Carcinogenic Process Research Articles

USP33 Regulates DNA Damage Response and Carcinogenesis Through Deubiquitylating and Stabilising p53.

The de-ubiquitinase USP33 has been shown to possess either tumour-promoting or inhibitory effect on human cancer cells. However, all these findings are mainly based on invitro cell culture models, and the invivo evidence, which is more plausible to digest the functional role of USP33 in carcinogenic process, is still lacking. Here, we demonstrate that USP33 modulates DNA damage responses including cell cycle arrest and apoptosis induction through associating with p53. It directly interacts with p53 to mediate its de-ubiquitination and further stabilisation under DNA damage condition. Depletion of USP33 induces an enhanced level of p53 ubiquitination, which de-stabilises p53 protein leading to impaired DNA damage responses. Furthermore, USP33 silencing shows either promoted or inhibited effect on cell proliferation in human cancer cells with p53 WT and mutant background, respectively. Consistently, mice with hepatocyte-specific USP33 knockout are more sensitive to nitrosodiethylamine (DEN)-induced hepatocarcinogenesis compared to wild type mice. Thus, our invitro and invivo evidences illustrate that USP33 possesses anti-tumour activity via regulating p53 stability and activity.

Recent Advances in miRNA-Based Therapy for MASLD/MASH and MASH-Associated HCC.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a growing health concern worldwide, affecting more than 1 billion adults. It may progress to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and ultimately hepatocellular carcinoma (HCC). Emerging evidence has demonstrated the role in this transition of microRNAs (miRNAs), which regulate the expression of genes associated with lipid metabolism, inflammation, fibrosis, and cell proliferation. Specific miRNAs have been identified to exacerbate or mitigate fibrotic and carcinogenic processes in hepatic cells. The modulation of these miRNAs through synthetic mimics or inhibitors represents a promising therapeutic strategy. Preclinical models have demonstrated that miRNA-based therapies can attenuate liver inflammation, reduce fibrosis, and inhibit tumorigenesis, thus delaying or preventing the onset of HCC. However, challenges such as delivery mechanisms, off-target effects, and long-term safety remain to be addressed. This review, focusing on recently published preclinical and clinical studies, explores the pharmacological potential of miRNA-based interventions to prevent MASLD/MASH and progression toward HCC.

Contribution of Cancer-Specific Protein Coronas to the Pro-Tumor Effects of Nanoplastics through Enhanced Cellular Interactions.

The potential impact of nanoplastics (NPs) on human carcinogenic processes is a matter of growing concern, particularly in light of the global plastic pollution crisis. Although the potential effects of NPs on human health have been well investigated, many uncertainties remain regarding their role in tumor behavior. Upon exposure, NPs can enter the bloodstream and are prone to interacting with plasma proteins to form a protein corona (PC), which can influence their interactions with cancer cells. However, how the PCs adsorbed on NPs affect the particle-to-tumor cell interaction and their effect on the tumor biological behavior remain unclear. To better understand the formation of PCs following NPs exposure in the bloodstream under various clinical conditions, we investigated the PC compositions of NPs derived from thyroid cancer (TC) patients and healthy volunteers. Our data revealed a significant enrichment of fibrinogen in the PCs formed on NPs derived from TC patient plasma, which in turn accelerated the endocytosis of NPs into TC cells. In addition, the uptake pathway of NPs into TC cells differed substantially between the two groups studied due to the different PC compositions in cancer patients and healthy individuals. Moreover, intriguingly alterations in the PCs induced by the clinical pathology status were also found to promote NPs engulfment by human macrophages, resulting in potent pro-inflammatory effects, in turn exerting pro-tumor effects. These findings emphasize the importance of considering the significance of a realistic biological identity on NPs and their interactions with cancer cells and also pinpoint the implications of the carcinogenesis outcomes of NPs exposure in humans.

Potential of Fiber and Probiotics to Fight Against the Effects of PhIP + DSS-Induced Carcinogenic Process of the Large Intestine.

We determined the in vivo counteracting effect of fiber and probiotic supplementation on colonic mucosal damage and alterations in gut microbiota caused by 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) and sodium dextran sulfate (DSS). Male Fischer-344 rats were randomly divided into 4 groups: control (standard diet), PhIP + DSS group (standard diet + PhIP + DSS), fiber (fiber diet + PhIP + DSS), and probiotic (probiotic diet + PhIP + DSS). The intake of PhIP + DSS for 3 weeks induced colonic mucosal erosion, crypt loss, and inflammation, and the distal colon was more severely damaged. Fiber alleviated colonic mucosal damage by reducing crypt loss and inflammation, while the probiotic increased colon length. The intake of PhIP + DSS increased the fecal relative abundance of Clostridia UCG014 along the intervention, in contrast to the lower abundances of these taxa found after PhIP + DSS administration in the rats supplemented with probiotics or fiber. Fiber supplementation mitigated the histological damage caused by PhIP + DSS shifting the gut microbiota toward a reduction of pro-inflammatory taxa.

Anti-VEGFR2 neutralising antibody slows the progression of multistep oral carcinogenesis.

Angiogenesis plays an important role in cancer growth and metastasis, and it is considered a therapeutic target to control tumour growth following anti-angiogenic therapy. However, it is still unclear when tissues initiate angiogenesis during malignant transformation from premalignant condition and whether this premalignant condition could be a therapeutic target of anti-angiogenic therapy. In this study, we aimed to analyse the onset of angiogenesis by evaluating morphological and functional alterations of microvessels during oral multistep carcinogenesis using a 4-nitroquinoline 1-oxide (4NQO)-induced oral carcinogenesis mouse model. In the study, we initially confirmed that with the use of 4NQO, oral lesions develop in a stepwise manner from normal mucosa through oral epithelial dysplasia (OED) to oral squamous cell carcinoma (OSCC). Evaluation of CD31-immunostained specimens revealed that microvessel density (MVD) increases in a stepwise manner from OEDs. Histological and functional analyses revealed the structural abnormalities and leakage of blood vessels had already taken place in OED. Then we evaluated the expression profiles of Hif1a and Vegfa along with hypoxic status and found that OED exhibited increased Vegfa expression under hypoxic conditions. Finally, we tested the possibility of OEDs as a target of anti-angiogenic therapy and found that anti-VEGFR2 neutralising antibody in OED slowed the disease progression from OED to OSCC. These data indicate that an angiogenic switch occurs at the premalignant stage and morphological, and functional alterations of microvessels already exist in OED. These findings also elucidate the tumour microenvironment, which gradually develops along with carcinogenic processes, and highlight usefulness of the 4NQO-induced carcinogenesis model in the study of epithelial and stromal components, which will support epithelial carcinogenesis. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

MUC17 is a potential new prognostic biomarker and promotes pancreatic cancer progression in obstructive jaundice.

Our working group has previously shown that bile acids (BAs) accelerate carcinogenic processes in pancreatic cancer (PC) in which mucin 4 (MUC4) expression has a central role. However, the role of other mucins in PC are less clear, especially in bile-induced cancer progression. The study aim was to investigate expression of MUC17 in BAs- or human serum-treated pancreatic ductal adenocarcinoma (PDAC) cell lines and use different assays with RNA silencing/overexpression to study the role of MUC17 in cancer progression. Protein expression of MUC17 was evaluated in 55 human pancreatic samples by immunohistochemistry, and Kaplan-Meier survival analysis was used to compare survival curves. Expression of MUC17 increased in PDAC patients, especially in obstructive jaundice (OJ) and the elevated MUC17 expression associated with poorer overall survival (10.66±1.99 vs. 15.05±2.03 months; Log rank: 0.0497). Treatment of Capan-1 and AsPC-1 cells with BAs or with human serum obtained from PDAC + OJ patients enhanced the expression of MUC17, as well as the proliferative potential of the cells, whereas knockdown of MUC17 alone or in combination with MUC4 decreased BAs-induced carcinogenic processes. Our results demonstrated that MUC17 has a central role in bile-induced PC progression, and in addition to MUC4, this isoform also can be used as a novel prognostic biomarker.

Vitamin C and its derivatives in maintaining the good skin condition

Vitamin C is one of the most important and necessary nutrient for human health, which has great potential as cosmeceutic, which protects health and the skin good condition. Thru the collagen biosynthesis stimulation it affects to the physiology of human skin, participating in the hydroxylation process of proline and lysine, and participates in tissue reconstruction while wound healing. Deficiency of vitamin C causes irregularities in the blood vessels functioning, epidermis and dermis. Is an effective antioxidant neutralizing free radicals, prevents inflammatory and carcinogenic processes. The epidermis and dermis are most exposed to free radicals from the external environment and from the inside of the body. In inflammatory diseases of the skin, such as atopic dermatitis, psoriasis, in the proper skin the levels of vitamin C are reduced. Therefore, delivering it to the skin using cosmetic preparations is important not only for cosmetic, but also health effect. The problem associated with the introduction of vitamin C in cosmetics is its limited penetration through the stratum corneum. Current studies are focused on searching for stable compounds of ascorbic acid and new media, which will allow for better way of delivery of ascorbic acid to the dermis in the future.

Oral squamous cell carcinoma identification by FTIR spectroscopy of oral biofluids.

This case study evaluated the efficacy of mid-infrared spectroscopy on the identification of oral squamous cell carcinoma, following the assessment of unstimulated whole saliva. The trial follows a matched case-control design. Saliva samples were characterized through mid-infrared spectroscopy, and chemometric tools were applied to distinguish between case and control participants, further identifying the spectral regions that played a pivotal role in the successful identification of oral squamous cell carcinoma. Mid-infrared spectroscopy was capable to discriminate between cancer patients and matched controls with 100% of correct predictions. Additionally, the spectral regions mostly contributing to the successful prediction were identified and found to be potentially associated with significant molecular changes crucial to the carcinogenic process. The application of mid-infrared spectroscopy in saliva analysis may be regarded as an innovative, noninvasive, low cost, and sensitive technique contributing to the identification of oral squamous cell carcionma.

MiR-381-3p/TET3 axis promotes cervical cancer: A bioinformatic integrative analysis

Cervical cancer (CC) is a global public health problem. Epigenetic factors, such as microRNAs, play a key role in the development of CC. Although a previous study reported that miR-381-3p inhibits CC by downregulating fibroblast growth factor 7, its role in CC remains largely unknown. This study aimed to fill the gap by analyzing the role of miR-381-3p in CC. Expression analysis was performed using databases including The Cancer Genome Atlas, Gene Expression Omnibus, and the Human Protein Atlas. Receiver operating characteristics and Kaplan–Meier curves were plotted using GraphPad Prism and Kaplan–Meier Plotter databases. Target messenger RNAs were identified using the miRDB and miRPathDB databases. Kyoto Encyclopedia of Genes and Genomes, Gene Ontology Biological Process, and Gene Set Enrichment Analysis were performed using Enrichr and WebGestalt databases. Mutation analysis was conducted using the cBioPortal database. In this study, we found that miR-381-3p expression is low in CC. Moreover, we identified a total of 1,191 potential targets of miR-381-3p that may be involved in key signaling pathways in this cancer. Interestingly, our results identified ten-eleven translocation 3 (TET3) as a potential target, with evidence suggesting that TET3 expression is increased in CC. This increase in TET3 expression may be useful as a diagnostic and prognostic biomarker. In addition, four mutations were identified in the TET3 protein. TET3 expression increases in patients with International federation of gynecology and obstetrics stage II CC and in those with lymph node metastasis. Mechanistically, TET3 expression may be induced by a gain in copy number, human papillomavirus infection, aberrant methylation, and activation of the transcription factor activator protein 2α. Finally, we identified 145 genes that are regulated by TET3 in CC, which are involved in key pathways and biological processes associated with CC, such as the cell cycle, DNA replication, mitogen-activated protein kinase signaling pathway, and basal transcription factors. In conclusion, we identified the miR-381-3p/TET3 axis as a key player in the carcinogenic process of CC.

NOD1 and NOD2 genetic variants: Impact on hepatocellular carcinoma susceptibility and progression in Moroccan population

BackgroundNucleotide-binding oligomerization domain 1 (NOD1) and NOD2 are involved in carcinogenic processes by recognizing bacterial cell wall components and triggering inflammation. This study explored the association between genetic variations in NOD1 and NOD2 and susceptibility to hepatocellular carcinoma (HCC) and its progression in a Moroccan population. MethodsGenotyping of NOD1 rs2075820 (C>T) and NOD2 rs718226 (A>G) was performed using the TaqMan allelic discrimination assay in 467 Moroccan individuals. The cohort included 156 patients with hepatocellular carcinoma (HCC), 155 patients with liver cirrhosis (LC) diagnosed with HBV, HCV, or MASLD, and 156 controls. ResultsThe NOD1 rs2075820 variant showed no association with HCC susceptibility or progression, which is consistent with in silico predictions. However, the NOD2 rs718226 G allele and GG genotype were more common in the HCC group compared to the cirrhosis and control groups. Individuals with the homozygous G variant had a 2-fold higher risk for HCC (ORad = 2.12; CI=1.01–4.44; Pad = 0.04). Those with the GG genotype also had an increased risk of HCC (GG vs. AG+AA ORad = 2.28; CI=1.15–4.54; Pad = 0.016). Furthermore, GG genotype carriers had a significantly higher risk of HCC progression (ORad = 2.58; CI=1.26–5.31; Pad​ = 0.031). Individuals with the rs718226 minor allele had a significantly elevated risk of progressing from LC to HCC (ORad = 1.50; CI=1.07–2.09; Pad = 0.016). Stratification analysis indicated that men had a higher risk of HCC progression compared to women (ORad = 4.63; CI=1.53–14.00 vs. ORad = 2.73; CI=1.05–7.09). ConclusionThe NOD1 rs2075820 polymorphism does not appear to be a genetic risk factor for susceptibility to HCC. In contrast, the non-coding NOD2 rs718226 variant significantly increases HCC susceptibility and promotes liver cancer progression in the Moroccan population. Further studies involving larger cohorts are warranted to definitively confirm or refute the effects of NOD1 and NOD2 genetic variants on liver cancer susceptibility and progression.

Bitter taste receptors as prognostic markers in adrenocortical carcinoma.

230 Background: Adrenocortical carcinoma (ACC) is a rare malignant neoplasm of the adrenal gland. Progressive forms of this cancer carry a dismal prognosis with 5-year survival rates < 40%. As such, predictors of stage progression and prognostic biomarkers are a must. Taste 2 receptors (TAS2Rs) are localized on the surface of bitter receptor cells. Recent evidence has shown their role as prognostic biomarkers in multiple cancers, such as breast, prostate, and head and neck squamous cell carcinoma. The aim of this study was to elucidate the role of TAS2Rs in ACC. Methods: Differentially expressed genes (DEGs) based on high and low expression groups of TAS2R genes were identified through the 'DESeq2' package on R. Subsequent Gene Set Enrichment Analysis (GSEA) was performed using the 'TCGAbiolinks' package on R and Enrichr online tool. Immune infiltration analysis was conducted using TIMER2.0 and CIBERSORT. Survival analysis with an optimal expression cutoff for overall survival (OS) and a median cutoff for disease-free survival (DFS) based on The Cancer Genome Atlas Adrenocortical carcinoma (TCGA-ACC) data was executed using the 'survival' and 'survminer' R packages and GEPIA2 online tool. Results: Analysis of the TCGA-ACC cohort revealed OS estimates that indicated worse survival in patients with higher TAS2R14, TAS2R19, TAS2R20, and TAS2R30 expression (Table). Further analysis produced consistent results, demonstrating that elevated expressions of TAS2R14 and TAS2R19 are correlated with decreased DFS, with Hazard Ratios (HR) of 2.60 (p = 0.0046) and 2.20 (p = 0.022), respectively. Furthermore, the F-test and stage plots have shown consistent upregulation of selected TAS2R genes across stages I–IV (p < 0.05). RNA-seq analysis revealed 1170 common (579 downregulated, 591 upregulated) DEGs between high and low TAS2R14 and TAS2R19 expression groups. GSEA showed upregulated genes in high expressers have relations to hedgehog signaling, epithelial to mesenchymal transition, TGF-B signaling, and organization of the extracellular matrix. On the other hand, down-regulated genes showed functions in metabolic reprogramming, chemokine receptor binding, MHC protein complex, and chemokine-mediated inflammation. GSEA on co-expressed genes showed pathways related to ferroptosis, autolysosome activity, and iron homeostasis and metabolism. Immune infiltration analysis revealed significantly increased CD4+, naïve and plasma B cell infiltration with higher TAS2R14 and TAS2R19 expression (Rho > 0.25, p < 0.05), in addition to increased M1 macrophage infiltration with higher TAS2R19 expression (Rho = 0.28, p < 0.05). Conclusions: TAS2R genes are potentially involved in modulating carcinogenic processes, including stage progression, metastasis and invasion, immune regulation, and metabolic processes. This modulation may explain the poorer prognostic outcomes in ACC patients with elevated TAS2R expression. Further validation in external cohorts is necessary to confirm these results. [Table: see text]

Evolving data on risk and current screening recommendations for colorectal cancer in cystic fibrosis: Pre- and posttransplant.

Advances in treatment for cystic fibrosis (CF), including cystic fibrosis transmembrane conductor regulator (CFTR) modulators, have ushered in an era where patients with CF have much longer life expectancies. This shift in life expectancy demands increased attention to diseases of aging in patients with CF. A notable complication of CF is early-onset colorectal cancer (CRC), which is especially prevalent in patients with severe mutations and after transplant. CFTR acts as a tumor suppressor gene based on knockout models. Lack of CFTR expression promotes carcinogenic processes such as intestinal inflammation and deleterious gut microbiome changes. The consensus Cystic Fibrosis Foundation recommendations advocate treating this population as a high-risk group, using a colonoscopy-only screening strategy starting at age 40 in patients without transplant and at age 30 after transplant. Screening should be considered every 5 years if negative and every 3 years or sooner for patients with adenomatous polyps. Future research will determine the role of noninvasive CRC screening tools in this population, as well as the effects of CFTR modulators on the risk of developing CRC.

The role of RRS1 in breast cancer cells metastasis and AEG-1/AKT/c-Myc signaling pathway.

Breast cancer is the most common malignant tumor in women. Recurrence, metastasis, and chemotherapy resistance are the main causes of death in breast cancer patients. The inhibition of breast cancer metastasis is of great significance for prolonging its survival. Ribosome biogenesis regulatory protein homolog (RRS1) is overexpressed in breast cancer tissues and is involved in regulating the carcinogenic process of breast cancer cells. However, the exact signaling pathway and molecular mechanism of RRS1 promoting breast cancer metastasis are not fully understood. Hence, the primary objective of our study is to investigate the correlation between RRS1 and breast cancer metastasis. Bioinformatic analysis was used to identify the expression levels and prognostic significance of RRS1 in breast cancer. Lenti-sh RRS1 lentivirus was constructed and employed to downregulate the RRS1 expression in MDA-MB-231 and BT549 cells, which had a high-level expression of RRS1. Subsequently, we assessed the impact of RRS1 downregulation on the proliferation, migration, and invasion of breast cancer cells using CCK-8, apoptosis, and cell cycle by flow cytometry, wound healing test, Transwell migration, and invasion experiments. Moreover, we utilized an in vivo imaging system to examine the metastatic potential of breast cancer cells after RRS1 knockdown. Picrate staining and hematoxylin-eosin staining were employed to evaluate the presence of metastatic lesions. To gain a deeper understanding of the molecular mechanism, we conducted co-immunoprecipitation and western blot. The significant overexpression of RRS1 in breast cancer indicates a worse prognosis, as determined through TCGA databases (p<0.01). Additionally, RRS1 exhibits upregulation in breast cancer (p<0.001), which is tightly linked to the occurrence of lymph node metastasis (p<0.001). Clinical breast cancer tissues and breast cancer cell lines also demonstrated a noteworthy upregulation of RRS1 (p<0.05). Loss-of-function experiment illustrated that the inhibiting of RRS1 expression reduced the rapid proliferation capacity of MDA-MB-231 and BT549 cells and hindered their migration and invasion capabilities (p<0.05). Importantly, the suppression of RRS1 significantly diminished lung metastasis in Balb/c nude mice that were injected with MDA-MB-231 cells (p<0.01). Mechanistically, RRS1 may interact with the AEG-1 to modulate the phosphorylation of AKT at T308 and S473, consequently impeding the activity of c-Myc (p<0.05). To conclude, RRS1 functions as a potential oncogene in breast cancer by leveraging the AEG-1/AKT/c-Myc signaling.

Correlation of syndecan gene amplification with metastatic potential and clinical outcomes in carcinomas.

Cell surface receptors play crucial roles in cellular responses to extracellular ligands, helping to modulate the functions of a cell based on information coming from outside the cell. Syndecan refers to a family of cell adhesion receptors that regulate both extracellular and cytosolic events. Alteration of syndecan expression disrupts regulatory mechanisms in a cell type-specific fashion, often leading to serious diseases, notably cancer. Given the multifaceted functions and distinct tissue distributions of syndecan, it will be important to unravel the gene-level intricacies of syndecan expression and thereby further understand its involvement in various carcinogenic processes. Although accumulating evidence indicates that the protein expression patterns of syndecan family members are significantly altered in cancer cells, the underlying gene-level mechanisms remain largely unknown. This review endeavors to explore syndecan gene expression levels across different cancer types by scrutinizing extensive cancer genome datasets using tools such as cBioPortal. Our analysis unveils that somatic mutations in SDC genes are rare occurrences, whereas copy number alterations are frequently observed across diverse cancers, particularly in SDC2 and SDC4. Notably, amplifications of SDC2 and SDC4 correlate with heightened metastatic potential and dismal prognosis. This underscores the recurrent nature of SDC2 and SDC4 amplifications during carcinogenesis and sheds light on their role in promoting cancer activity through augmented protein expression. The identification of these amplifications not only enriches our understanding of carcinogenic mechanisms but also hints at the potential therapeutic avenue of targeting SDC2 and SDC4 to curb cancer cell proliferation and metastasis.

Cationic Liposomes Carrying HPV16 E6-siRNA Inhibit the Proliferation, Migration, and Invasion of Cervical Cancer Cells.

The E6 and E7 oncoproteins of high-risk types of human papillomavirus (HR-HPV) are crucial for the development of cervical cancer (CC). Small interfering RNAs (siRNAs) are explored as novel therapies that silence these oncogenes, but their clinical use is hampered by inefficient delivery systems. Modification (pegylation) with polyethylene glycol (PEG) of liposomal siRNA complexes (siRNA lipoplexes) may improve systemic stability. We studied the effect of siRNA targeting HPV16 E6, delivered via cationic liposomes (lipoplexes), on cellular processes in a cervical carcinoma cell line (CaSki) and its potential therapeutic use. Lipoplexes-PEG-HPV16 E6, composed of DOTAP, Chol, DOPE, and DSPE-PEG2000 were prepared. The results showed that pegylation (5% DSPE-PEG2000) provided stable siRNA protection, with a particle size of 86.42 ± 3.19 nm and a complexation efficiency of over 80%; the siRNA remained stable for 30 days. These lipoplexes significantly reduced HPV16 E6 protein levels and restored p53 protein expression, inhibiting carcinogenic processes such as proliferation by 25.74%, migration (95.7%), and cell invasion (97.8%) at concentrations of 20 nM, 200 nM, and 80 nM, respectively. In conclusion, cationic lipoplexes-PEG-HPV16 E6 show promise as siRNA carriers for silencing HPV16 E6 in CC.

Circular RNA circNIPBL regulates TP53-H179R mutations in NNK-induced bronchial epithelial carcinogenesis

Exposure to environmental carcinogens is a significant contributor to cancer development, with genetic and epigenetic alterations playing pivotal roles in the carcinogenic process. However, the interplay between epigenetic regulation and genetic changes in carcinogenesis has yet to receive comprehensive attention. This study investigates the impact of continuous exposure to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on bronchial epithelial cells, leading to malignant transformation. Our findings reveal the down-regulation of the tumor suppressor-like circular RNA circNIPBL during oncogenic processes concomitant with the accumulation of the TP53-H179R, a single nucleotide variant. Diminished circNIPBL expression enhances the proliferative, distant metastatic, and tumor-forming capabilities of NNK-induced cancerous cells and lung cancer cell lines (A549, H1299), while also promoting the accumulation of TP53-H179R during NNK-induced carcinogenesis. Mechanistic investigations demonstrate that circNIPBL interacts with HSP90α to regulate the translocation of AHR into the nucleus, which may be a potential regulatory mechanism for NNK-induced carcinogenesis and TP53-H179R accumulation. This study introduces a novel perspective on the interplay between genetic alterations and epigenetic regulation in chemical carcinogenesis, which provides novel insight into the etiology of cancer.

USP15, activated by TFAP4 transcriptionally, stabilizes SHC1 via deubiquitination and deteriorates renal cell carcinoma.

Ubiquitin-specific peptidase 15 (USP15), a critical deubiquitinating enzyme, has been demonstrated to improve substrate stabilization by hydrolyzing the bond between the substrate and ubiquitin, and is implicated in multiple carcinogenic processes. Prompted by the information cited from The Cancer Genome Atlas (TCGA) database and the Cancer Proteogenomic Data Analysis Site (cProSite), USP15 is selectively overexpressed in clear cell renal cell carcinoma (ccRCC) samples. We aimed to investigate the function of USP15 on ccRCC malignant features, which was emphasized in its deubiquitination of SHC adaptor protein 1 (SHC1). The overexpression of USP15 promoted the capacity of proliferation, migration, and invasion in ccRCC CAKI1 and 769-P cells, and these malignant biological properties were diminished by USP15 deletion in 786-O cells. USP15 accelerated tumor growth and lung metastasis invivo. In addition, deubiquitinase USP15 was further identified as a new protector for SHC1 from degradation by the ubiquitination pathway, the post-translational modification. In sequence, transcription factor activating enhancer binding protein 4 (TFAP4) was shown to be partly responsible for USP15 expression at the level of transcription, as manifested by the chromatin immunoprecipitation and pull-down assay. Based on the invitro and invivo data, we postulate that USP15 regulated by TFAP4 transcriptionally deteriorates ccRCC malignant biological properties via stabilizing SHC1 by deubiquitination.

Unraveling the Keratin Expression in Oral Leukoplakia: A Scoping Review.

Intermediate filaments are one of three polymeric structures that form the cytoskeleton of epithelial cells. In the epithelium, these filaments are made up of a variety of keratin proteins. Intermediate filaments complete a wide range of functions in keratinocytes, including maintaining cell structure, cell growth, cell proliferation, cell migration, and more. Given that these functions are intimately associated with the carcinogenic process, and that hyperkeratinization is a quintessential feature of oral leukoplakias, the utility of keratins in oral leukoplakia is yet to be fully explored. This scoping review aims to outline the current knowledge founded on original studies on human tissues regarding the expression and utility of keratins as diagnostic, prognostic, and predictive biomarkers in oral leukoplakias. After using a search strategy developed for several scientific databases, namely, PubMed, Scopus, Web of Science, and OVID, 42 papers met the inclusion and exclusion criteria. One more article was added when it was identified through manually searching the list of references. The included papers were published between 1989 and 2024. Keratins 1-20 were investigated in the 43 included studies, and their expression was assessed in oral leukoplakia and dysplasia cases. Only five studies investigated the prognostic role of keratins in relation to malignant transformation. No studies evaluated keratins as a diagnostic adjunct or predictive tool. Evidence supports the idea that dysplasia disrupts the terminal differentiation pathway of primary keratins. Gain of keratin 17 expression and loss of keratin 13 were significantly observed in differentiated epithelial dysplasia. Also, the keratin 19 extension into suprabasal cells has been associated with the evolving features of dysplasia. The loss of keratin1/keratin 10 has been significantly associated with high-grade dysplasia. The prognostic value of cytokeratins has shown conflicting results, and further studies are required to ascertain their role in predicting the malignant transformation of oral leukoplakia.

Monitoring and Assessment of the Quality of Chlorinated Water in Schools

All water destined for human consumption must be subjected to disinfection processes via chlorination with the aim of eliminating the risk of the transmission of waterborne diseases. However, the treatment of water using this method leads to the formation of trihalomethanes (THMs), which are toxic compounds that may be ingested, inhaled, or absorbed by the skin, increasing the risk of carcinogenic and mutagenic processes. High trihalomethane concentrations in water may be directly related to physicochemical properties, such as temperature, pH, hardness, and potentially toxic metal concentrations. In this work, physicochemical characterization was performed and water quality was assessed with regard to the presence of trihalomethanes in 17 samples collected from points before and after storage in reservoirs. Atomic absorption spectroscopy to determine potentially toxic metals and the measurement of physicochemical properties demonstrated that all results were in accordance with the standards established by Brazilian legislation. Gas chromatography–mass spectrometry was used to determine levels of trihalomethanes in the water samples (trichloromethane, bromodichloromethane, chlorodibromomethane, and bromoform), which were also in accordance with the limits established by Brazilian legislation. Hierarchical clustering on principal components confirmed changes in the water quality depending on location. This work constitutes a paradigm for future studies on the monitoring of toxic organic compounds in water to avoid health problems in humans and animals.

β-hydroxybutyrate restrains colitis-associated tumorigenesis by inhibiting HIF-1α-mediated angiogenesis

Decreased levels of β-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon mucosa of patients with inflammatory bowel diseases (IBD). In particular, patients with recurrent IBD present an increased risk of developing colitis-associated colorectal cancer (CAC). The role and molecular mechanism of BHB in the inflammatory and carcinogenic process of CAC remains unclear. Here, the anti-tumor effect of BHB was investigated in the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-induced CAC model and tumor organoids derivatives. The underlying mechanisms were studied using transcriptome and non-target metabolomic assay and further validated in colon tumor cell lineage CT26 in vitro. The tumor tissues and the nearby non-malignant tissues from colon cancer patients were collected to measure the expression levels of ketogenic enzymes. The exogenous BHB supplement lightened tumor burden and angiogenesis in the CAC model. Notably, transcriptome analysis revealed that BHB effectively decreased the expression of VEGFA in the CAC tumor mucosa. In vitro, BHB directly reduced VEGFA expression in hypoxic-treated CT26 cells by targeting transcriptional factor HIF-1α. Conversely, the deletion of HIF-1α largely reversed the inhibitory effect of BHB on CAC tumorigenesis. Additionally, decreased expression of ketogenesis-related enzymes in tumor tissues were associated with poor survival outcomes in patients with colon cancer. In summary, BHB carries out anti-angiogenic activity in CAC by regulating HIF-1α/VEGFA signaling. These findings emphasize the role of BHB in CAC and may provide novel perspectives for the prevention and treatment of colonic tumors.