Types Of Human Cancer Research Articles

Phytocompounds and Nanoformulations for Anticancer Therapy: A Review.

Cancer is a complex disease that affects millions of people and remains a major public health problem worldwide. Conventional cancer treatments, including surgery, chemotherapy, immunotherapy, and radiotherapy, have limited achievements and multiple drawbacks, among which are healthy tissue damage and multidrug-resistant phenotype onset. Increasing evidence shows that many plants' natural products, as well as their bioactive compounds, have promising anticancer activity and exhibit minimal toxicity compared to conventional anticancer drugs. However, their widespread use in cancer therapy is severely restricted by limitations in terms of their water solubility, absorption, lack of stability, bioavailability, and selective targeting. The use of nanoformulations for plants' natural product transportation and delivery could be helpful in overcoming these limitations, thus enhancing their therapeutic efficacy and providing the basis for improved anticancer treatment strategies. The present review is aimed at providing an update on some phytocompounds (curcumin, resveratrol, quercetin, and cannabinoids, among others) and their main nanoformulations showing antitumor activities, both in vitro and in vivo, against such different human cancer types as breast and colorectal cancer, lymphomas, malignant melanoma, glioblastoma multiforme, and osteosarcoma. The intracellular pathways underlying phytocompound anticancer activity and the main advantages of nanoformulation employment are also examined. Finally, this review critically analyzes the research gaps and limitations causing the limited success of phytocompounds' and nanoformulations' clinical translation.

Comprehensive pan-cancer analysis of ZNF337 as a potential diagnostic, immunological, and prognostic biomarker

BackgroundZinc Finger Protein 337 (ZNF337) is a novel Zinc Finger (ZNF) protein family member. However, the roles of ZNF337 in human cancers have not yet been investigated.MethodsIn this study, with the aid of TCGA databases, GTEx databases, and online websites, we determined the expression levels of ZNF337 in pan-cancer and its potential value as a diagnostic and prognostic marker for pan-cancer and analyzed the relationship between ZNF337 expression and immune cell infiltration and immune checkpoint genes. We then focused our research on the potential of ZNF337 as a biomarker for diagnostic and prognostic in KIRC (kidney renal clear cell carcinoma) and validated in the E-MTAB-1980 database. Moreover, the expression of ZNF337 was detected through qRT-PCR and Western blotting (WB). CCK-8 experiment, colony formation experiment, and EDU experiment were performed to evaluate cell proliferation ability. Wound healing assay and transwell assay were used to analyze its migration ability. The qRT-PCR and WB were used to detect the expression of ZNF337 in tumor tissues and paracancerous tissues of KIRC patients.ResultsThe pan-cancer analysis revealed that abnormal ZNF337 expression was found in multiple human cancer types. ZNF337 had a high diagnostic value in pan-cancer and a significant association with the prognosis of certain cancers, indicating that ZNF337 may be a valuable prognostic biomarker for multiple cancers. Further analysis demonstrated that the expression level of ZNF337 displayed significant correlations with cancer-associated fibroblasts, immune cell infiltration, and immune checkpoint genes in many tumors. Additionally, ZNF337 was observed to have a high expression in KIRC. Its expression was significantly associated with poor prognosis [overall survival (OS), disease-specific survival (DSS)], age, TNM stage, histologic grade, and pathologic stage. The high ZNF337 expression was associated with poor prognosis in the E-MTAB-1980 validation cohort. The in vitro experiments suggested that the expression of ZNF337 in KIRC tumor tissues was higher than in adjacent tissues, and ZNF337 knockdown inhibited the proliferation and migration of KIRC cells, whereas overexpression of ZNF337 had the opposite effects.ConclusionsZNF337 might be an important prognostic and immunotherapeutic biomarker for pan-cancer, especially in KIRC.

GC–MS analysis, molecular docking, and apoptotic-based cytotoxic effect of Caladium lindenii Madison extracts toward the HeLa cervical cancer cell line

Utilizing medicinal plants and other natural resources to prevent different types of human cancers is the prime focus of attention. Cervical cancer in women ranks as the fourth most common type of malignancy. The current study used gas chromatography-mass spectrometry (GC–MS) to identify the active phytochemical constituents from Caladium lindenii leaf extracts using ethanol (ECL) and n-hexane (HCL) solvents. Plant extracts were tested for potential cytotoxic effects on HeLa and HEK-293 T cells using the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) and the crystal violet assays. SYBR Green-based real-time PCR was performed to assess the mRNA expression profile of the apoptosis biomarkers (BCL-2 and TP53). The molecular interaction of the compounds with the targeted proteins (TP53, BCL2, EGFR, and HER2) was determined using molecular docking. GC–MS analysis revealed a total of 93 compounds in both extracts. The ECL extract significantly reduced the proliferation of HeLa cervical cancer cells, with an IC50 value of 40 µg/mL, while HEK-293 T cells showed less effect (IC50 = 226 µg/mL). The quantitative RT-PCR gene expression analysis demonstrated the ethanol extract regulated TP53 and BCL2 mRNA expressions in treated cancer cell samples. Heptanediamide, N,Nʹ-di-benzoyloxy-(− 10.1) is the best-docked ligand with a TP53 target found in the molecular docking study, whereas EGFR/Clionasterol had the second highest binding affinity (− 9.7), followed by EGFR/Cycloeucalenol (− 9.6). It is concluded that ECL extract has promising anti-cervical cancer potential and might be valued for developing new plant-derived anticancer agents after further investigations.

The Microenvironment of Solid Tumors: Components and Current Challenges of Tumor-on-a-Chip Models.

Solid tumors represent the most common type of cancer in humans and are classified into sarcomas, lymphomas, and carcinomas based on the originating cells. Among these, carcinomas, which arise from epithelial and glandular cells lining the body's tissues, are the most prevalent. Around the world, a significant increase in the incidence of solid tumors is observed during recent years. In this context, efforts to discover more effective cancer treatments have led to a deeper understanding of the tumor microenvironment (TME) and its components. Currently, the interactions between cancer cells and elements of the TME are being intensely investigated. Remarkable progress in research is noted, largely owing to the development of advanced in vitro models, such as tumor-on-a-chip models that assist in understanding and ultimately discovering new effective treatments for a specific type of cancer. The purpose of this article is to provide a review of the TME and cancer cell components, along with the advances on tumor-on-a-chip models designed to mimic tumors, offering a perspective on the current state of the art. Recent studies using this kind of microdevices that reproduce the TME have allowed a better understanding of the cancer and its treatments. Nevertheless, current applications of this technology present some limitations that must be overcome to achieve a broad application by researchers looking for a deeper knowledge of cancer and new strategies to improve current therapies.

GeneRaMeN enables integration, comparison, and meta-analysis of multiple ranked gene lists to identify consensus, unique, and correlated genes.

High-throughput experiments often produce ranked gene outputs, with forward genetic screening being a notable example. While there are various tools for analyzing individual datasets, those that perform comparative and meta-analytical examination of such ranked gene lists remain scarce. Here, we introduce Gene Rank Meta Analyzer (GeneRaMeN), an R Shiny tool utilizing rank statistics to facilitate the identification of consensus, unique, and correlated genes across multiple hit lists. We focused on two key topics to showcase GeneRaMeN: virus host factors and cancer dependencies. Using GeneRaMeN 'Rank Aggregation', we integrated 24 published and new flavivirus genetic screening datasets, including dengue, Japanese encephalitis, and Zika viruses. This meta-analysis yielded a consensus list of flavivirus host factors, elucidating the significant influence of cell line selection on screening outcomes. Similar analysis on 13 SARS-CoV-2 CRISPR screening datasets highlighted the pivotal role of meta-analysis in revealing redundant biological pathways exploited by the virus to enter human cells. Such redundancy was further underscored using GeneRaMeN's 'Rank Correlation', where a strong negative correlation was observed for host factors implicated in one entry pathway versus the alternate route. Utilizing GeneRaMeN's 'Rank Uniqueness', we analyzed human coronaviruses 229E, OC43, and SARS-CoV-2 datasets, identifying host factors uniquely associated with a defined subset of the screening datasets. Similar analyses were performed on over 1000 Cancer Dependency Map (DepMap) datasets spanning 19 human cancer types to reveal unique cancer vulnerabilities for each organ/tissue. GeneRaMeN, an efficient tool to integrate and maximize the usability of genetic screening datasets, is freely accessible via https://ysolab.shinyapps.io/GeneRaMeN.

Synaptotagmin 13 Could Drive the Progression of Esophageal Squamous Cell Carcinoma Through Upregulating ACRV1.

SYT13 is one of the atypical members of the synaptotagmin (SYT) family whose function has attracted considerable attention in recent years. Although SYT13 has been studied in several types of human cancers, such as lung cancer, its role in esophageal squamous cell carcinoma (ESCC) is still unclear. It was demonstrated that SYT13 is significantly upregulated in ESCC tissues compared with normal ones and correlated with higher degree of malignancy. Knockdown of SYT13 could inhibit ESCC cell proliferation and migration, while promoting cell apoptosis. Meanwhile, ESCC cells with relatively lower SYT13 expression grew slower invivo and finally formed smaller xenografts. Furthermore, acrosomal vesicular protein 1 was identified as a potential downstream target of SYT13, which regulates cell phenotypes of ESCC cells in cooperation with SYT13. All the in vitro and invivo results in this study identified that SYT13 silencing could be an effective strategy to inhibit the development of ESCC, which could be considered as a promising therapeutic target in the treatment of ESCC.

Targeted delivery of activatable 131I-radiopharmaceutical for sustained radiotherapy with improved pharmacokinetics

Targeted radionuclide therapy (TRT) is an effective treatment for tumors. Self-condensation strategies can enhance the retention of radionuclides in tumors and enhance the anti-tumor effect. Considering legumain is overexpressed in multiple types of human cancers, a 131I-labeled radiopharmaceutical ([131I]MAAN) based on the self-condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys) was developed by us recently for treating legumain-overexpressed tumors. However, liver enrichment limits its application. In this study, a new radiopharmaceutical [131I]IM(HE)3AAN was designed and synthesized by introducing a hydrophilic peptide sequence His-Glu-His-Glu-His-Glu ((HE)3) into [131I]MAAN to optimize the pharmacokinetics. Upon activation by legumain under a reducing environment, hydrophilic [131I]IM(HE)3AAN could react with its precursor to form heterologous dimer [131I]H-Dimer that is highly hydrophobic. Cerenkov imaging revealed that [131I]IM(HE)3AAN displayed superior tumor selectivity and longer tumor retention time as compared with [131I]MAAN, with a significant reduction in the liver uptake. After an 18-day treatment with [131I]IM(HE)3AAN, the tumor proliferation was obviously inhibited, while no obvious injury was observed in the normal organs. These findings suggest that [131I]IM(HE)3AAN could serve as a promising drug candidate for treating legumain-overexpressed tumors.

MicroRNA-143 overexpression enhances the chemosensitivity of A172 glioblastoma cells to carmustine.

As an aggressive malignancy, glioblastoma multiforme (GBM) is the most common type of brain tumor. The existing treatments have shown limited achievement in increasing the overall survival of patients. Therefore, identifying the key molecules involved in GBM will provide new potential therapeutic targets. Carmustine is an alkylating agent used as a supplementary therapeutic option for GBM. However, the extensive use of carmustine has been limited by uncertainty about its efficacy. MicroRNAs (miRNAs) are essential in post-transcriptional gene regulation. Many aberrantly expressed miRNAs have been detected in various types of human cancer, including GBM. In this study, we evaluated the potential therapeutic effect of miR-143 in combination with carmustine on GBM cells. A172 cells were transfected with miR-143 mimics and then treated with carmustine. To assess the cell viability, apoptosis induction, and cell cycle progression, the MTT assay, Annexin V/PI apoptosis assay, and flow cytometry were used, respectively. Furthermore, qRT-PCR assay was applied to evaluate the expression level of genes related to apoptosis. The obtained results evidenced that miR-143 transfection could promote the sensitivity of A172 cells to carmustine and enhance carmustine-induced apoptosis via modulating the expression levels of Caspase-3, Caspase-9, Bax, and Bcl-2. Also, our results revealed that combination therapy could effectively diminish cell cycle progression in A172 cells. In conclusion, these results confirmed that miR-143 could enhance carmustine-mediated suppression of cell proliferation and improve the chemosensitivity of A172 cells to this chemotherapeutic agent. Therefore, miR-143 combination therapy may be a promising GBM treatment approach.

Functional and clinical roles of stromal PDGF receptors in tumor biology.

PDGF receptors play pivotal roles in both developmental and physiological processes through the regulation of mesenchymal cells involved in paracrine instructive interactions with epithelial or endothelial cells. Tumor biology studies, alongside analyses of patient tissue samples, provide strong indications that the PDGF signaling pathways are also critical in various types of human cancer. This review summarizes experimental findings and correlative studies, which have explored the biological mechanisms and clinical relevance of PDGFRs in mesenchymal cells of the tumor microenvironment. Collectively, these studies support the overall concept that the PDGF system is a critical regulator of tumor growth, metastasis, and drug efficacy, suggesting yet unexploited targeting opportunities. The inter-patient variability in stromal PDGFR expression, as being linked to prognosis and treatment responses, not only indicates the need for stratified approaches in upcoming therapeutic investigations but also implies the potential for the development of PDGFRs as biomarkers of clinical utility, interestingly also in settings outside PDGFR-directed treatments.

Advances in nanocarrier-mediated delivery of chrysin: Enhancing solubility, bioavailability, and anticancer efficacy

Chrysin, a natural phytochemical compound found in various plant sources, possesses diverse pharmacological benefits, including anticancer, antioxidant, antidiabetic, neuroprotective, cardioprotective, hepatoprotective, immunoregulatory, and anti-inflammatory properties. Despite its well-documented biological activities, chrysin's low water solubility and bioavailability hinder its clinical development. This review explores the application of nanocarriers as a strategic approach to overcome these challenges and enhance the delivery of chrysin. Nanocarriers, including polymer-based nanoparticles (NPs), lipid-based NPs, and inorganic nanocarriers, have shown promise in improving the solubility, bioavailability, and tumor-targeted delivery of chrysin. The paper discusses chrysin's anticancer effects on different types of human cancers, elucidating its impact on crucial signaling pathways involved in tumorigenesis. The review categorizes and analyzes various nanocarriers, providing insights into their structural properties and drug release profiles. Among the nanocarriers, polymer-based NPs, especially those utilizing PLGA, emerge as promising strategies for chrysin encapsulation, demonstrating improvements in drug release, stability, and bioavailability. Lipid-based NPs and inorganic nanocarriers also exhibit potential in enhancing chrysin delivery. The comprehensive insights provided contribute to a deeper understanding of chrysin's pharmacological properties and its potential clinical applications, offering valuable perspectives for future research and translation into clinical settings. The review underscores the importance of selecting suitable structures for chrysin encapsulation to enhance its physicochemical properties and anticancer effects, paving the way for innovative nanomedicine approaches in cancer therapy.

Co-targeting CDK 4/6 and C-MYC/STAT3/CCND1 axis and inhibition of tumorigenesis and epithelial-mesenchymal-transition in triple negative breast cancer by Pt(II) complexes bearing NH3 as trans-co-ligand

In search of potential anticancer agents, we synthesized SNO-donor salicylaldimine main ligand-based Pt(II) complexes bearing NH3 as co-ligand at trans-position (C1-C6). These complexes showed similarity in structure with transplatin as the two N donor atoms of the main ligand and NH3 co-ligand were coordinated to Pt in trans position to each other. Each complex with different substituents on the main ligand was characterized thoroughly by detailed spectroscopic and spectrophotometric methods. Four of these complexes were studied in solid state by single crystal X-ray analysis. The stability of reference complex C1 was measured in solution state in DMSO‑d6 or its mixture with D2O using 1H NMR methods. These complexes were further investigated for their anticancer activity in triple-negative-breast (TNBC) cells including MDA-MB-231, MDA-MB-468 and MDA-MB-436 cells. All these complexes showed satisfactory cytotoxic effect as revealed by the MTT results. Importantly, the highly active complex C4 anticancer effect was compared to the standard chemotherapeutic agents including cisplatin, oxaliplatin and 5-fluorouracil (5-FU). Functionally, C4 suppressed invasion, spheroids formation ability and clonogenic potential of cancer cells. C4 showed synergistic anticancer effect when used in combination with palbociclib, JQ1 and paclitaxel in TNBC cells. Mechanistically, C4 inhibited cyclin-dependent kinase (CDK)4/6 pathway and targeted the expressions of MYC/STAT3/CCND1/CNNE1 axis. Furthermore, C4 suppressed the EMT signaling pathway that suggested a role of C4 in the inhibition of TNBC metastasis. Our findings may pave further in detailed mechanistic study on these complexes as potential chemotherapeutic agents in different types of human cancers.

Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance

Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ Tcell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.

Expression pattern analysis of the MAGE family genes in breast cancer patients and hypomethylation activation in the MCF-7 cells

Melanoma antigen gene (MAGE) families are cancer-testis genes that normally show expression in the testes. However, their expressions have been linked with various types of human cancers, including BC. Therefore, the primary purposes of the present research were to assess the expression of MAGE-A, -B, and –C genes in Saudi female patients with BC and determine their regulation via the epigenetic mechanism. Ten BC samples were analyzed for the expression levels of nine MAGE-A genes, six MAGE-B genes, and three MAGE-C genes using the RT-PCR technique. All 18 evaluated genes except for MAGE-A1, -A3, -A4, and -B5 showed weak band expressions in some BC specimens. MAGE-A6 and -B2 were expressed in 40 % of the BC tissue samples, and MAGE-A9, -A10, and -B6 were expressed in 30 %. The lowest expression levels were found for MAGE-A11, -B1, -B3, -B4, -C1, and -C2 in 10 % of the BC specimens and for MAGE-A9,--B2, and --C3 in 20 % of the samples. The most frequently expressed gene was MAGE-A8 (found in 70 % of the BC samples), which suggests that it may serve as - a marker for screening of BC. In vitro treatment, the 5-aza-2′-deoxycytidine agent led to a significant rise in mRNA expressions for all tested genes related to the MAGE-A family, except for MAGE-A10. By contrast, among the genes in the MAGE-B and -C families, only MAGE-B1 and -C2 exhibited detectable mRNA expression levels after treatment.

Pan-Cancer Analysis Links Altered RNA m7G Methyltransferase Expression to Oncogenic Pathways, Immune Cell Infiltrations and Overall Survival.

N7-methylguanosine (m7G) modification is one of the most prevalent RNA modifications in humans. Dysregulated m7G modifications caused by aberrant expression of m7G writers contribute to cancer progression and result in worse patient survival in several human cancers. However, studies that systematically assess the frequency and clinical relevance of aberrant m7G writer expression in a pan-cancer cohort remain to be performed. This study aims to systematically investigate the molecular alteration and clinical relevance of m7G methyltransferase in human cancers. We analysed genome, transcriptome and clinical data from the Cancer Genome Atlas Research Network spanning 33 types of human cancers for aberrant changes in genes encoding m7G writers. We demonstrate that m7G writers are dysregulated in human cancers and are associated predominantly with poorer survival. By dividing patients into those with high and low m7G scores, we show that a lower m7G score is generally associated with immune infiltration and better response to immunotherapy. Our analyses indicate the genetic alterations, expression patterns and clinical relevance of m7G writers across various cancers. This study provides insights into the potential utility of m7G writer expression as a cancer biomarker and proposes the possibility of targeting m7G writers for cancer therapy.

Integrative pan-cancer analysis reveals the prognostic and immunotherapeutic value of ALKBH7 in HNSC.

The AlkB homolog 7 (ALKBH7) is a nonheme iron (II) α-ketoglutarate-dependent dioxygenase superfamily member, which may affect the progression of several types of human cancer. However, the biological effect, especially the immune-related effect, of ALKBH7 in HNSC remains unclear. Herein, several databases were employed at first to assess the different expression of ALKBH7 as well as their relationship to the prognosis, RNA modification, DNA methylation modulation, immune microenvironment and chemotherapeutic responses of various types of cancers. We found that ALKBH7 was expressed differentially in pan-cancer, and correlated with a satisfied prognosis especially in HNSC. The expression of ALKBH7 was also associated with the level of immune cell infiltration, TMB, MSI, HRD, MMR deficiency, and DNA methyltransferases in a wide variety of cancers, which might be potentially related to the responses against chemotherapeutic agents. Next, the role of ALKBH7 in HNSC was further investigated. Western blot and immunohistochemical analysis in HNSC patients from the NMU cohort showed the reduced ALKBH7 expression level in tumor tissues. In vitro experiments of cell migration, invasion, and proliferation showed a potential protective effect of ALKBH7 in HNSC. Collectively, ALKBH7 might play a protective role in the development and progression of multiple cancers by affecting the metabolism and immune cell infiltration, especially HNSC, which could be a potential biomarker to predict prognosis and chemotherapeutic response.

Cosmos caudatus Leaf Extract Triggers Apoptosis of HSC-3 Cancer Cells by Decreasing Bcl-2 and Increasing Bax

BACKGROUND: Previous studies have demonstrated that Cosmos caudatus leaf extract (CCLE) exhibits cytotoxic effects against various types of human cancer. However, the CCLE cytotoxic effect towards oral squamous cell carcinoma (OSCC) cells has not been investigated. Therefore, this study was conducted to evaluate the effect of CCLE towards the viability and apoptosis in human oral squamous carcinoma (HSC)-3 cells.METHODS: HSC-3 cells were treated with various concentrations of CCLE for 24 h. The number of viable HSC-3 cells were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), meanwhile the apoptotic HSC-3 cells were measured using sub-G1 assay. Mitochondrial membrane potential was measured using flow cytometry. Bcl-2 and Bax protein content of HSC-3 cells were measured using enzyme-linked immunosorbent assay (ELISA).RESULTS: CCLE treatment could decrease the number of HSC-3 viable cells and increase the percentage of HSC-3 apoptotic cells in concentration-dependent manner. In mitochondrial membrane potential assay, CCLE-treated group displayed a peak shifment from 104 to 103. Bcl-2 protein contents of CCLE-treated group were decrease in concentration-dependent manner, meanwhile Bax protein contents of CCLE-treated group were increase in concentration-dependent manner.CONCLUSION: CCLE could trigger apoptosis in HSC-3 cells by decreasing Bcl-2 protein content and increasing Bax protein content in concentration-dependent manner, leading to intrinsic apoptotic pathway.KEYWORDS: Cosmos caudatus, HSC-3, apoptosis, mitochondrial membrane potential, Bcl-2, Bax

Widespread chromatin context-dependencies of DNA double-strand break repair proteins

DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ). The balance of these pathways is dependent on the local chromatin context, but the underlying mechanisms are poorly understood. By combining knockout screening with a dual MMEJ:NHEJ reporter inserted in 19 different chromatin environments, we identified dozens of DNA repair proteins that modulate pathway balance dependent on the local chromatin state. Proteins that favor NHEJ mostly synergize with euchromatin, while proteins that favor MMEJ generally synergize with distinct types of heterochromatin. Examples of the former are BRCA2 and POLL, and of the latter the FANC complex and ATM. Moreover, in a diversity of human cancer types, loss of several of these proteins alters the distribution of pathway-specific mutations between heterochromatin and euchromatin. Together, these results uncover a complex network of proteins that regulate MMEJ:NHEJ balance in a chromatin context-dependent manner.

A selective Fibroblast Growth Factor Receptor 1/2 PROTAC degrader with antitumor activity.

The aberrant activation of fibroblast growth factor receptor (FGFR) acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised due to low selectivity and side effects. Here, we report the selective FGFR1/2-targeting proteolysis targeting chimeric (PROTAC), BR-cpd7 that displays significant isoform specificity to FGFR1/2 with DC50 values around 10 nM, while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no anti-proliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.

Systematic pan-cancer analysis identified RASSF1 as an immunological and prognostic biomarker and validated in lung cancer

BackgroundRas association domain family member 1 (RASSF1) encodes the RASSF1A protein, serving as a scaffold protein situated at the intersection of a complex signalling network. AimsTo evaluate the immunological and prognostic significance of RASSF1 expression in various types of human cancers, with a specific focus on lung cancer. MethodsDifferential expression analysis of RASSF1 was conducted based on data from The Cancer Genome Atlas, Genotype-Tissue Expression, and Cancer Cell Line Encyclopaedia databases. Prognostic analysis was performed using the Cox regression test and Kaplan-Meier test. Spearman's test was utilized for correlation analysis. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) gene sets were employed to enrich the associated signaling pathways. Immunohistochemical staining and quantitative real-time PCR were employed to detect protein and mRNA expression levels, respectively. ResultsRASSF1 expression was significantly lower in tumour tissues than in normal tissues in most cancers, and Cox regression analysis demonstrated a significant correlation between RASSF1 expression and the prognosis of over 12 types of cancer. Specifically, high RASSF1 expression was associated with poor OS in nine cancer types, including GBMLGG (HR = 4.98, P = 1.2e-31), LGG (HR = 3.72, P = 2.5e-10), and LAML (HR = 1.48, P = 2.4e-3). Further analysis showed that RASSF1 expression was significantly correlated with immune checkpoint- and immune-related genes. Moreover, RASSF1 expression is involved in tumour microenvironment (TME), RNA modification, genomic heterogeneity, and tumour stemness. GO and KEGG analyses showed that RASSF1 was closely related to tumour immune-related pathways. Finally, RASSF1A was moderately correlated with PD-L1 (R = 0.556), and RASSF1A overexpression significantly affected the expression of several genes involved in the Th17 cell differentiation signalling pathway in lung cancer. ConclusionsRASSF1 was differentially expressed in 29 human cancers and played a critical role in tumour immunity. Thus, RASSF1 has the potential to be used as a prognostic marker and reference for achieving more precise immunotherapy, particularly in lung cancer.

ATXN3 functions as a tumor suppressor through potentiating galectin-9-mediated apoptosis in human colon adenocarcinoma

While the deubiquitinase ATXN3 has been implicated as a potential oncogene in various types of human cancers, its role in colon adenocarcinoma remains understudied. Surprisingly, our findings demonstrate that ATXN3 exerts an anti-tumor effect in human colon cancers through potentiating Galectin-9-induced apoptosis. CRISPR-mediated ATXN3 deletion unexpectedly intensified colon cancer growth both in vitro and in xenograft colon cancers. At the molecular level, we identified ATXN3 as a bona fide deubiquitinase specifically targeting Galectin-9, as ATXN3 interacted with and inhibited Galectin-9 ubiquitination. Consequently, targeted ATXN3 ablation resulted in reduced Galectin-9 protein expression, thereby diminishing Galectin-9-induced colon cancer apoptosis and cell growth arrest. The ectopic expression of Galectin-9 fully reversed the growth of ATXN3-null colon cancer in mice. Furthermore, immunohistochemistry staining revealed a significant reduction in both ATXN3 and Galectin-9 protein expression, along with a positive correlation between them in human colon cancer. Our study identifies the first Galectin-9-specific deubiquitinase and unveils a tumor-suppressive role of ATXN3 in human colon cancer.