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Purpose: The pathogenesis of head and neck squamous cell carcinoma (HNSCC) was complex and the overall survival was not satisfying. It was urgent to uncover novel molecules that play vital role in HNSCC for disease monitoring and drug development. Methods: Distinguished expression of FCGBP mRNA in HNSCC was analyzed by TCGA-HNSC and three GEO datasets, the relationship between FCGBP and clinical stage and survival was analyzed by GEPIA 2, the immune infiltration pattern analysis was conducted by TIMER 2.0, pathways affected by FCGBP was conducted by GSEA and GO/KEGG. In vitro experiments (including qRT-PCR, siRNA transfection, CCK8, transwell assay and flow cytometry) were conducted to confirm bioinformatic analysis. Results: FCGBP was down-regulated in tumor samples compared with normal tissues at both mRNA and protein levels, and positively correlated with survival in HNSCC. Genes co-expressed with FCGBP were mainly enriched in immune-related biological processes and pathways. GSEA indicated that FCGBP was associated with activated immune reaction and inhibiting well-known pro-tumor pathways. GSE41613 validated FCGBP as an independent prognostic marker for HNSCC and FCGBP was down-regulated in HNSCC cell lines by qRT-PCR. Migration and invasion of SCC9 and CAL27 were enhanced by FCGBP-targeting siRNAs, the ratio of cytotoxic T lymphocytes were down-regulated while the ratio of myeloid-derived suppressor cells were increased by FCGBP-targeting siRNAs. Conclusion: FCGBP was a tumor suppressor gene and was an independent prognostic marker for better survival. The underlying mechanism may be that FCGBP inhibited tumor migration and invasion and activated immune response against tumor cells. [ABSTRACT FROM AUTHOR]

Objective: Downregulation of N‐myc downstream‐regulated gene 2 (NDRG2), a tumor suppressor gene, has been associated with poor clinical outcomes in various cancers. However, the prognostic significance of NDRG2 in oral squamous cell carcinoma (OSCC) remains unknown. This study aimed to evaluate the prognostic value of NDRG2 downregulation in OSCC and to elucidate the mechanism by which NDRG2 is downregulated and the biological role of NDRG2 in tumor progression. Methods: Immunohistochemical and in silico analyses of NDRG2 expression were performed, and the correlation between NDRG2 expression and clinicopathological data was analyzed. The effect of NDRG2 knockdown on the biological behavior of OSCC cells was investigated and the effect of 5‐aza‐2′‐deoxycytidine (5‐aza‐dC) on NDRG2 expression was determined. Results: NDRG2 expression was significantly downregulated and DNA hypermethylation of NDRG2 was frequently found in head and neck SCC, including OSCC. Low NDRG2 expression was significantly correlated with adverse clinicopathological features and worse survival in OSCC. NDRG2 knockdown could enhance the oncogenic properties of OSCC cells. NDRG2 mRNA levels in OSCC cells could be restored by 5‐aza‐dC. Conclusion: Downregulation of NDRG2 promotes tumor progression and predicts poor prognosis in OSCC. Therefore, restoration of NDRG2 expression may be a potential therapeutic strategy in OSCC. [ABSTRACT FROM AUTHOR]

Zinc and RING finger 3 (ZNRF3) is a negative-feedback regulator of Wnt/β-catenin signaling, which plays an important role in human brain development. Although somatically frequently mutated in cancer, germline variants in ZNRF3 have not been established as causative for neurodevelopmental disorders (NDDs). We identified 12 individuals with ZNRF3 variants and various phenotypes via GeneMatcher/Decipher and evaluated genotype-phenotype correlation. We performed structural modeling and representative deleterious and control variants were assessed using in vitro transcriptional reporter assays with and without Wnt-ligand Wnt3a and/or Wnt-potentiator R-spondin (RSPO). Eight individuals harbored de novo missense variants and presented with NDD. We found missense variants associated with macrocephalic NDD to cluster in the RING ligase domain. Structural modeling predicted disruption of the ubiquitin ligase function likely compromising Wnt receptor turnover. Accordingly, the functional assays showed enhanced Wnt/β-catenin signaling for these variants in a dominant negative manner. Contrarily, an individual with microcephalic NDD harbored a missense variant in the RSPO-binding domain predicted to disrupt binding affinity to RSPO and showed attenuated Wnt/β-catenin signaling in the same assays. Additionally, four individuals harbored de novo truncating or de novo or inherited large in-frame deletion variants with non-NDD phenotypes, including heart, adrenal, or nephrotic problems. In contrast to NDD-associated missense variants, the effects on Wnt/β-catenin signaling were comparable between the truncating variant and the empty vector and between benign variants and the wild type. In summary, we provide evidence for mirror brain size phenotypes caused by distinct pathomechanisms in Wnt/β-catenin signaling through protein domain-specific deleterious ZNRF3 germline missense variants. [Display omitted] Boonsawat et al. establish germline missense variants in the tumor suppressor gene ZNRF3 as a cause of neurodevelopmental disorders (NDDs) with microcephaly or macrocephaly, depending on the functional/domain-specific effects of the variants on Wnt/β-catenin signaling. This study finds that ZNRF3 haploinsufficiency does not cause NDDs but rather other phenotypes. [ABSTRACT FROM AUTHOR]

Tazarotene-induced gene 1 (TIG1) is induced by a derivative of vitamin A and is known to regulate many important biological processes and control the development of cancer. TIG1 is widely expressed in various tissues; yet in many cancer tissues, it is not expressed because of the methylation of its promoter. Additionally, the expression of TIG1 in cancer cells inhibits their growth and invasion, suggesting that TIG1 acts as a tumor suppressor gene. However, in some cancers, poor prognosis is associated with TIG1 expression, indicating its protumor growth characteristics, especially in promoting the invasion of inflammatory breast cancer cells. This review comprehensively summarizes the roles of the TIG1 gene in cancer development and details the mechanisms through which TIG1 regulates cancer development, with the aim of understanding its various roles in cancer development. [ABSTRACT FROM AUTHOR]

Abstract Purpose The pathogenesis of head and neck squamous cell carcinoma (HNSCC) was complex and the overall survival was not satisfying. It was urgent to uncover novel molecules that play vital role in HNSCC for disease monitoring and drug development. Methods Distinguished expression of FCGBP mRNA in HNSCC was analyzed by TCGA-HNSC and three GEO datasets, the relationship between FCGBP and clinical stage and survival was analyzed by GEPIA 2, the immune infiltration pattern analysis was conducted by TIMER 2.0, pathways affected by FCGBP was conducted by GSEA and GO/KEGG. In vitro experiments (including qRT-PCR, siRNA transfection, CCK8, transwell assay and flow cytometry) were conducted to confirm bioinformatic analysis. Results FCGBP was down-regulated in tumor samples compared with normal tissues at both mRNA and protein levels, and positively correlated with survival in HNSCC. Genes co-expressed with FCGBP were mainly enriched in immune-related biological processes and pathways. GSEA indicated that FCGBP was associated with activated immune reaction and inhibiting well-known pro-tumor pathways. GSE41613 validated FCGBP as an independent prognostic marker for HNSCC and FCGBP was down-regulated in HNSCC cell lines by qRT-PCR. Migration and invasion of SCC9 and CAL27 were enhanced by FCGBP-targeting siRNAs, the ratio of cytotoxic T lymphocytes were down-regulated while the ratio of myeloid-derived suppressor cells were increased by FCGBP-targeting siRNAs. Conclusion FCGBP was a tumor suppressor gene and was an independent prognostic marker for better survival. The underlying mechanism may be that FCGBP inhibited tumor migration and invasion and activated immune response against tumor cells.

The evolving history of BRCA1 research demonstrates the profound interconnectedness of a single protein within the web of crucial functions in human cells. Mutations in BRCA1, a tumor suppressor gene, have been linked to heightened breast and ovarian cancer risks. However, despite decades of extensive research, the mechanisms underlying BRCA1's contribution to tissue-specific tumor development remain elusive. Nevertheless, much of the BRCA1 protein's structure, function, and interactions has been elucidated. Individual regions of BRCA1 interact with numerous proteins to play roles in ubiquitination, transcription, cell checkpoints, and DNA damage repair. At a cellular scale, these BRCA1 functions coordinate tumor suppression, R-loop prevention, and cellular differentiation, all of which may contribute to BRCA1's role in cancer tissue specificity. As research on BRCA1 and breast cancer continues to evolve, it will become increasingly evident that modern materials such as Bisphenol A should be examined for their relationship with DNA stability, cancer incidence, and chemotherapy. Overall, this review offers a comprehensive understanding of BRCA1's many roles at a molecular, cellular, organismal, and environmental scale. We hope that the knowledge gathered here highlights both the necessity of BRCA1 research and the potential for novel strategies to prevent and treat cancer in individuals carrying BRCA1 mutations.

Abstract Prostate cancer (PRAD) is one of the leading malignancies in men all around the world. Here, we identified Myosin Heavy Chain 6 (MYH6) as a potential tumor suppressor gene in the development of prostate cancer. We found lower expression of MYH6 in prostate cancer tissues, and its lower gene expression was also associated with worse clinical outcomes. In vitro and in vivo assays indicated that overexpressed MYH6 could suppress the proliferation and migration progression of prostate cancer cells. RNA-seq was employed to investigate the mechanism, and KIT Proto-Oncogen (KIT) was determined as the downstream gene of MYH6, which was further confirmed using rescue assays. In all, we provide the evidence that MYH6 could serve as a tumor suppressor in prostate cancer. Our results highlight the potential role of MYH6 in the development of prostate cancer.

Background and Aim: Canine transmissible venereal tumor (CTVT), a unique transmissible cancer in dogs, affects the external genitalia and potentially spreads to other parts of the body. While somatic mutations in oncogenic and tumor-suppressing genes are linked to CTVT development, the impact of DNA methylation, which affects gene expression, remains unclear. This study explored whether DNA methylation in the promoter regions of the MYC oncogene and CDKN2B tumor suppressor genes in CTVTs is associated with their expression, both at the gene and protein levels. Materials and Methods: To investigate promoter DNA methylation of MYC and CDKN2B in CTVTs, we analyzed frozen tissue samples from genital CTVT (GTVTs) and extragenital CTVT (ETVTs). Genomic DNA was extracted, bisulfite-treated, and analyzed using bisulfite polymerase chain reaction (PCR) and sequencing. The messenger RNA and protein of MYC and CDKN2B were also extracted and assessed by real-time PCR and Western blotting. Matching formalin-fixed, paraffin-embedded blocks were used for immunohistochemical staining to visualize protein distribution in GTVT and ETVT tissues. Results: Although both GTVT and ETVT samples showed MYC promoter methylation, the extent of methylation differed significantly. GTVTs displayed a much higher degree of methylation, potentially explaining the more pronounced downregulation of MYC gene expression and reduction in c-MYC protein levels observed in GTVTs compared with ETVTs. Our data revealed a prevalent hypermethylation pattern in the CDKN2B promoter across both sample types. However, DNA methylation, which was expected to have a suppressive effect, did not correlate with gene/protein expression. GTVTs displayed high protein levels despite significantly reduced CDKN2B expression. Conversely, ETVTs maintained regular CDKN2B expression but exhibited reduced protein production, suggesting a complex interplay between methylation and expression in these tumors. Conclusion: MYC demonstrated a clear association between its promoter methylation status, gene expression, and protein levels; however, CDKN2B lacked this correlation, implying the involvement of methylation-independent regulatory mechanisms and highlighting the need for further investigation.

The effect of grainyhead‐like transcription factor 3 (GRHL3) on cancer development depends on the cancer subtypes as shown in tumor entities such as colorectal or oral squamous cell carcinomas. Here, we analyzed the subtype‐specific role of GRHL3 in bladder carcinogenesis, comparing common urothelial carcinoma (UC) with squamous bladder cancer (sq‐BLCA). We examined GRHL3 mRNA and protein expression in cohorts of patient samples, its prognostic role and its functional impact on tumorigeneses in different molecular and histopathological subtypes of bladder cancer. We showed for GRHL3 a reverse expression in squamous and urothelial bladder cancer subtypes. Stably GRHL3‐overexpressing EJ28, J82, and SCaBER in vitro models revealed a tumor‐suppressive function in squamous and an oncogenic role in the urothelial cancer cells affecting cell and colony growth, and migratory and invasive capacities. Transcriptomic profiling demonstrated highly subtype‐specific GRHL3‐regulated expression networks coined by the enrichment of genes involved in integrin‐mediated pathways. In SCaBER, loss of ras homolog family member A (RHOA) GTPase activity was demonstrated to be associated with co‐regulation of eukaryotic translation initiation factor 4E family member 3 (EIF4E3), a potential tumor suppressor gene. Thus, our data provide for the first time a detailed insight into the role of the transcription factor GRHL3 in different histopathological subtypes of bladder cancer.

Prostate cancer (PRAD) is one of the leading malignancies in men all around the world. Here, we identified Myosin Heavy Chain 6 (MYH6) as a potential tumor suppressor gene in the development of prostate cancer. We found lower expression of MYH6 in prostate cancer tissues, and its lower gene expression was also associated with worse clinical outcomes. In vitro and in vivo assays indicated that overexpressed MYH6 could suppress the proliferation and migration progression of prostate cancer cells. RNA-seq was employed to investigate the mechanism, and KIT Proto-Oncogen (KIT) was determined as the downstream gene of MYH6, which was further confirmed using rescue assays. In all, we provide the evidence that MYH6 could serve as a tumor suppressor in prostate cancer. Our results highlight the potential role of MYH6 in the development of prostate cancer. [ABSTRACT FROM AUTHOR]

ErbB3‐binding protein 1(Ebp1) has two isoforms, p42 Ebp1 and p48 Ebp1, both of which can regulate cell growth and differentiation. But these isoforms often have opposite effects, including contradictory roles in regulation of cell growth in different tissues and cells. P48 Ebp1 belongs to the full‐length sequence, while conformational changes in the crystal structure of p42 Ebp1 reveals a lack of an α helix at the amino terminus. Due to the differences in the structures of these two isoforms, they have different binding partners and protein modifications. Ebp1 can function as both an oncogene and a tumor suppressor factor. However, the underlying mechanisms by which these two isoforms exert opposite functions are still not fully understood. In this review, we summarize the genes and the structures of protein of these two isoforms, protein modifications, binding partners and the association of different isoforms with diseases. [ABSTRACT FROM AUTHOR]

Background: Choroid plexus carcinomas (CPCs) are rare malignant tumors primarily affecting pediatric patients and often co-occur with Li-Fraumeni Syndrome (LFS), an inherited predisposition to early-onset malignancies in multiple organ systems. LFS is closely linked to TP53 mutations, with germline TP53 gene mutations present in approximately 75% of Li-Fraumeni syndrome families and 25% of Li-Fraumeni-like syndrome families. Individuals with TP53 mutations also have an elevated probability of carrying mutations in BRCA1 and BRCA2 genes. Objective: To investigate the structural and functional implications of the TP53: 799C > T, p. (Arg267Trp) missense mutation, initially identified in a Saudi family, and understand its impact on TP53 functionality and related intermolecular interactions. Methods: Computational analyses were conducted to examine the structural modifications resulting from the TP53: 799C > T, p. (Arg267Trp) mutation. These analyses focused on the mutation's impact on hydrogen bonding, ionic interactions, and the specific interaction with Cell Cycle and Apoptosis Regulator 2 (CCAR2), as annotated in UniProt. Results: The study revealed that the native Arg267 residue is critical for a salt bridge interaction with glutamic acid at position 258. The mutation-induced charge alteration has the potential to disrupt this ionic bonding. Additionally, the mutation is located within an amino acid region crucial for interaction with CCAR2. The altered properties of the amino acid within this domain may affect its functionality and disrupt this interaction, thereby impacting the regulation of catalytic enzyme activity. Conclusions: Our findings highlight the intricate intermolecular interactions governing TP53 functionality. The TP53: 799C > T, p. (Arg267Trp) mutation causes structural modifications that potentially disrupt critical ionic bonds and protein interactions, offering valuable insights for the development of targeted mutants with distinct functional attributes. These insights could inform therapeutic strategies for conditions associated with TP53 mutations. [ABSTRACT FROM AUTHOR]

Cancer research is linked to modern life-sciences, encompassing achievements in virology, yeast-biology, molecular-biology, genetics, systems-biology, bioinformatics, and so on. With these fascinating developments, it's easy to overlook that the fundamental theories and treatment strategies were established in the early 20th century and have remained valid ever since. Therefore, tribute must be paid to the founders of the field. The main hypotheses on carcinogenesis, the genetic model and the metabolic model, and the concept of cancer-treatment with cytotoxic, targeted or metabolic drugs were proposed more than 100 years ago by great minds such as T. Boveri, O. Warburg, and P. Ehrlich. Hence nothing about these cancer concepts is really new. Through development of powerful new technologies, we have been able to decipher the mechanisms of malignant transformation, thus significantly advancing the field. Our own studies have been focused on the cross-talk between cell-growth-signaling and lipid-metabolism in ovarian cancer to find crossover-points for co-targeting in order to achieve synergistic treatment effects. Notably, a side-effect of the application of current methods of molecularcell-biology is a deeper knowledge of the laws of normal cell-biology and cell-life. Thus we anticipate the field will advance rapidly in the near future. [ABSTRACT FROM AUTHOR]

Gastric cancer is a multifactorial heterogeneous disease involving various subgroups with different molecular features and it is one of the leading causes of cancer deaths worldwide. Although dietary conditions (fried, fatty and salty foods), tobacco and alcohol consumption, and some gastrointestinal infections are important in gastric cancer, the development of the disease is complex. It is clear that tumor suppressor genes and proto-oncogenes have a significant impact on the formation of gastric cancer. CDKN2A is a tumor suppressor gene that encodes two different proteins, and methylation, deletion and other mutations of this gene are effective in both the development and prognosis of gastric cancer. CDKN2A hypermethylation is common in gastric cancer related with H. Pylori and EBV infections. A connection is often established between metastases of gastric cancer and losses of this tumor suppressor gene (deletions). In this context, possible changes in the CDKN2A gene should be taken into consideration as a biomarker in the treatment and follow-up of gastric cancer. [ABSTRACT FROM AUTHOR]

The effect of grainyhead‐like transcription factor 3 (GRHL3) on cancer development depends on the cancer subtypes as shown in tumor entities such as colorectal or oral squamous cell carcinomas. Here, we analyzed the subtype‐specific role of GRHL3 in bladder carcinogenesis, comparing common urothelial carcinoma (UC) with squamous bladder cancer (sq‐BLCA). We examined GRHL3 mRNA and protein expression in cohorts of patient samples, its prognostic role and its functional impact on tumorigeneses in different molecular and histopathological subtypes of bladder cancer. We showed for GRHL3 a reverse expression in squamous and urothelial bladder cancer subtypes. Stably GRHL3‐overexpressing EJ28, J82, and SCaBER in vitro models revealed a tumor‐suppressive function in squamous and an oncogenic role in the urothelial cancer cells affecting cell and colony growth, and migratory and invasive capacities. Transcriptomic profiling demonstrated highly subtype‐specific GRHL3‐regulated expression networks coined by the enrichment of genes involved in integrin‐mediated pathways. In SCaBER, loss of ras homolog family member A (RHOA) GTPase activity was demonstrated to be associated with co‐regulation of eukaryotic translation initiation factor 4E family member 3 (EIF4E3), a potential tumor suppressor gene. Thus, our data provide for the first time a detailed insight into the role of the transcription factor GRHL3 in different histopathological subtypes of bladder cancer. [ABSTRACT FROM AUTHOR]

Non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long ncRNAs (lncRNAs), are essential regulators of processes, such as the cell cycle and apoptosis. In addition to interacting with intracellular complexes and participating in diverse molecular pathways, ncRNAs can be used as clinical diagnostic biomarkers and therapeutic targets for fighting cancer. Studying ncRNA gene clusters is crucial for understanding their role in cancer and developing new treatments. LOC124905135 is a protein-coding gene encoding a collagen alpha-1(III) chain-like protein, and also acts as a gene for several ncRNAs, including miR-3619, PRR34 antisense RNA 1 (PRR34-AS1), PRR34, long intergenic ncRNA 2939 (LINC02939), LOC112268288, and MIRLET7BHG. It also serves as a host gene for three miRNAs (hsa-let7-A3, hsa-miR-4763, and hsa-let-7b). Notably, the ncRNAs derived from this particular genomic region significantly affect various cell functions, including the cell cycle and apoptosis. This cluster of ncRNAs is dysregulated in several types of cancer, exhibiting mutations, alterations in copy number, and being subject to DNA methylation and histone modification. In summary, the ncRNAs derived from the LOC124905135 cluster could be used as targets for diagnosis, therapy monitoring, and drug discovery in human cancers.

Background: BRCA1 and BRCA2 are tumor suppressor genes associated with increased risk of breast and ovarian cancer in adulthood. Patients with germline pathogenic variants in these genes have also been reported to develop brain tumors, although it is unclear whether these syndromes are associated with significant increased risk of brain tumor formation. Results: Here, we report a case of a child with germline BRCA2 pathogenic variant presenting with a symptomatic ganglioglioma. To our knowledge, this is the first such patient to be reported. We discuss prior cases of brain tumors in BRCA1/2 patients and evidence for a potential role for BRCA1/2 pathogenic variants in brain tumor formation. Conclusion: BRCA2 germline variants may increase the risk of developing some types of pediatric brain tumors, but further study is needed to determine its effect on low-grade glioma formation. [ABSTRACT FROM AUTHOR]

PTPRD, a well‐established tumor suppressor gene, encodes the protein tyrosine phosphatase‐type D. This protein consists of three immunoglobulin‐like (Ig) domains, four to eight fibronectin type 3 (FN) domains, a single transmembrane segment, and two cytoplasmic tandem tyrosine phosphatase domains. PTPRD is known to harbor various cancer‐associated point mutations. While it is assumed that PTPRD regulates cellular functions as a tumor suppressor through the tyrosine phosphatase activity in the intracellular region, the function of its extracellular domain (ECD) in cancer is not well understood. In this study, we systematically examined the impact of 92 cancer‐associated point mutations within the ECD. We found that 69.6% (64 out of 92) of these mutations suppressed total protein expression and/or plasma membrane localization. Notably, almost all mutations (20 out of 21) within the region between the last FN domain and transmembrane segment affected protein expression and/or localization, highlighting the importance of this region for protein stability. We further found that some mutations within the Ig domains adjacent to the glycosaminoglycan‐binding pocket enhanced PTPRD's binding ability to heparan sulfate proteoglycans (HSPGs). This interaction is proposed to suppress phosphatase activity. Our findings therefore suggest that HSPG‐mediated attenuation of phosphatase activity may be involved in tumorigenic processes through PTPRD dysregulation. [ABSTRACT FROM AUTHOR]

Background: The present study attempts to assess the role of BCL-2 and p53 family of genes in chronic myeloid leukemia (CML) and correlation of their immunoreactivity with the status of remission on followup. Objectives: Primary objective of the study is to assess and score the expression of BCL2 and p53 in bone marrow trephine biopsies of cases of CML and to correlate the expression of these markers with the prognosis of the patients. Assessment of demographic distribution of CML were also included as secondary objective. Methods: Present study is a cross-sectional study conducted in the Department of Pathology, Govt. Medical College, Kozhikode from January 2017 to December 2020. The study population included confirmed cases of CML received in Pathology Department during the study period. 55 cases were selected. The paraffin embedded blocks of bone marrow trephine biopsy were retrieved and immunohistochemical testing were done in the department. Clinical details of patients were obtained from patient records. All variables needed for study were collected. Consecutive sampling technique was adopted for the study. Statistical analysis was done by chi square test. A p value less than 0.05 was considered as statistically significant. Results: Among the study population, majority (69%) of patients were in chronic phase at initial presentation. Most of the patients in chronic phase were in remission(62%). 25% of the study population presented in the blast crisis phase. Majority of the patients in blast crisis were not in remission and were in an elderly age group. Most of the patients presented with massive splenomegaly at diagnosis and only 5 patients didn't have significant organomegaly. It was found that there is an association between BCL2, haemoglobin, platelet and age with the status of remission (p<0.05) and there is no association between P53 and total count with the status of remission (p>0.05). Conclusion: These findings are in line with numerous studies that discovered a unique approach to eliminate quiescent stem cells in CML that cause relapse by targeting BCL-2 coupled with BCR-ABL and inhibiting the MDM2 protein that breaks down p53. [ABSTRACT FROM AUTHOR]

MicroRNAs are key regulators of gene expression in tumorigenesis. In this study, we investigated the tumor-suppressive function of miR-31-3p. Analysis of the Gene Expression Omnibus database revealed that the expression of miR-31-3p in prostate cancer tissues is lower than that in adjacent normal tissues from patients with prostate cancer. Moreover, miR-31-3p induces apoptosis in DU145, PC-3, and LNCap prostate cancer cells, while those transfected with miR-31-3p exhibit significantly decreased cell proliferation, migration, invasiveness, and tumor sphere-forming ability, as determined using the cell counting kit-8, transwell, and sphere-forming assays. Further analysis revealed that GABBR2 is a direct target of miR-31-3p. Within a DU145 xenograft murine model, intratumoral injection of a miR-31-3p mimic suppresses tumor growth. Taken together, the findings of this study suggest that miR-31-3p performs a novel tumor-suppressive function in prostate cancer and may represent a novel target for anti-prostate cancer miRNA therapeutics. [ABSTRACT FROM AUTHOR]

A sensitive electrochemical genosensor was introduced and developed for a tumor suppressor gene, p53, detection. An Au screen-printed electrode coated with polyaniline film and ceria nanoparticles decorated on reduced graphene oxide was employed. To generate the genosensor, a suitable ssDNA probe sequence was immobilized on the modified surface of a screen-printed electrode without requiring any labeling or tagging moieties. The surface properties of the resulting electrodes were evaluated through scanning electron microscopy (SEM) and atomic force microscopy (AFM). The hybridization phenomena of the probe and its target sequence were followed by a differential pulse voltammetric signal of tris(bipyridine) ruthenium(II) chloride as an electrochemical probe. The detection limit was found 1.3 fM, and the DPV current was proportional to the logarithm of the p53 ssDNA concentration from 10 fM to 0.1 nM. The proposed genosensor showed excellent sensitivity, high selectivity, and reasonable reproducibility, which can be useful in future cancer diagnosis microdevice development. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancer with increased expression levels of HOXA1 tends to have a worse outcome. This gene is regulated by DNA methylation. Herein, we studied the methylation pattern of HOXA1 in oral cavity tumors. We found that methyl groups gather more often in a specific region of HOXA1, named 3′UTR, in tumor cells compared to healthy tissues. Interestingly, patients with increased methylation levels were preferentially detected in heavier smokers and patients with a longer survival. Our findings suggest that the analysis of the DNA methylation located in the 3′UTR of HOXA1 could help predict the patient's prognosis. Our findings could potentially guide treatment decisions and improve patient care in the future. Background: HOXA1 is a prognostic marker and a potential predictive biomarker for radioresistance in head and neck tumors. Its overexpression has been associated with promoter methylation and a worse prognosis in oral squamous cell carcinoma (OSCC) patients. However, opposite outcomes are also described. The effect of the methylation of this gene on different gene regions, other than the promoter, remains uncertain. We investigated the methylation profile at different genomic regions of HOXA1 in OSCC and correlated differentially methylated CpG sites with clinicopathological data. Methods: The HOXA1 DNA methylation status was evaluated by analyzing data from The Cancer Genome Atlas and three Gene Expression Omnibus datasets. Significant differentially methylated CpG sites were considered with a |∆β| ≥ 0.10 and a Bonferroni-corrected p-value < 0.01. Differentially methylated CpGs were validated by pyrosequencing using two independent cohorts of 15 and 47 OSCC patients, respectively. Results: Compared to normal tissues, we found significantly higher DNA methylation levels in the 3′UTR region of HOXA1 in OSCC. Higher methylation levels in tumor samples were positively correlated with smoking habits and patients' overall survival. Conclusions: Our findings suggest that HOXA1 gene body methylation is a promising prognostic biomarker for OSCC with potential clinical applications in patient monitoring. [ABSTRACT FROM AUTHOR]

Aims: Neuroblastoma (NB) is the most common extracranial solid tumor in children, with a 5‐year survival rate of <50% in high‐risk patients. MYCN amplification is an important factor that influences the survival rate of high‐risk patients. Our results indicated MYCN regulates the expression of SESN1. Therefore, this study aimed to investigate the role and mechanisms of SESN1 in NB. Methods: siRNAs or overexpression plasmids were used to change MYCN, SESN1, or MyD88's expression. The role of SESN1 in NB cell proliferation, migration, and invasion was elucidated. Xenograft mice models were built to evaluate SESN1's effect in vivo. The correlation between SESN1 expression and clinicopathological data of patients with NB was analyzed. RNA‐Seq was done to explore SESN1's downstream targets. Results: SESN1 was regulated by MYCN in NB cells. Knockdown SESN1 promoted NB cell proliferation, cell migration, and cell invasion, and overexpressing SESN1 had opposite functions. Knockdown SESN1 promoted tumor growth and shortened tumor‐bearing mice survival time. Low expression of SESN1 had a positive correlation with poor prognosis in patients with NB. RNA‐Seq showed that Toll‐like receptor (TLR) signaling pathway, and PD‐L1 expression and PD‐1 checkpoint pathway in cancer were potential downstream targets of SESN1. Knockdown MyD88 or TLRs inhibitor HCQ reversed the effect of knockdown SESN1 in NB cells. High expression of SESN1 was significantly associated with a higher immune score and indicated an active immune microenvironment for patients with NB. Conclusions: SESN1 functions as a new tumor suppressor gene via TLR signaling pathway in NB. [ABSTRACT FROM AUTHOR]

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Background: Glioma is a type of malignant cancer that affect the central nervous system. New predictive biomarkers have been investigated in recent years, but the clinical prognosis for glioma remains poor. The function of CPLX2 in glioma and the probable molecular mechanism of tumor suppression were the focus of this investigation. Methods: The glioma transcriptome profile was downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases for analysis of CPLX2 expression in glioma. RT-qPCR was performed to detect the expression of CPLX2 in 68 glioma subjects who have been followed up. Kaplan-Meier survival analyses were conducted to assess the effect of CPLX2 on the prognosis of glioma patients. The knockdown and overexpressed cell lines of CPLX2 were constructed to investigate the impact of CPLX2 on glioma. The cell growth, colony formation, and tumor formation in xenograft were performed. Results: The expression of CPLX2 was downregulated in glioma and was negatively correlated with the grade of glioma. The higher expression of CPLX2 predicted a longer survival, as indicated by the analysis of Kaplan-Meier survival curves. Overexpressed CPLX2 impaired tumorigenesis in glioma progression both in vivo and in vitro. Knocking down CPLX2 promoted the proliferation of glioma cells. The analysis of GSEA and co-expression analysis revealed that CPLX2 may affect the malignancy of glioma by regulating the hypoxia and inflammation pathways. Conclusions: Our data indicated that CPLX2 functions as a tumor suppressor and could be used as a potential prognostic marker in glioma. [ABSTRACT FROM AUTHOR]

Background: LIN9, a gene associated with various cancers, is considered a tumor suppressor. However, the role of LIN9 in lung adenocarcinoma (LUAD) remains unknown. In this study, we aimed to assess the role of LIN9 in the occurrence and prognosis of LUAD. Methods: Using three-tier HTSeq count RNA sequencing data from The Cancer Genome Atlas, we assessed LIN9 expression for the LUAD dataset using the DESeq2 R package and RT-qPCR experiments. Biological functions were assessed using gene set enrichment analysis (clusterProfiler and GOplot). The expression of LIN9 and the infiltration of immune cells were assessed by Single-sample gene set enrichment analysis. We conducted correlation study using clinical characteristics and receiver operating characteristic curve analysis. The predictive value of LIN9 was determined using univariate and multivariate Cox regression as well as Kaplan-Meier analysis. Additionally, functional studies were conducted to validate its role in the progression of LUAD. Results: Expression of LIN9 was significantly elevated in LUAD, primarily influencing cell cycle, division, and signaling pathways. High LIN9 expression correlated positively with the infiltration of Th2 cells and inversely with that of plasmacytoid dendritic cells. Furthermore, LIN9 was associated with older age and advanced clinical stages, posing risks to overall, progression-free, and disease-specific survival. LIN9 served as a good diagnostic marker, particularly in females, patients aged over 65, and those with clinical N1–3 and M1 stages. Elevated LIN9 expression enhanced proliferation, migration, and invasion of LUAD cells. Conclusion: High LIN9 expression potentially contributes to LUAD occurrence through cell cycle regulation and chromosomal modification. It promotes the malignant characteristics of LUAD cells and holds prognostic value for affected patients.

Abstract Background GBM is the most frequent malignant primary brain tumor in humans. The CLEC19A is a member of the C-type lectin family, which has a high expression in brain tissue. Herein, we sought to carry out an in-depth analysis to pinpoint the role of CLEC19A expression in GBM. Methods To determine the localization of CLEC19A, this protein was detected using Western blot, Immunocytochemistry/Immunofluorescence, and confocal microscopy imaging. CLEC19A expression in glioma cells and tissues was evaluated by qRT-PCR. Cell viability, proliferation, migration, and apoptosis were examined through MTT assay, CFSE assay, colony formation, wound healing assay, transwell test, and flow cytometry respectively after CLEC19A overexpression. The effect of CLEC19A overexpression on the PI3K/AKT/NF-κB signaling pathway was investigated using Western blot. An in vivo experiment substantiated the in vitro results using the glioblastoma rat models. Results Our in-silico analysis using TCGA data and measuring CLEC19A expression level by qRT-PCR determined significantly lower expression of CLEC19A in human glioma tissues compared to healthy brain tissues. By employment of ICC/IF, confocal microscopy imaging, and Western blot we could show that CLEC19A is plausibly a secreted protein. Results obtained from several in vitro readouts showed that CLEC19A overexpression in U87 and C6 glioma cell lines is associated with the inhibition of cell proliferation, viability, and migration. Further, qRT-PCR and Western blot analysis showed CLEC19A overexpression could reduce the expression levels of PI3K, VEGFα, MMP2, and NF-κB and increase PTEN, TIMP3, RECK, and PDCD4 expression levels in glioma cell lines. Furthermore, flow cytometry results revealed that CLEC19A overexpression was associated with significant cell cycle arrest and promotion of apoptosis in glioma cell lines. Interestingly, using a glioma rat model we could substantiate that CLEC19A overexpression suppresses glioma tumor growth. Conclusions To our knowledge, this is the first report providing in-silico, molecular, cellular, and in vivo evidences on the role of CLEC19A as a putative tumor suppressor gene in GBM. These results enhance our understanding of the role of CLEC19A in glioma and warrant further exploration of CLEC19A as a potential therapeutic target for GBM.

A close relationship between fatty acid metabolism and cancer development is well-established. The hydroxyacyl-coenzyme a dehydrogenase (HADH), a key enzyme in fatty acid beta-oxidation, has recently been identified as an anti-oncogenic factor in various cancers and an oncogenic factor in conditions like acute myeloid leukemia. In cancer cells, HADH not only directly catalyzes fatty acid beta-oxidation but also indirectly influences multiple signaling pathways such as PPAR, TNF-α, JAK-STAT3, PI3K/Akt, IFN-γ, MAPK, and non-canonical Wnt signaling pathways, affecting cancer cell proliferation and migration. HADH shows promise as a potential tumor biomarker for diagnosis, treatment, and prognosis in different cancer types, holding significant clinical value.

Simple Summary: This study focused on exploring the biochemical attributes of bazedoxifene acetate (BZA), a promising candidate for breast cancer treatment. It functions as an osteoprotective agent by maintaining bone density while concurrently displaying antiestrogenic properties in breast tissue—a valuable characteristic for breast cancer endocrine therapy. Our study investigated how BZA affects certain key proteins associated with Estrogen Receptor Alpha (ERα) and tumor suppressor gene BRCA1 in breast cancer cells. The findings demonstrated a substantial reduction in the levels of these proteins, signifying the potential therapeutic relevance of BZA in managing breast cancer. Furthermore, BZA exhibited antiproliferative properties, suggestive of its capacity to inhibit cell growth. Understanding the role of BZA in regulating these proteins is crucial for advancing breast cancer treatment and hormone receptor research. Selective estrogen receptor modulators (SERMs) are steroid analogs with dual functionality, acting as partial estrogen receptor agonists to preserve postmenopausal bone density and as estrogen receptor antagonists in breast tissue. Bazedoxifene acetate (BZA) is an FDA-approved, third-generation SERM used in the treatment of osteoporosis in women. It demonstrates potential as a therapeutic option for breast cancer patients undergoing endocrine therapy. Our study aimed to assess BZA's effects on Estrogen Receptor Alpha (ERα) and tumor suppressor gene BRCA1 in T-47D and MCF-7 breast cancer cells, using Western blots, cellular viability, apoptosis assays, and RT-qPCR. Cells were cultured in 5% charcoal-stripped fetal bovine serum for six days to deplete endogenous steroids. Following a 24 h exposure to 2 µM BZA (optimal concentration determined from 1 nM–2 µM studies), Western blot analyses revealed reduced ERα and BRCA1 protein levels in both cell lines. ERα decreased by 48–63% and BRCA1 by 61–64%, indicating sensitivity to antiestrogens. Cytolocalization of ERα and BRCA1 remained unchanged after BZA and 17-β-estradiol (E2) treatment. ESR1 mRNA expression correlated with Western blot findings. Image cytometric analysis using the stain, propidium iodide, detected decreased cellular proliferation in T-47D and MCF-7 cells following a 6-day treatment ranging from 1 nM to 2 µM BZA. BZA treatment alone led to a tenfold reduction in cellular proliferation compared to estrogen-treated cells, suggesting antiproliferative effects. Understanding BZA's modulation of BRCA1 and ERα, along with their mechanistic interactions, is vital for comprehending its impact on breast cancer tumor suppressors and hormone receptors. [ABSTRACT FROM AUTHOR]

For several decades, cancers have demonstrably been one of the most frequent causes of death worldwide. In addition to genetic causes, cancer can also be caused by epigenetic gene modifications. Frequently, tumor suppressor genes are epigenetically inactivated due to hypermethylation of their CpG islands, actively contributing to tumorigenesis. Since CpG islands are usually localized near promoters, hypermethylation of the promoter can have a major impact on gene expression. In this study, the potential tumor suppressor gene Receptor Interacting Serine/Threonine Protein Kinase 3 (RIPK3) was examined for an epigenetic regulation and its gene inactivation in melanomas. A hypermethylation of the RIPK3 CpG island was detected by bisulfite pyrosequencing and was accompanied by a correlated loss of its expression. In addition, an increasing RIPK3 methylation rate was observed with increasing tumor stage of melanomas. For further epigenetic characterization of RIPK3, epigenetic modulation was performed using a modified CRISPR/dCas9 (CRISPRa activation) system targeting its DNA hypermethylation. We observed a reduced fitness of melanoma cells by (re-)expression and demethylation of the RIPK3 gene using the epigenetic editing-based method. The tumor suppressive function of RIPK3 was evident by phenotypic determination using fluorescence microscopy, flow cytometry and wound healing assay. Our data highlight the function of RIPK3 as an epigenetically regulated tumor suppressor in melanoma, allowing it to be classified as a biomarker. [ABSTRACT FROM AUTHOR]

Background: GBM is the most frequent malignant primary brain tumor in humans. The CLEC19A is a member of the C-type lectin family, which has a high expression in brain tissue. Herein, we sought to carry out an in-depth analysis to pinpoint the role of CLEC19A expression in GBM. Methods: To determine the localization of CLEC19A, this protein was detected using Western blot, Immunocytochemistry/Immunofluorescence, and confocal microscopy imaging. CLEC19A expression in glioma cells and tissues was evaluated by qRT-PCR. Cell viability, proliferation, migration, and apoptosis were examined through MTT assay, CFSE assay, colony formation, wound healing assay, transwell test, and flow cytometry respectively after CLEC19A overexpression. The effect of CLEC19A overexpression on the PI3K/AKT/NF-κB signaling pathway was investigated using Western blot. An in vivo experiment substantiated the in vitro results using the glioblastoma rat models. Results: Our in-silico analysis using TCGA data and measuring CLEC19A expression level by qRT-PCR determined significantly lower expression of CLEC19A in human glioma tissues compared to healthy brain tissues. By employment of ICC/IF, confocal microscopy imaging, and Western blot we could show that CLEC19A is plausibly a secreted protein. Results obtained from several in vitro readouts showed that CLEC19A overexpression in U87 and C6 glioma cell lines is associated with the inhibition of cell proliferation, viability, and migration. Further, qRT-PCR and Western blot analysis showed CLEC19A overexpression could reduce the expression levels of PI3K, VEGFα, MMP2, and NF-κB and increase PTEN, TIMP3, RECK, and PDCD4 expression levels in glioma cell lines. Furthermore, flow cytometry results revealed that CLEC19A overexpression was associated with significant cell cycle arrest and promotion of apoptosis in glioma cell lines. Interestingly, using a glioma rat model we could substantiate that CLEC19A overexpression suppresses glioma tumor growth. Conclusions: To our knowledge, this is the first report providing in-silico, molecular, cellular, and in vivo evidences on the role of CLEC19A as a putative tumor suppressor gene in GBM. These results enhance our understanding of the role of CLEC19A in glioma and warrant further exploration of CLEC19A as a potential therapeutic target for GBM. [ABSTRACT FROM AUTHOR]

A close relationship between fatty acid metabolism and cancer development is well-established. The hydroxyacyl-coenzyme a dehydrogenase (HADH), a key enzyme in fatty acid beta-oxidation, has recently been identified as an anti-oncogenic factor in various cancers and an oncogenic factor in conditions like acute myeloid leukemia. In cancer cells, HADH not only directly catalyzes fatty acid beta-oxidation but also indirectly influences multiple signaling pathways such as PPAR, TNF-α, JAK-STAT3, PI3K/Akt, IFN-γ, MAPK, and non-canonical Wnt signaling pathways, affecting cancer cell proliferation and migration. HADH shows promise as a potential tumor biomarker for diagnosis, treatment, and prognosis in different cancer types, holding significant clinical value. [ABSTRACT FROM AUTHOR]

HACE1 is a HECT family E3 ubiquitin–protein ligase with broad but incompletely understood tumor suppressor activity. Here, we report a previously unrecognized link between HACE1 and signaling complexes containing mammalian target of rapamycin (mTOR). HACE1 blocks mTORC1 and mTORC2 activities by reducing mTOR stability in an E3 ligase‐dependent manner. Mechanistically, HACE1 binds to and ubiquitylates Ras‐related C3 botulinum toxin substrate 1 (RAC1) when RAC1 is associated with mTOR complexes, including at focal adhesions, leading to proteasomal degradation of RAC1. This in turn decreases the stability of mTOR to reduce mTORC1 and mTORC2 activity. HACE1 deficient cells show enhanced mTORC1/2 activity, which is reversed by chemical or genetic RAC1 inactivation but not in cells expressing the HACE1‐insensitive mutant, RAC1K147R. In vivo, Rac1 deletion reverses enhanced mTOR expression in KRasG12D‐driven lung tumors of Hace1−/− mice. HACE1 co‐localizes with mTOR and RAC1, resulting in RAC1‐dependent loss of mTOR protein stability. Together, our data demonstrate that HACE1 destabilizes mTOR by targeting RAC1 within mTOR‐associated complexes, revealing a unique ubiquitin‐dependent process to control the activity of mTOR signaling complexes. Synopsis: HACE1 E3 ligase mediated degradation of RAC1 within mTORC1 and mTORC2 signaling complexes controls the signalling activity of both complexes.HACE1 regulates mTORC1 and mTORC2 activity in an E3 ligase dependent manner.HACE1 targets RAC1 for ubiquitylation when it is associated with mTOR signaling complexes.RAC1 inactivation reduces activity of mTOR signaling complexes. [ABSTRACT FROM AUTHOR]

Simple Summary: The tumor microenvironment (TME) of HNSCC is heterogeneous and complex, and it plays a crucial role in achieving effective cancer therapy. To develop effective cancer therapies, it is important to understand the crosstalk between cancer inflammation and immunity, as well as oncogenes and tumor suppressor genes. In this study, we aimed to gain a more comprehensive understanding of the transcriptomes of the TME in HPV-associated and HPV-non-associated TSCC by studying the gene expression profiles of 168 genes linked to various cellular mediators and factors involved in inflammation, immune crosstalk, transcription, signal transduction, oncogenesis, tumor suppression, angiogenesis, and apoptosis. We found that the TME of HPV-associated and HPV-non-associated TSCC exhibited a remarkable heterogeneity of gene expression associated with cellular mediators and factors involved in inflammation, immune crosstalk, transcription factors, immune signaling pathways, signal transduction, oncogenesis, tumor suppression, angiogenesis, and apoptosis. Head and neck squamous cell carcinomas (HNSCCs) are a common type of cancer, ranking as the sixth most prevalent cancer worldwide and having a high morbidity and mortality rate. Among oropharyngeal squamous cell carcinoma (OPSCC) cancers, tonsillar squamous cell carcinoma (TSCC) is the most prevalent and has a particularly aggressive clinical course with poor disease outcomes. The tumor microenvironment (TME) of HNSCC is complex and heterogeneous, playing a crucial role in effective cancer therapy. Understanding the interaction between cancer inflammation, immunity, oncogenes, and tumor suppressor genes is essential for developing effective cancer treatments. This study aimed to gain a comprehensive understanding of the transcriptomes of the TME in TSCC, both associated with human papillomavirus (HPV) and not associated with HPV. The gene expression profiles of 168 genes linked to various cellular mediators and factors involved in inflammation, immunity crosstalk, transcription, signal transduction, oncogenesis, tumor suppression, angiogenesis, and apoptosis were analyzed. We identified 40 differentially expressed genes related to the communication between tumor cells and the cellular mediators of inflammation and immunity crosstalk. In HPV-positive TSCC patients, 33 genes were over-expressed with a fold change greater than 1.5, and 26 of these genes were unique to this group. In contrast, HPV-negative TSCC patients had 11 up-regulated genes. The results further showed that 48 gene transcripts related to oncogenesis, tumor suppression, angiogenesis, and apoptosis were up-regulated in both HPV-positive and HPV-negative TSCC patients. Among the HPV-positive TSCC patients, 37 genes were over-expressed, while the HPV-negative TSCC patients had 11 up-regulated genes. The tumor microenvironment (TME) of HPV-associated and HPV-non-associated TSCC exhibited distinct characteristics, including the dysregulation of various genes involved in cellular mediators, inflammation, immunity crosstalk, transcription factors, immune signaling pathways, signal transduction, oncogenesis, tumor suppression, angiogenesis, and apoptosis. Additionally, we detected six Hr-HPV genotypes in 81% of the TSCC patients, with HPV-16 and HPV-35 being the most common types, followed by HPV-45 and HPV-18. HPV-39 and 31 were also identified. The presence of Hr-HPV genotypes in TSCC patients varied from single to multiple infections. In conclusion, we observed distinct heterogeneity in the transcriptome of the microenvironment in HPV-associated and non-associated TSCC. Further in vitro and in vivo studies are needed to investigate the functional implications of the identified over-expressed genes. Also, deeper molecular pathways and immunological studies on the TME are required to determine the potential of targeting genes for cancer therapy. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) play a critical role in a variety of human diseases such as cancer. Here, to elucidate a novel function of a lncRNA called LINC00173, we investigated its binding partner, target gene, and its regulatory mechanism in lung adenocarcinoma, including the A549 cell line and patients. In the A549 cell line, RNA immunoprecipitation (RIP) assays revealed that LINC00173 efficiently binds to SNAIL. RNA-seq and RT-qPCR analyses revealed that the expression of FHIT was decreased upon LINC00173 depletion, indicating that FHIT is a target gene of LINC00173. Overexpression of SNAIL suppressed and depletion of SNAIL increased the expression of FHIT, indicating that SNAIL negatively regulates FHIT. The downregulation of FHIT expression upon LINC00173 depletion was restored by additional SNAIL depletion, revealing a LINC00173-SNAIL-FHIT axis for FHIT regulation. Data from 501 patients with lung adenocarcinoma also support the existence of a LINC00173-SNAIL-FHIT axis, as FHIT expression correlated positively with LINC00173 (p = 1.75 × 10−6) and negatively with SNAIL (p = 7.00 × 10−5). Taken together, we propose that LINC00173 positively regulates FHIT gene expression by binding to SNAIL and inhibiting its function in human lung adenocarcinoma. Thus, this study sheds light on the LINC00173-SNAIL-FHIT axis, which may be a key mechanism for carcinogenesis and progression in human lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Worldwide, the number of cancer-related deaths continues to increase due to the ability of cancer cells to become chemotherapy-resistant and metastasize. For women with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. Although many mechanisms of cisplatin resistance have been proposed, the key mechanisms of such resistance remain elusive. The RNA binding protein with multiple splicing (RBPMS) binds to nascent RNA transcripts and regulates splicing, transport, localization, and stability. Evidence indicates that RBPMS also binds to protein members of the AP-1 transcription factor complex repressing its activity. Until now, little has been known about the biological function of RBPMS in ovarian cancer. Accordingly, we interrogated available Internet databases and found that ovarian cancer patients with high RBPMS levels live longer compared to patients with low RBPMS levels. Similarly, immunohistochemical (IHC) analysis in a tissue array of ovarian cancer patient samples showed that serous ovarian cancer tissues showed weaker RBPMS staining when compared with normal ovarian tissues. We generated clustered regularly interspaced short palindromic repeats (CRISPR)-mediated RBPMS knockout vectors that were stably transfected in the high-grade serous ovarian cancer cell line, OVCAR3. The knockout of RBPMS in these cells was confirmed via bioinformatics analysis, real-time PCR, and Western blot analysis. We found that the RBPMS knockout clones grew faster and had increased invasiveness than the control CRISPR clones. RBPMS knockout also reduced the sensitivity of the OVCAR3 cells to cisplatin treatment. Moreover, β-galactosidase (β-Gal) measurements showed that RBPMS knockdown induced senescence in ovarian cancer cells. We performed RNAseq in the RBPMS knockout clones and identified several downstream-RBPMS transcripts, including non-coding RNAs (ncRNAs) and protein-coding genes associated with alteration of the tumor microenvironment as well as those with oncogenic or tumor suppressor capabilities. Moreover, proteomic studies confirmed that RBPMS regulates the expression of proteins involved in cell detoxification, RNA processing, and cytoskeleton network and cell integrity. Interrogation of the Kaplan-Meier (KM) plotter database identified multiple downstream-RBPMS effectors that could be used as prognostic and response-to-therapy biomarkers in ovarian cancer. These studies suggest that RBPMS acts as a tumor suppressor gene and that lower levels of RBPMS promote the cisplatin resistance of ovarian cancer cells.

This article provides an overview of recent advancements in the diagnosis, prognosis, and treatment of cancer caused by oncogenic viruses. It emphasizes that certain viruses can lead to the development of cancer in humans and are responsible for more than 20% of human cancers. The article explores the role of inflammation, immune suppression, and mutagens in viral tumorigenesis. It also discusses the potential of new biomarkers and targeted therapies for early detection and treatment of virus-driven tumors. The article includes several research studies that focus on different aspects of viral oncogenesis, such as specific viral antigens and the presence of oncogenic viruses in urine specimens of patients with urothelial cell carcinomas. The findings contribute to our understanding of viral oncogenesis and provide insights into diagnostic and therapeutic strategies for virus-associated cancers. [Extracted from the article]

Abstract Background TP53, encoding the tumor suppressor p53, is frequently mutated in various cancers, producing mutant p53 proteins (mutp53) which can exhibit neomorphic, gain-of-function properties. The latter transform p53 into an oncoprotein that promotes metastatic tumor progression via downstream effectors such as ENTPD5, an endoplasmic reticulum UDPase involved in the calnexin/calreticulin cycle of N-glycoprotein biosynthesis. Elucidating the mechanisms underlying the pro-metastatic functions of the mutp53-ENTPD5 axis is crucial for developing targeted therapies for aggressive metastatic cancer. Methods We analyzed pancreatic, lung, and breast adenocarcinoma cells with p53 missense mutations to study the impact of mutp53 and ENTPD5 on the N-glycoproteins integrin-α5 (ITGA5) and integrin-β1 (ITGB1), which heterodimerize to form the key fibronectin receptor. We assessed the role of the mutp53-ENTPD5 axis in integrin-dependent tumor-stroma interactions and tumor cell motility using adhesion, migration, and invasion assays, identifying and validating therapeutic intervention targets. We employed an orthotopic xenograft model of pancreatic ductal adenocarcinoma to examine in vivo targeting of mutp53-ENTPD5-mediated ITGA5 regulation for cancer therapy. Results Mutp53 depletion diminished ITGA5 and ITGB1 expression and impaired tumor cell adhesion, migration, and invasion, rescued by ENTPD5. The mutp53-ENTPD5 axis maintained ITGA5 expression and function via the calnexin/calreticulin cycle. Targeting this axis using ITGA5-blocking antibodies, α-glucosidase inhibitors, or pharmacological degradation of mutp53 by HSP90 inhibitors, such as Ganetespib, effectively inhibited ITGA5-mediated cancer cell motility in vitro. In the orthotopic xenograft model, Ganetespib reduced ITGA5 expression and metastasis in an ENTPD5-dependent manner. Conclusions The mutp53-ENTPD5 axis fosters ITGA5 and ITGB1 expression and tumor cell motility through the calnexin/calreticulin cycle, contributing to cancer metastasis. ITGA5-blocking antibodies or α-glucosidase inhibitors target this axis and represent potential therapeutic options worth exploring in preclinical models. The pharmacologic degradation of mutp53 by HSP90 inhibitors effectively blocks ENTPD5-ITGA5-mediated cancer cell motility and metastasis in vivo, warranting further clinical evaluation in p53-mutant cancers. This research underscores the significance of understanding the complex interplay between mutp53, ENTPD5, and the calnexin/calreticulin cycle in integrin-mediated metastatic tumor progression, offering valuable insights for the development of potential therapeutic strategies.

Abstract Benzo(a)pyrene (BaP), the earliest and most significant carcinogen among polycyclic aromatic hydrocarbons (PAHs), has been found in foods, tobacco smoke, and automobiles exhaust, etc. Exposure to BaP induced DNA damage directly, or oxidative stress-related damage, resulting in cell apoptosis and carcinogenesis in human respiratory system, digestive system, reproductive system, etc. Moreover, BaP triggered genome-wide epigenetic alterations by methylation, which might cause disturbances in regulation of gene expression, and thereby induced cancer. It has been proved that BaP reduced genome-wide DNA methylation, and activated proto-oncogene by hypomethylation in the promoter region, but silenced tumor suppressor genes by promoter hypermethylation, resulting in cancer initiation and progression. Here we summarized the changes in DNA methylation in BaP exposure, and revealed the methylation of DNA plays a role in cancer development. Graphical Abstract

Objective: More than 75% of ovarian cancer patients are diagnosed at advanced stages and die of tumor cell metastasis. This study aimed to identify new epigenetic and transcriptomic alterations associated with ovarian cancer metastasis. Methods: Two cell sublines with low- and high-metastasis potentials were derived from the ovarian cancer cell line A2780. Genome-wide DNA methylome and transcriptome profiling were carried out in these two sublines by Reduced Representation Bisulfite Sequencing and RNA-seq technologies. Cell-based assays were conducted to support the clinical findings. Results: There are distinct DNA methylation and gene expression patterns between the two cell sublines with low- and high-metastasis potentials. Integrated analysis identified 33 methylation-induced genes potentially involved in ovarian cancer metastasis. The DNA methylation patterns of two of them (i.e., SFRP1 and LIPG) were further validated in human specimens, indicating that they were hypermethylated and downregulated in peritoneal metastatic ovarian carcinoma compared to primary ovarian carcinoma. Patients with lower SFRP1 and LIPG expression tend to have a worse prognosis. Functionally, knockdown of SFRP1 and LIPG promoted cell growth and migration, whereas their overexpression resulted in the opposite effects. In particular, knockdown of SFRP1 could phosphorylate GSK3β and increase β-catenin expression, leading to deregulated activation of the Wnt/β-catenin signaling. Conclusion: Many systemic and important epigenetic and transcriptomic alterations occur in the progression of ovarian cancer. In particular, epigenetic silencing of SFRP1 and LIPG is a potential driver event in ovarian cancer metastasis. They can be used as prognostic biomarkers and therapeutic targets for ovarian cancer patients. [ABSTRACT FROM AUTHOR]

Adenoid cystic carcinoma (ACC) is a MYB‐driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long‐term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow‐up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene PARK2 (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (n = 20) had significantly shorter overall survival (OS) than those with one or no deletions (p < 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (p = 0.02). Two pro‐apoptotic genes, TP73 and KIF1B, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. PARK2 expression was markedly reduced in tumors with 6q deletions, and PARK2 knockdown increased spherogenesis and decreased apoptosis, indicating that PARK2 is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of TP73. Taken together, the results indicate that TP73 and PARK2 are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker‐driven stratification of patients in clinical trials. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Introduction: RNA sequence analysis can be effectively used to identify aberrant splicing, and tumor suppressor genes are adequate targets considering their lossof-function mechanisms. Sanger sequencing is the simplest method for RNA sequence analysis; however, because of its insufficient sensitivity in cases with nonsense-mediated mRNA decay (NMD), the use of cultured specimens with NMD inhibition has been recommended, hindering its wide adoption. Method: The results of Sanger sequencing of peripheral blood RNA without NMD inhibition performed on potential splicing variants of tumor suppressor genes were retrospectively reviewed. For negative cases, in which no change was identified in the transcript, the possibility of false negativity caused by NMD was assessed through a review of the up-to-date literature. Results: Eleven potential splice variants of various tumor suppressor genes were reviewed. Six variants were classified as pathogenic or likely pathogenic based on the nullifying effect identified by Sanger RNA sequencing. Four variants remained as variants of uncertain significance because of identified in-frame changes or normal expression of both alleles. The result of one variant was suspected to be a false negative caused by NMD after reviewing a recent study that reported the same variant as causing a nullifying effect on the affected transcript. Conclusion: Although RNA changes found in the majority of cases were expected to undergo NMD by canonical rules, most cases (10/11) were interpretable by Sanger RNA sequencing without NMD inhibition due to incomplete NMD efficiency or allele-specific expression despite highly efficient NMD. [ABSTRACT FROM AUTHOR]

Intratumor heterogeneity (ITH) results from accumulation of somatic mutations in the fractions of successive cancer cell generations. We aimed to use deep sequencing to investigate ITH in colorectal tumors with particular emphasis on variants in oncogenes (ONC) and tumor suppressor genes (TSG). Samples were collected from 16 patients with colorectal cancer and negative or positive lymph node status (n = 8 each). We deep‐sequenced a panel of 56 cancer‐related genes in the central and peripheral locations of T3 size primary tumors and healthy mucosa. The central region of T3 tumors has a different frequency profile and composition of genetic variants. This mutation profile is capable of independently discriminating patients with different lymph node status (p = 0.028) in the central region. We noted an increasing number of mutations outside of the central region of the tumor and a higher number of mutations in tumors from node‐positive patients. Unexpectedly, in the healthy mucosa, we identified somatic mutations with variant allele frequencies, characteristic not only of heterozygotes and homozygotes but also of other discrete peaks (e.g., around 10%, 20%), suggestive of clonal expansion of certain mutant alleles. We found differences in the distribution of variant allele frequencies in TSGs when comparing node‐negative and node‐positive tumors (p = 0.029), as well as central and peripheral regions (p = 0.00399). TSGs may play an important role in the escape of the tumor toward metastatic colonization. [ABSTRACT FROM AUTHOR]