cells to attack cancer cells, but also promotes cancer invasion and metastasis. Immune checkpoint molecule PD-L1 is transcriptionally induced by inflammation, and the immunological state of PD-L1-positive tumors influences the efficacy of Immune checkpoint inhibitors (ICIs). ICIs are effective against the PD-L1-positive "hot" tumors; however, the non-immunoactive "cold" tumors that express PD-L1 rarely respond to ICIs, suggesting that converting PD-L1-positive "cold" tumors into "hot" tumors would improve the efficacy of ICIs. To eliminate cancer via the innate immune system, a therapeutic strategy for manipulating inflammatory responses must be established. To date, the molecular mechanisms of inflammation-induced tumorigenesis are not yet fully understood. However, it is becoming clear that the regulatory mechanisms of inflammation in cancer via the cGAS-STING pathway play an important role in both cancer and sensescent cells. In this review, we focus on inflammation and immune escape triggered by DNA damage in cancer and senescent cells.

Gansui Banxia Decoction (GSBXD) is a traditional Chinese medicine formula for the treatment of hepatocellular carcinoma (HCC). Preliminary studies have identified the constituents and anticancer efficacy of GSBXD, but there is a gap in the screening of its lead compounds. Using live cell affinity combined with solid-phase extraction (LCA-SPE) and virtual screening and in vitro activity assays, we obtained 14 reliable potential lead compounds.

Coculturing H22 mouse HCC cells with GSBXD ethanol extract, isolating and purifying the bioactive fractions using LCA-SPE, and identifying the unknown bioactive components by ultraperformance liquid chromatography coupled with quadrupole time-of-flight full information tandem mass spectrometry (UPLC-QTOF-MSE) with the UNIFI information processing platform were performed. Network pharmacology and molecular docking techniques predicted the potential mechanisms of these compounds against HCC. The enzyme-linked immunosorbent assay was used to examine the effects of core compounds on the expression of p53 and Bcl-2 in vitro.

Fourteen compounds screened from GSBXD using SPE-LCA-UPLC-QTOF-MSE may be the main bioactive components. Network pharmacology predictions suggested that protein kinases regulate Bcl-2 and p53 expression to trigger the apoptosis in cancer cells. Molecular docking identified three core compounds, namely, lactiflorin, schaftoside, and violanthin, which showed high affinities for the relevant proteins. Experimental verification confirmed their superior anticancer activity in vitro. Their anti-HCC effects likely involved in the upregulation of p53 and downregulation of Bcl-2 expression at the cellular level.

We developed a stable and accurate SPE-LCA method, which successfully isolated and characterized 14 potentially active compounds from GSBXD. They may improve HCC by promoting p53 expression and reducing Bcl-2 expression. This work lays a foundation for discovering lead compounds and exploring potential mechanisms in traditional Chinese medicine formulas.

Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer worldwide, continues to pose a substantial health challenge with limited treatment options for advanced stages. Despite progress in therapies such as surgery, transplantation, and targeted treatments, prognosis remains bleak for many patients. The advent of immunotherapy has revolutionized the landscape of advanced HCC treatment, offering hope for improved outcomes. However, its efficacy is limited, with a modest response rate of approximately 20% as a single-agent therapy, underscoring the urgent need to decipher mechanisms of immunotherapy resistance. Tumor protein 53 gene (TP53), a pivotal tumor suppressor gene, and Programmed death ligand 1 (PD-L1), a crucial immune checkpoint ligand, play central roles in HCC's evasion of immune responses. Understanding how tumor protein 53 (p53) influences PD-L1 expression and immune system interactions is essential for unraveling the complexities of immunotherapy resistance mechanisms. Elucidating these molecular interactions not only enhances our understanding of HCC's underlying mechanisms but also lays the foundation for developing targeted treatments that may improve outcomes for patients with advanced-stage liver cancer. Ultimately, deciphering the nexus of p53 and PD-L1 in immunotherapy resistance promises to advance treatment strategies and outcomes in the challenging landscape of HCC. This review delves into the intricate relationship between p53 and PD-L1 concerning immunotherapy resistance in HCC, offering insights that could pave the way for novel therapeutic strategies aimed at enhancing treatment efficacy and overcoming resistance in advanced stages of the disease.

The stress-associated chaperone system is an actionable target in cancer therapies. It is ubiquitously upregulated in cancer tissues and enables tumorigenicity by stabilizing oncoproteins. Most inhibitors target the key component, heat-shock protein 90 (HSP90). Although HSP90 inhibitors are highly tumor-selective, they fail in clinical trials. These failures are partly due to interference with a negative regulatory feedback loop in the heat-shock response (HSR): in response to HSP90 inhibition, there is compensatory synthesis of stress-inducible chaperones, mediated by the transcription factor heat-shock-factor 1 (HSF1). We recently identified that wild-type p53 reduces the HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here, we test whether in HSP90-based therapies, simultaneous p53 activation or direct cell cycle inhibition interrupts the deleterious HSF1-HSR axis and improves the efficiency of HSP90 inhibitors. We found that the clinically relevant p53 activator Idasanutlin suppresses the HSF1-HSR activity in HSP90 inhibitor-based therapies. This combination synergistically reduces cell viability and accelerates cell death in p53-proficient colorectal cancer (CRC) cells, murine tumor-derived organoids, and patient-derived organoids (PDOs). Mechanistically, upon combination therapy, CRC cells upregulate p53-associated pathways, apoptosis, and inflammatory pathways. Likewise, in a CRC mouse model, dual HSF1-HSP90 inhibition represses tumor growth and remodels immune cell composition. Importantly, inhibition of the cyclin-dependent kinases 4/6 (CDK4/6) under HSP90 inhibition phenocopies synergistic repression of the HSR in p53-proficient CRC cells. Moreover, in p53-deficient CRC cells, HSP90 inhibition in combination with CDK4/6 inhibitors similarly suppresses the HSF1-HSR and reduces cancer growth. Likewise, p53-mutated PDOs respond to dual HSF1-HSP90 inhibition, providing a strategy to target CRC independent of the p53 status. In sum, we provide new options to improve HSP90-based therapies to enhance CRC therapies.

Cancer is complex because of the critical imbalance in genetic regulation as characterized by both the overexpression of oncogenes (OGs), mainly through mutations, amplifications, and translocations, and the inactivation of tumor-suppressor genes (TSGs), which entail the preservation of genomic integrity by inducing apoptosis to counter the malignant growth. Reviewing the intricate molecular interplay between OGs and TSGs draws attention to their cell cycle, apoptosis, and cancer metabolism regulation. In the present review, we discuss seminal discoveries, such as Knudson's two-hit hypothesis, which framed the field's understanding of cancer genetics, leading to the next breakthroughs with next-generation sequencing and epigenetic profiling, revealing novel insights into OG and TSG dysregulation with opportunities for targeted therapy. The key pathways, such as MAPK/ERK, PI3K/AKT/mTOR, and Wnt/β-catenin, are presented in the context of tumor progression. Importantly, we further highlighted the advances in therapeutic strategies, including inhibitors of KRAS and MYC and restoration of TSG function, despite which mechanisms of resistance and tumor heterogeneity pose daunting challenges. A high-level understanding of interactions between OG-TSGs forms the basis for effective, personalized cancer treatment-something to strive for in better clinical outcomes. This synthesis should integrate foundational biology with translation and, in this case, contribute to the ongoing effort against cancer.

Heat-shock protein 90 (HSP90) is a highly active molecular chaperone that plays a crucial role in cellular function. It facilitates the folding, assembly and stability of various oncogenic proteins, particularly kinases and transcription factors involved in regulating tumor growth and maintenance signaling pathways. Consequently, HSP90 inhibitors are being explored as drugs for cancer therapy. Crystallographic fragment screening is a novel screening method that has been developed in recent years for fragment-based drug discovery and is known for its high hit rate and its ability to provide direct insights into the complex structures of proteins and compounds. In this paper, high-diffraction-resolution crystals of the N-terminal domain of human HSP90α were employed in crystallographic fragment screening to discover binding fragments and binding sites. A diverse library of 800 structurally distinct fragments was screened, yielding 91 starting points for the fragment-based drug design of new HSP90α N-terminal inhibitors. Nearly a thousand crystals were measured, with 738 being processed and phased using a highly automated data-processing pipeline including data reduction and phasing, refinement and hit identification via PanDDA multi-data-set analysis. The 91 identified compounds bind to eight distinct regions of the HSP90α N-terminus, with 63 fragments located in the ATP-binding pocket and its surroundings, thus demonstrating the potential for the development of HSP90α- and ATP-binding inhibitors. This study emphasizes crystallographic fragment screening as a powerful method that can effectively identify fragment molecules and inhibitors that bind to HSP90α, contributing to ongoing efforts in cancer drug discovery.

Mutations in the p53 gene compromise its role as guardian of genomic integrity, yielding predominantly missense p53 mutant proteins. The gain-of-function hypothesis has long suggested that these mutant proteins acquire new oncogenic properties; however, recent studies challenge this notion, indicating that targeting these mutants may not impact the fitness of cancer cells. Mounting evidence indicates that tumorigenesis involves a cooperative interplay between driver mutations and cellular state, influenced by developmental stage, external insults, and tissue damage. Consistently, the behavior and properties of p53 mutants are altered by the context. This article aims to provide a balanced summary of the evolving evidence regarding the contribution of p53 mutants in the biology of cancer while contemplating alternative frameworks to decipher the complexity of p53 mutants within their physiological contexts.

Over the years, the numbers of treatment options for colorectal cancer (CRC) have increased, leading to notable improvements in the overall survival of CRC patients. Although therapy may initially yield positive results, the development of drug resistance can result in treatment failure and cancer recurrence. This resistance is often attributed to the presence of cancer stem cells (CSCs). These CSCs not only contribute to therapeutic resistance but also play crucial roles in the initiation and development of tumor metastasis.

To investigate the antitumor effects of SH-4-54, which are mediated by targeting CSCs relative to treatment outcomes.

CSCs were enriched by culturing CRC cells in serum-free medium. Hallmarks of stemness and IL-6/JAK2/STAT3 signaling were detected by Western blotting. Indicators of CSC malignancy, including proliferation, invasion, and tumor formation, were measured.

In this study, we employed SH-4-54, which exhibits anticancer activity in solid tumors through targeting the SH2 domain of both the signal transducer and activator of transcription (STAT)3 and the STAT5, and evaluated its effects on stemness and chemoresistance in colorectal CSCs. As expected, SH-4-54 treatment inhibited the phosphorylation of STAT3 (p-STAT3) and decreased the percentage of ALDH1A1-positive CRC cells. The addition of SH-4-54 dissociated colorectal spheroids and decreased the expression of stemness markers, including ALDH1A1, CD44 and Nanog. SH-4-54 treatment decreased IL-6/JAK2/STAT3 signaling by inhibiting p-STAT3 and thus inhibited spheroid formation by SW480 and LoVo cells. Moreover, SH-4-54 treatment inhibited indicators of malignancy, including cell proliferation, invasion, and tumor formation, in CSCs in vitro and in vivo. Notably, SH-4-54 treatment significantly increased chemosensitivity to oxaplatin.

Taken together, these results indicate that SH-4-54 is a promising molecule that exerts antitumor effects on colorectal CSCs by inhibiting STAT3 signaling.

Cannabidiol (CBD) is a non-neurotoxic, phytocannabinoid from cannabis with reported medicinal properties, including antiepileptic and anti-inflammatory activity. Several in vitro and in vivo studies have shown that CBD has antitumor potential against colorectal cancer (CRC), the third deadliest cancer in the world. However, as different mutations influence the antitumor effects and CBD can bind a variety of receptors, it is yet to be determined whether specific CRC mutations affect CBD's efficacy in treatment of CRC. To investigate this, we selected four CRC cell lines, including HCT116, HT-29, LS174T, and LS153, which harbor distinct mutations. Cells were treated with a range of concentrations of CBD to evaluate its cytotoxic effects and impact on cell proliferation, migration, and invasion by using a live-cell imaging system. IC50 values were then calculated for each parameter. The level of endoplasmic reticulum (ER) stress pathway markers was also measured using qRTPCR. The requirements for CB1 or CB2 receptor-medicated signaling were investigated using the selective inhibitors AM251 and SR144528, respectively. Our results demonstrate that CBD induces apoptosis and halts proliferation, migration, and invasion of CRC cell lines in a concentration-dependent manner. CBD showed potent antitumor effects in the tested cell lines with no obvious effect from different mutations such as KRAS, BRAF, APC, PTEN, etc. CBD also induced ER stress in CRC cells but not in healthy intestinal organoids. Cotreatment with SR144528 inhibited the effects of indicating involvement of CB2 receptor activation in the anticancer effects of CBD. Together, these results demonstrated that CBD could be effective for CRC regardless of the underlying mutation through CB2 receptor activation.

Inflammatory Bowel Disease (IBD) is an inflammatory intestinal disease, and with prolonged illness duration, the annual risk of IBD progressing to colitis-associated colorectal cancer (CAC) gradually increases. In recent years, there has been a noticeable trend towards the application of traditional Chinese medicine (TCM) in the treatment of CAC.

This comprehensive review summarizes the pathogenesis of CAC and details the therapeutic benefits of TCM in treating CAC, including various TCM prescriptions and ingredients, establishing the theoretical foundation for the application of TCM in CAC treatment.

We assessed literature published before March 24, 2024, from several databases, including Web of Science, PubMed, Scopus and Google Scholar. The keywords used include "traditional Chinese medicine", "traditional Chinese medicine prescriptions", "traditional Chinese medicine ingredients", "herbal medicine", "colitis-associated colorectal cancer", "inflammatory bowel disease", "colorectal cancer" and "colitis-cancer transformation". We conducted a comprehensive collection and collation of pertinent scientific articles from various databases, focusing on the efficacy of TCM in the prevention and treatment of "colitis-cancer transformation".

This paper provides a concise summary and thorough analysis of twenty-eight prescriptions and ingredients of TCM for the prevention and treatment of CAC, based on existing experimental and clinical research. There are positive signs that TCM can effectively prevent and treat the "colitis-cancer transformation" through repairing the intestinal mucosal barrier, correcting intestinal flora imbalance, and regulating intestinal immune responses.

TCM possesses comprehensive regulatory advantages that are multifaceted, multilevel, and multitarget. It has a definite curative effect in the prevention and treatment of CAC. It is essential to enhance the clinical efficacy of TCM in the prevention and treatment of CAC based on syndrome differentiation and treatment, with the assistance of modern medicine.

Nuclear receptor-binding SET domain 2 (NSD2) is a histone methyltransferase, that catalyzes dimethylation of lysine 36 of histone 3 (H3K36me2) and is associated with active transcription of a series of genes. NSD2 is overexpressed in multiple types of solid human tumors and has been proven to be related to unfavorable prognosis in several types of tumors.

We established a mouse model in which the NSD2 gene was conditionally knocked out in intestinal epithelial cells. We used azoxymethane and dextran sodium sulfate to chemically induce murine colorectal cancer. The development of colorectal tumors were investigated using post-necropsy quantification, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA).

Compared with wild-type (WT) control mice, NSD2fl/fl-Vil1-Cre mice exhibited significantly decreased tumor numbers, histopathological changes, and cytokine expression in colorectal tumors.

Conditional knockout of NSD2 in intestinal epithelial cells significantly inhibits colorectal cancer progression.

Colorectal cancer (CRC) development is a complex, multi-stage process, transitioning from normal to adenomatous tissue, and then to invasive carcinoma. Despite research, there's a knowledge gap on using high-resolution spatial omics to understand CRC's tumor microenvironment dynamics.

We used single-cell transcriptomics to study major biological changes and cell interactions in CRC progression. Additionally, high-resolution spatial transcriptomics helped us examine the spatial distribution of cells with significant pathway changes, offering insights into the tumor microenvironment's development throughout CRC stages.

In the progression of CRC, plasma cells, neutrophils, and fibroblasts exhibit the most significant changes in hallmark pathways, while epithelial cells show the most pronounced alterations in metabolic pathways. We also identified a population of NOTUM + epithelial cells and IGHG1/3 + plasma cells that are concentrated at the boundary between normal tissue and adenomas. Pathway analysis further suggests that these NOTUM + cells activate numerous cancer-related pathways, despite the absence of significant pathological morphological changes. Additionally, we conducted a targeted drug prediction analysis to identify potential therapeutic agents for NOTUM-expressing epithelial cells.

Analyzing scRNA-seq and Visium HD data, we found that IGHG1/3 + plasma cells and tumor-associated neutrophil (TANs) may significantly affect colorectal tissue transformation from normal to adenoma and carcinoma. These cells are concentrated at the transition between normal and adenomatous tissue. We also found NOTUM-expressing cells at the edge of normal and adenomatous areas, possibly indicating a morphological transition as normal cells evolve into adenoma cells.

Inflammatory bowel disease (IBD), a chronic inflammatory condition of the human intestine, comprises Crohn's disease (CD) and ulcerative colitis (UC). IBD causes severe gastrointestinal symptoms and increases the risk of developing colorectal carcinoma. Although the etiology of IBD remains ambiguous, complex interactions between genetic predisposition, microbiota, epithelial barrier, and immune factors have been implicated. The disruption of intestinal homeostasis is a cardinal characteristic of IBD. Patients with IBD exhibit intestinal microbiota dysbiosis, impaired epithelial tight junctions, and immune dysregulation; however, the relationship between them is not completely understood. As the largest body surface is exposed to the external environment, the gastrointestinal tract epithelium is continuously subjected to environmental and endogenous stressors that can disrupt cellular homeostasis and survival. Heat shock proteins (HSPs) are endogenous factors that play crucial roles in various physiological processes, such as maintaining intestinal homeostasis and influencing IBD progression. Specifically, HSPs share an intricate association with microbes, intestinal epithelium, and the immune system. In this review, we aim to elucidate the impact of HSPs on IBD development by examining their involvement in the interactions between the intestinal microbiota, epithelial barrier, and immune system. The recent clinical and animal models and cellular research delineating the relationship between HSPs and IBD are summarized. Additionally, new perspectives on IBD treatment approaches have been proposed.

There is intratumor heterogeneity in the stabilization of missense mutant p53, and it has been thought that only cells with nuclear accumulation of mutant p53 have oncogenic function. However, using mouse intestinal tumor-derived organoids, we show that mutant p53-stabilized cells transactivate Wnt/β-catenin signaling in neighboring p53-destabilized cells through activating the COX-2/PGE2 pathway. These results suggest that both p53-stabilized cells and p53-destabilized cells contribute to malignant progression through interaction within the intratumor microenvironment.

Wnt/β-catenin/transcription factor (TCF) transcriptional activity plays an integral role in colorectal cancer (CRC) carcinogenesis. However, to date, no drugs targeting this pathway are used in clinical practice owing to the undesirable and serious side effects. In this study, it is found that the transcriptional regulation of Wnt pathway is activated and associated with liver metastasis in CRC. Through high-throughput screening of 24 inhibitors on 12 CRC and three colorectal organoids in this organoid living biobank, adavivint is found to exhibit anti-tumor activity and low toxicity in colorectal organoids, independent of the canonical Wnt/β-catenin signaling. Mechanistically, ADAM10 is screened as a target of adavivint to specifically regulate the protein expression of NOTCH2, which mediates the transcriptional regulation of the Wnt pathway. NOTCH2 not directly interact with TCF7-like 2 (TCF7L2), a key downstream transcriptional factor of canonical Wnt/β-catenin signaling, but directly activated the transcription of TCF7L2 and Wnt target genes, such as MYC, JUN and CCND1/2. Furthermore, use of adavivint or blockage of ADAM10/NOTCH2/TCF7L2 signaling enhances the chemosensitivity of CRC cells. Overall, this study provides a promising candidate for the development of small-molecule inhibitors and reveals a potential therapeutic target for CRC.

Multiple myeloma (MM) remains incurable despite novel therapeutics. A major contributor to the development of relapsed/refractory and resistant MM is extraosseous extramedullary disease (EMD), whose molecular biology is still not fully understood. We analyzed 528 MM patients who presented to our institution between 2014 and 2021 and who had undergone molecular testing. We defined EMD as organ plasmacytoma distinct from bones and evaluated patients for the development of EMD with the goal of defining their molecular characteristics. Here, we show that RAS/BRAF mutations are likely essential for the development of EMD. Our results also indicate that the underlying reason for the negative outcomes in patients with poor prognostic factors such as duplication 1q and deletion 17p is largely due to the development of EMD. However, the presence of TP53 mutation remains a poor prognostic factor regardless of EMD development. Furthermore, mutation sites of TP53 were different between EMD versus non-EMD patients, with gain-of-function mutations enriched in patients with EMD. Our data highlights distinct molecular abnormalities in patients with EMD and provides potential mechanistic insights for novel therapeutic targets for the future.

Drug resistance limits the efficacy of chemotherapy for colorectal cancer liver metastasis (CRLM). However, the evolution of CRLM during drug treatment remains poorly elucidated. Multi-omics and treatment response data from 115 samples of 49 patients with CRLM undergoing bevacizumab (BVZ)-based chemotherapy show little difference in genomic alterations in 92% of cases, while remarkable differences are observed at the transcriptomic level. By decoupling intrinsic and acquired resistance, we find that hepatocyte and myeloid cell infiltration contribute to 38.5% and 23.1% of acquired resistance, respectively. Importantly, SMAD4 mutations and chr20q copy-number gain are associated with intrinsic chemoresistance. Gene interference experiments suggest that SMAD4R361H/C mutations confer BVZ and 5-fluorouracil (5-FU) resistance through STAT3 signaling. Notably, supplementing BVZ and 5-FU with the STAT3 inhibitor GB201 restores therapeutic efficacy in SMAD4R361H/C cancer cells. Our study uncovers the evolutionary dynamics of CRLM and its microenvironment during treatment and offers strategies to overcome drug resistance.

Enhancer of zeste homolog 2 (EZH2) is a methyltransferase involved in cell cycle regulation, cell differentiation, and cell death and plays a role in modulating the immune response. Although it mainly functions by catalyzing the tri-methylation of H3 histone on K27 (H3K27), to inhibit the transcription of target genes, EZH2 can directly methylate several transcription factors or form complexes with them, regulating their functions. EZH2 expression/activity is often dysregulated in cancer, contributing to carcinogenesis and immune escape, thereby representing an important target in anti-cancer therapy. This review summarizes some of the mechanisms through which EZH2 regulates the expression and function of tumor suppressor genes and oncogenic molecules such as STAT3, mutant p53, and c-Myc and how it modulates the anti-cancer immune response. The influence of posttranslational modifications on EZH2 activity and stability and the possible strategies leading to its inhibition are also reviewed.

The p53 protein, encoded by the TP53 gene, serves as a critical tumor suppressor, playing a vital role in maintaining genomic stability and regulating cellular responses to stress. Dysregulation of p53 is frequently observed in hematological malignancies, significantly impacting disease progression and patient outcomes. This review aims to examine the regulatory mechanisms of p53, the implications of TP53 mutations in various hematological cancers, and emerging therapeutic strategies targeting p53. We conducted a comprehensive literature review to synthesize recent findings related to p53's multifaceted role in hematologic cancers, focusing on its regulatory pathways and therapeutic potential. TP53 mutations in hematological malignancies often lead to treatment resistance and poor prognosis. Current therapeutic strategies, including p53 reactivation and gene therapy, show promise in improving treatment outcomes. Understanding the intricacies of p53 regulation and the consequences of its mutations is essential for developing effective diagnostic and therapeutic strategies in hematological malignancies, ultimately enhancing patient care and survival.

The p53 gene is one of the genes most closely associated with human tumors and has become a popular target for tumor drug design. Currently, p53-based gene therapy techniques have been developed, but these therapies face challenges such as immaturity, high safety hazards, limited efficacy, and low patient acceptance. However, researchers are no less enthusiastic about the treatment because of its theoretical potential to treat cancer. In this paper, the advances in p53-based gene therapy and related nucleic acid delivery technologies were reviewed and prospected in order to support further development in this field.

Esophageal Squamous Cell Carcinoma (ESCC) remains a predominant health concern in the world, characterized by high prevalence and mortality rates. Advances in single-cell transcriptomics have revolutionized cancer research by enabling a precise dissection of cellular and molecular diversity within tumors.

This study aims to elucidate the cellular dynamics and molecular mechanisms in ESCC, focusing on the transcriptional influence of STAT3 (Signal Transducer and Activator of Transcription 3) and its interaction with LHPP, thereby uncovering potential therapeutic targets.

Single-cell RNA sequencing was employed to analyze 44,206 cells from tumor and adjacent normal tissues of ESCC patients, identifying distinct cell types and their transcriptional shifts. We conducted differential gene expression analysis to assess changes within the tumor microenvironment (TME). Validation of key regulatory interactions was performed using qPCR in a cohort of 21 ESCC patients and further substantiated through experimental assays in ESCC cell lines.

The study revealed critical alterations in cell composition and gene expression across identified cell populations, with a notable shift towards pro-tumorigenic states. A significant regulatory influence of STAT3 on LHPP was discovered, establishing a novel aspect of ESCC pathogenesis. Elevated levels of STAT3 and suppressed LHPP expression were validated in clinical samples. Functional assays confirmed that STAT3 directly represses LHPP at the promoter level, and disruption of this interaction by promoter mutations diminished STAT3's repressive effect.

This investigation underscores the central role of STAT3 as a regulator in ESCC, directly impacting LHPP expression and suggesting a regulatory loop crucial for tumor behavior. The insights gained from our comprehensive cellular and molecular analysis offer a deeper understanding of the dynamics within the ESCC microenvironment. These findings pave the way for targeted therapeutic interventions focusing on the STAT3-LHPP axis, providing a strategic approach to improve ESCC management and prognosis.

Gut microbiota plays a vital role in host metabolism; however, the influence of gut microbes on polyamine metabolism is unknown. Here, we found germ-free models possess elevated polyamine levels in the colon. Mechanistically, intestinal Lactobacillus murinus-derived small RNAs in extracellular vesicles down-regulate host polyamine metabolism by targeting the expression of enzymes in polyamine metabolism. In addition, Lactobacillus murinus delays recovery of dextran sodium sulfate-induced colitis by reducing polyamine levels in mice. Notably, a decline in the abundance of small RNAs was observed in the colon of mice with colorectal cancer (CRC) and human CRC specimens, accompanied by elevated polyamine levels. Collectively, our study identifies a specific underlying mechanism used by intestinal microbiota to modulate host polyamine metabolism, which provides potential intervention for the treatment of polyamine-associated diseases.

Zinc finger protein 263 (ZNF263) is frequently upregulated in various tumor types; however, its function and regulatory mechanism in colorectal cancer (CRC) have not yet been elucidated. In this study, the expression of ZNF263 was systematically examined using data from The Cancer Genome Atlas database and samples from patients with CRC. The results indicated that high expression of ZNF263 in CRC tissues is significantly associated with tumor grade, lymph node metastasis and disant metastasis. Additionally, overexpression of ZNF263 significantly promoted the proliferation, invasion, migration, and epithelial-mesenchymal transition of CRC cells, while also increasing signal transducer and activator of transcription 3 (STAT3) expression and mRNA stability. Conversely, knockdown of ZNF263 inhibited the malignant behavior of CRC cells and decreased STAT3 expression and mRNA stability. Further mechanism studies using chromatin immunoprecipitation (CHIP) and luciferase assays verified that ZNF263 directly binds to the STAT3 promoter. Rescue experiments demonstrated that the knockdown or overexpression of STAT3 could significantly reverse the effects of ZNF263 on CRC cells. Additionally, our study found that overexpression of ZNF263 enhanced the resistance of CRC cells to the chemoradiotherapy. In summary, this study not only elucidated the significant role of ZNF263 in CRC but also proposed novel approaches and methodologies for the diagnosis and treatment of this malignancy.

Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of KrasG12D;Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.

VDUP1 acts as a tumor suppressor gene in various cancers. VDUP1 is expressed at low levels in sporadic and ulcerative-colitis-associated colorectal cancer. However, the effects of VDUP1 deficiency on CAC remain unclear. In this study, we found that VDUP1 deficiency promoted CAC development in mice. Wild-type (WT) and VDUP1 KO mice were used to investigate the role of VDUP1 in the development of azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced CAC. VDUP1 levels significantly decreased in the colonic tumor and adjacent nontumoral tissues of WT mice after AOM/DSS treatment. Moreover, AOM/DSS-treated VDUP1 KO mice exhibited a worse survival rate, disease activity index, and tumor burden than WT mice. VDUP1 deficiency significantly induced cell proliferation and anti-apoptosis in tumor tissues of VDUP1 KO mice compared to WT littermates. Additionally, mRNA levels of interleukin-6 and tumor necrosis factor-alpha and active forms of signal transducer and activator of transcription 3 and nuclear factor-kappa B p65 were significantly increased in the tumor tissues of VDUP1 KO mice. Overall, this study demonstrated that the loss of VDUP1 promoted AOM/DSS-induced colon tumorigenesis in mice, highlighting the potential of VDUP1-targeting strategies for colon cancer prevention and treatment.

Krüppel-like factor 4 (KLF4) has been demonstrated to exert a pro-carcinogenic effect in solid tissues. However, the precise biological function and underlying mechanisms in colorectal cancer (CRC) remains elucidated.

To investigate whether KLF4 participates in the proliferation and invasion of CRC.

The expression of KLF4 was investigated using immunohistochemistry and immunoblotting. The clinical significance of KLF4 was evaluated. Furthermore, the effect of inhibiting or overexpressing KLF4 on tumor was examined. Immunoblotting and qPCR were used to detect Epithelial-mesenchymal transition-related proteins levels. Additionally, the molecular function of KLF4 is related to the STAT3 signaling pathway and was determined through JASPAR, GSEA analysis, and in vitro experiments.

KLF4 exhibits down-regulated expression in CRC and is part of the vessel invasion, TNM stage, and worse prognosis. In vitro studies have shown that KLF4 promotes cellular proliferation and invasion, as well as EMT processes. Xenograft tumor models confirmed the oncogenic role of KLF4 in nude mice. Furthermore, GSEA and JASPAR databases analysis reveal that the binding of KLF4 to the signal transducer and activator of transcription 3 (STAT3) promoter site induces activation of p-STAT3 signaling. Subsequent targeting of STAT3 confirmed its pivotal role in mediating the oncogenic effects exerted by KLF4.

The study suggests that KLF4 activates STAT3 signaling, inducing epithelial-mesenchymal transition, thereby promoting CRC progression.

Wild-type (wt) p53 and mutant forms (mutp53) play a key but opposite role in carcinogenesis. wtP53 acts as an oncosuppressor, preventing oncogenic transformation, while mutp53, which loses this property, may instead favor this process. This suggests that a better understanding of the mechanisms activating wtp53 while inhibiting mutp53 may help to design more effective anti-cancer treatments. In this review, we examine possible PTMs with which both wt- and mutp53 can be decorated and discuss how their manipulation could represent a possible strategy to control the stability and function of these proteins, focusing in particular on mutp53. The impact of ubiquitination, phosphorylation, acetylation, and methylation of p53, in the context of several solid and hematologic cancers, will be discussed. Finally, we will describe some of the recent studies reporting that wt- and mutp53 may influence the expression and activity of enzymes responsible for epigenetic changes such as acetylation, methylation, and microRNA regulation and the possible consequences of such changes.

Radiotherapy (RT) and immune checkpoint inhibitor (ICI) are important treatments for esophageal cancer. Some studies have confirmed the safety and effectiveness of using RT in combination with ICI, while serious side effects have been exhibited by some patients. We report a patient with metastatic esophageal cancer who received RT combined with ICI. The patient experienced severe thrombocytopenia, and treatment with thrombopoietin and corticosteroids were ineffective. Finally, the patient developed abscopal hyperprogression outside the radiation field. Interestingly, next-generation sequencing revealed increased JAK2 gene copies in the surgical slices. The JAK2/STAT3 pathway is involved in the regulation of megakaryocyte development. Recurrent thrombocytopenia may activate the JAK2/STAT3 pathway, leading to megakaryocyte differentiation and platelet biogenesis. However, persistent activation of the JAK2/STAT3 pathway has been associated with immune ICI resistance and tumor progression. This case indicates that thrombocytopenia and increased JAK2 gene copies may be risk factors for poor prognosis after ICI and RT treatment.

Early-onset colorectal cancer (EOCRC), defined as colorectal cancer in individuals under 50 years of age, has shown an alarming increase in incidence worldwide. We report a case of a twenty-four-year-old female with a strong family history of colorectal cancer (CRC) but without an identified underlying genetic predisposition syndrome. Two years after primary surgery and adjuvant chemotherapy, the patient developed new liver lesions. Extensive diagnostic imaging was conducted to investigate suspected liver metastases, ultimately leading to a diagnosis of focal nodular hyperplasia. The young age of the patient has prompted comprehensive genomic and transcriptomic profiling in order to identify potential oncogenic drivers and inform further clinical management of the patient. Besides a number of oncogenic mutations identified in the patient's tumour sample, including KRAS G12D, TP53 R248W and TTN L28470V, we have also identified a homozygous deletion of 24.5 MB on chromosome 8. A multivariate Cox regression analysis of this patient's mutation profile conferred a favourable prognosis when compared with the TCGA COADREAD database. Notably, the identified deletion on chromosome 8 includes the WRN gene, which could contribute to the patient's overall positive response to chemotherapy. The complex clinical presentation, including the need for emergency surgery, early age at diagnosis, strong family history, and unexpected findings on surveillance imaging, necessitated a multidisciplinary approach involving medical, radiation, and surgical oncologists, along with psychological support and reproductive medicine specialists. Molecular profiling of the tumour strongly indicates that patients with complex mutational profile and rare genomic rearrangements require a prolonged surveillance and personalised informed interventions.

The reciprocal modulation between the CXCL12/CXCR4/ACKR3 axis and the STAT3 signaling pathway plays a crucial role in the progression of various diseases and neoplasms. Activation of the CXCL12/CXCR4/ACKR3 axis triggers the STAT3 pathway through multiple mechanisms, while the STAT3 pathway also regulates the expression of CXCL12. This review offers a thorough and systematic analysis of the reciprocal regulatory mechanisms between the CXCL12/CXCR4/ACKR3 signaling axis and the STAT3 signaling pathway in the context of diseases, particularly tumors. It explores the potential clinical applications in tumor treatment, highlighting possible therapeutic targets and novel strategies for targeted tumor therapy.

p53 was discovered 45 years ago as an SV40 large T antigen binding protein, coded by the most frequently mutated TP53 gene in human cancers. As a transcription factor, p53 is tightly regulated by a rich network of post-translational modifications to execute its diverse functions in tumor suppression. Although early studies established p53-mediated cell-cycle arrest, apoptosis, and senescence as the classic barriers in cancer development, a growing number of new functions of p53 have been discovered and the scope of p53-mediated anti-tumor activity is largely expanded. Here, we review the complexity of different layers of p53 regulation, and the recent advance of the p53 pathway in metabolism, ferroptosis, immunity, and others that contribute to tumor suppression. We also discuss the challenge regarding how to activate p53 function specifically effective in inhibiting tumor growth without harming normal homeostasis for cancer therapy.

Although LncRNA JPX has been linked to a number of malignancies, it is yet unknown how it relates to endometrial carcinoma (EC). Investigating the expression, functional activities, and underlying molecular processes of lncRNA JPX in EC was the goal of this work.

RT-qPCR was used to examine the differences in lncRNA/microRNA (miRNA, miR)/mRNA expression between normal cervical and EC tissues or cells. Cell Counting Kit-8, flow cytometry, and transwell were used to evaluate the association between lncRNA JPX/miR-140-3p/phosphoinositide-3-kinase catalytic subunit α (PIK3CA) in Ishikawa and JEC cell lines. The impact of JPX on the downstream janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling pathway was investigated using Western blot analysis.

When comparing EC tissues to nearby normal tissues, JPX expression is markedly increased in EC tissues, with greater expression in advanced-stage EC. Furthermore, compared to normal epithelial cells, EC cell lines have higher levels of JPX expression. In Ishikawa and JEC endometrial cancer cell lines, we used siRNA-mediated suppression of JPX to find lower cell viability, increased apoptosis, cell cycle arrest, and reduced migration and invasion. We next verified that miR-140-3p binds to downstream target cells to impede the transcription and translation of PIK3CA, which in turn prevents the growth of Ishikawa and JEC cells. JPX functions as a ceRNA to adsorb miR-140-3p. This procedure required controlling JAK2/STAT3, a downstream signal.

JPX enhances the development of Ishikawa and JEC cells and activates downstream JAK2/STAT3 signal transduction via the miR-140-3p/PIK3CA axis, offering a possible therapeutic target for the treatment of EC.

In some cancers mutant p53 promotes the occurrence, development, metastasis and drug resistance of tumours, with targeted protein degradation seen as an effective therapeutic strategy. However, a lack of specific autophagy receptors limits this. Here, we propose the synthesis of biomimetic nanoreceptors (NRs) that mimic selective autophagy receptors. The NRs have both a component for targeting the desired protein, mutant-p53-binding peptide, and a component for enhancing degradation, cationic lipid. The peptide can bind to mutant p53 while the cationic lipid simultaneously targets autophagosomes and elevates the levels of autophagosome formation, increasing mutant p53 degradation. The NRs are demonstrated in vitro and in a patient-derived xenograft ovarian cancer model in vivo. The work highlights a possible direction for treating diseases by protein degradation.

Here we present the generation and characterization of patient-derived organoids (PDOs) from colorectal cancer patients. PDOs derived from two patients with TP53 mutations were tested with two different HDAC inhibitors (SAHA and NKL54). Cell death induction, transcriptome, and chromatin accessibility changes were analyzed. HDACIs promote the upregulation of low expressed genes and the downregulation of highly expressed genes. A similar differential effect is observed at the level of chromatin accessibility. Only SAHA is a potent inducer of cell death, which is characterized by the upregulation of BH3-only genes BIK and BMF. Up-regulation of BIK is associated with increased accessibility in an intronic region that has enhancer properties. SAHA, but not NKL54, also causes downregulation of BCL2L1 and decreases chromatin accessibility in three distinct regions of the BCL2L1 locus. Both inhibitors upregulate the expression of innate immunity genes and members of the MHC family. In summary, our exploratory study indicates a mechanism of action for SAHA and demonstrate the low efficacy of NKL54 as a single agent for apoptosis induction, using two PDOs. These observations need to be validated in a larger cohort of PDOs.

One of the most common causes of lung cancer relapse after clinical treatment is radioresistance. However, the mechanism underlying radioresistance remains unclear. In this study, we investigated the role of Ras p21 protein activator (RASA2) in non-small cell lung cancer (NSCLC).

The messenger RNA (mRNA) of RASA2 was tested via reverse-transcription quantitative polymerase chain reaction (RT-qPCR) of cancer tissues from patients with NSCLC. Computed tomography (CT) and bioluminescent imaging (BLI) were used to monitor the tumor growth of patients and orthotopic mice, respectively. Protein-protein interaction was quantified via immunoprecipitation and glutathione S transferase (GST) pulldown assay. Western blotting was used to evaluate the phosphorylation and ubiquitination level of p53.

The results indicated a negative correlation between the mRNA expression levels of RASA2 in tumor tissues with patients' response to radiotherapy. Patients with a high expression of RASA2 had a lower objective response rate (ORR) after 1 month of radiotherapy than patients with low expression of RASA2 after 1 month of radiotherapy. In terms of mechanism, we proved that RASA2 can directly bind to p53 to promote the phosphorylation of p53, which inhibits its transcriptional activity and further promotes its degradation through the ubiquitin/proteasome pathway. In this process, the apoptosis of tumor cells is inhibited due to impaired p53 surveillance, which leads to radioresistance.