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Copyright of Revista de Ciencias Médicas de Pinar del Río is the property of Editorial Ciencias Medicas and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Objective To investigate the effect and mechanism of hyperoside on the biological behavior such as cell proliferation, migration and invasion of nasopharyngeal carcinoma cells. Methods SUNE1 cells were incubated with hyperin medium of 10 mg/L, 20 mg/L and 40 mg/L, and cells were divided into the low, the medium and the high dose groups. The lncRNA PAX8-AS1 overexpression or knockdown plasmid and miR-494-3p mimic were transfected into 40 mg/L hypericin-treated SUNE1 cells respectively. The activity, clonal formation, migration and invasion of SUNE1 cells were detected by CCK-8 assays, plate cloning experiment and Transwell assays. Western blot assay was used to analyze the expression of matrix metalloproteinase (MMP) -2 and MMP-9 proteins. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of long non-coding RNA (lncRNA) paired-box gene 8 antisense RNA 1 (PAX8-AS1) and miR-494-3p. Dual luciferase report experiment and RT-qPCR were used to determine the targeting relationship between lncRNA PAX8-AS1 and miR-494-3p. Results Low, medium and high dose-hyperoside significantly reduced the cell viability, migration number and invasion number of SUNE1 cells, and down-regulated expression levels of MMP-2 protein, MMP-9 protein and miR-494-3p, and up-regulated the expression level of lncRNA PAX8-AS1 (P＜0.05). lncRNA PAX8-AS1 negatively regulated miR-494-3p expression. lncRNA PAX8-AS1 overexpression significantly enhanced inhibitory effects of 40 mg/L hyperoside on SUNE1 cell viability, migration and invasion, and MMP-2 and MMP-9 protein expression (P＜0.05). Knockdown of lncRNA PAX8-AS1 and overexpression of miR-494-3p significantly reduced inhibitory effects of 40 mg/L hyperoside on SUNE1 cell viability, migration, invasion and MMP-2 and MMP-9 protein expression (P＜0.05). Conclusion Hyperoside may inhibit the proliferation and migration, and invasion of nasopharyngeal carcinoma cells by up-regulating the lncRNA PAX8-AS1 /miR-494-3p axis. [ABSTRACT FROM AUTHOR]

Background/Aim. Oral squamous cell carcinoma (OSCC) is the most common tumor type of head and neck carcinomas, characterized by a high recurrence rate and patients’ poor survival. Further elucidation of the function and regulation of the TP53, a pivotal tumor suppressor gene, would provide advances in predicting the clinical behavior, prognosis, and chemotherapy response of OSCC patients. Thus, we investigated the association of TP53 gene mutations with survival and response to cisplatin chemotherapy in human papilloma virus (HPV)-negative OSCC patients. Methods. The potential clinical relevance of TP53 mutations was analyzed in 82 patients with HPV-negative OSCC. All patients underwent radiotherapy, and 25 patients received cisplatin chemotherapy. A negative HPV status was deter-mined by type-specific polymerase chain reaction (PCR) for high-risk HPV 16, 18, 31, and 33. Targeted sequencing of TP53 exons 4–8 was assessed by Sanger sequencing. Results. Of 82 HPV-negative OSCC patients, 49 (59.79%) had TP53 mutations, and 26 patients (31.7%) carried pathogenic TP53 mutations. Patients with pathogenic TP53 mutations had significantly reduced overall survival (p = 0.009). Recurrence status, but not TP53 mutations, was an independent marker of poor survival in our cohort [hazard ratio (HR) = 4.733, 95% confidence interval (95% CI): 2.027–11.053, p = 0.0001]. In the sub-cohort of patients who underwent cisplatin-based chemotherapy, pathogenic TP53 mutations were predictors of poor response to chemotherapy (p = 0.026). Conclusion. Our findings indicate that pathogenic TP53 mutations in HPV-negative OSCC tumors could be a prognostic marker of patients’ reduced overall survival. In addition, pathogenic TP53 mutations in HPV-negative OSCC could be a marker of poor chemotherapy response of OSCC patients.

Despite the recent progresses in therapeutic and diagnostic methods, there is still a significantly high rate of mortality among cancer patients. One of the main reasons for the high mortality rate in cancer patients is late diagnosis, which leads to the failure of therapeutic strategies. Therefore, investigation of cancer biology can lead to the introduction of early diagnostic markers in these patients. MicroRNAs (miRNAs) play an important role in regulation of cellular processes associated with tumor progression. Due to the high stability of miRNAs in body fluids, these factors can be considered as the non-invasive tumor markers. Deregulation of miR-382 has been widely reported in different cancers. Therefore, in this review, we investigated the role of miR-382 during tumor development. It has shown that miR-382 has mainly a tumor suppressive, which inhibits the growth of tumor cells through the regulation of signaling pathways, RNA-binding proteins, and transcription factors. Therefore, miR-382 can be suggested as a diagnostic and therapeutic marker in cancer patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Dysfunction of zinc finger protein 652 (ZNF652) is associated with various malignant tumors. However, the role of ZNF652 in lung cancer (LC) is poorly understood. Here, we identified that ZNF652 was downregulated in human LC tissues and cell lines. Low ZNF652 expression was associated with poor survival in LC patients. Overexpression of ZNF652 inhibited cell viability, proliferation, migration, and invasion of LC cells, whereas ZNF652 knockdown promoted these malignant phenotypes. Using RNA-seq analysis revealed that ZNF652 overexpression resulted in obvious alterations of various biological processes, especially cell cycle and cellular senescence. Subsequently, we confirmed that ZNF652 overexpression arrested the cell cycle at the G1 phase, increased ROS-mediated DNA damage, induced LC cell senescence, and enhanced cisplatin-induced apoptosis in LC cells. Mechanistically, ZNF652 directly bound to the promoter of cyclin D3 (CCND3), inhibited its transcription, thereby arresting the cell cycle at the G1 phase. Ectopic expression of cyclin D3 rescued the decreased cell viability and cell cycle arrest induced by ZNF652. In vivo studies further showed that ZNF652 overexpression suppressed the tumorigenic potential of LC. Collectively, our findings reveal that ZNF652 exerts a tumor suppressor role in lung cancer by inducing cell cycle arrest and cellular senescence via transcriptionally downregulating cyclin D3. Thus, ZNF652 may be a prognostic predictive factor for LC patients., (© 2024. The Author(s).)

Nonstop extension mutations, a.k.a. stop-lost or stop-loss mutations, convert a stop codon into a sense codon resulting in translation into the 3' untranslated region until the next in-frame stop codon, thereby extending the C-terminus of a protein. In cancer, only nonstop mutations in SMAD4 have been functionally characterized, while the impact of other nonstop mutations remain unknown. Here, we exploit our pan-cancer NonStopDB dataset and test all 2335 C-terminal extensions arising from somatic nonstop mutations in cancer for their impact on protein expression. In a high-throughput screen, 56.1% of the extensions effectively reduce protein abundance. Extensions of multiple tumor suppressor genes like PTEN, APC, B2M, CASP8, CDKN1B and MLH1 are effective and validated for their suppressive impact. Importantly, the effective extensions possess a higher hydrophobicity than the neutral extensions linking C-terminal hydrophobicity with protein destabilization. Analyzing the proteomes of eleven different species reveals conserved patterns of amino acid distribution in the C-terminal regions of all proteins compared to the proteomes like an enrichment of lysine and arginine and a depletion of glycine, leucine, valine and isoleucine across species and kingdoms. These evolutionary selection patterns are disrupted in the cancer-derived effective nonstop extensions., (© 2024. The Author(s).)

Integrin α7 (ITGA7) is an extracellular matrix-binding protein. Integrins are the main type of cell adhesive molecules in mammals, playing a role in many biological pathways. Although various studies have shown correlations between ITGA7 and various types of cancer, a comprehensive study at a pan-cancer level has not yet been conducted. In this study, we investigated the function of ITGA7 in distinct tumor types using the multi-omics relevant information, then two CeRNA regulatory network was drawn to identify the ITGA7 hub regulatory RNAs. The results indicated that the expression of ITGA7 varies in different tumors. Overexpression of ITGA7 was correlated with a worse OS in BLCA, LGG, and UVM, and the downregulation of ITGA7 was related to a worse OS in PAAD. In addition, BLCA, and UVM showed poor PFS in association with ITGA7 overexpression, and PAAD, SARC, and THCA indicated poor PFS in correlation with ITGA7 under expression. Further analyses of ITGA7 gene alteration data showed that ITGA7 amplifications may have an impact on Kidney Chromophobe prognosis. In 20 types of tumors, ITGA7 expression was linked to cancer-associated fibroblast infiltration. ITGA7 expression was linked to cancer-associated fibroblast infiltration. ITGA7-Related Gene Enrichment Analysis indicated that ITGA7 expression-correlated and functional binding genes were enriched in homotypic cell-cell adhesion, focal adhesion, and ECM-receptor interaction. This pan-cancer study found that abnormal expression of ITGA7 was correlated with poor prognosis and metastasis in different types of tumors. Thus, the ITGA7 gene may prove to be a promising biomarker for the prognosis and complication prevention of different cancers., (© 2024 Federation of American Societies for Experimental Biology.)

Objective: To explore the effect of heterozygous deletion of histone methyltransferase Kmt2c gene on the hematological system of mice., Methods: CRISPR/Cas9 technology was used to construct mice model of Kmt2c heterozygous deletion ( Kmt2c +/- ) and the changes of whole blood cell count in mice were continuously monitored by blood routine test. The clonal expansion ability of bone marrow cells was explored by colony formation assay in vitro and the proportion of primitive hematopoietic cells, including long-term hematopoietic stem cell (LT-HSC), short-term hematopoietic stem cell (ST-HSC), and multipotent progenitor cell in mutant mice was analyzed by flow cytometry., Results: Kmt2c +/- mice model was successfully constructed, and the mRNA expression level of Kmt2c was 28% of that of C57BL/6J mice. The colony formation ability of bone marrow cells of Kmt2c +/- mice in vitro increased with the passage times, and the colony number in the fourth generation was significantly higher than that of control group ( P <0.05). The proportions of LT-HSC and ST-HSC in the primitive hematopoietic cell population of Kmt2c +/- mice was 19.6%±3.3% and 28.9%±4.9%, respectively, which showed an increasing trend compared with 16.9%±2.6% and 18.9%±2.5% in control group, but the difference was not statistically significant ( P >0.05). The white blood cell count of Kmt2c +/- mice gradually increased after 12 weeks of monitoring and reached (9.8±1.0)×10 9 /L at the 14 th week, which was significantly higher than (7.3±1.4)×10 9 /L of control group ( P < 0.05)., Conclusion: The bone marrow cells of Kmt2c +/- mice have potential of clonal expansion.

The term 'tumor suppressor' describes a widely diverse set of genes that are generally involved in the suppression of metastasis, but lead to tumorigenesis upon loss-of-function mutations. Despite the protein products of tumor suppressors exhibiting drastically different structures and functions, many share a common regulatory mechanism-they are molecular chaperone 'clients'. Clients of molecular chaperones depend on an intracellular network of chaperones and co-chaperones to maintain stability. Mutations of tumor suppressors that disrupt proper chaperoning prevent the cell from maintaining sufficient protein levels for physiological function. This review discusses the role of the molecular chaperones Hsp70 and Hsp90 in maintaining the stability and functional integrity of tumor suppressors. The contribution of cochaperones prefoldin, HOP, Aha1, p23, FNIP1/2 and Tsc1 as well as the chaperonin TRiC to tumor suppressor stability is also discussed. Genes implicated in renal cell carcinoma development- VHL , TSC1/2 , and FLCN -will be used as examples to explore this concept, as well as how pathogenic mutations of tumor suppressors cause disease by disrupting protein chaperoning, maturation, and function.

Gastric cancer (GC) is one of the crucial causes of cancer-associated death worldwide. This study aimed to investigate the biological function of miR-1286 in GC progression in vitro, evaluate the clinical value of serum miR-1286 to screen GC patients and explore its relationship with helicobacter pylori (HP) infection and peritoneal metastasis in GC patients. Expression of miR-1286 was measured by RT-qPCR. Cell Counting Kit-8 assay was utilized for measuring GC cell proliferation ability. The migration and invasion abilities of GC cells were measured using Transwell assays. Serum samples were obtained from 108 GC patients, 62 gastritis cases and 62 healthy volunteers. The diagnostic performance of miR-1286 was assessed using ROC analysis, and the predictive value of miR-1286 for peritoneal metastasis onset was analyzed using logistic regression analysis. miR-1286 played as a tumor suppressor in GC progression by inhibiting GC cell proliferation, migration and invasion. In GC patients, significantly decreased miR-1286 was observed compared to gastritis and healthy controls, and had considerable diagnostic accuracy to distinguish GC from the controls. A significant association was found between miR-1286 expression and HP infection, peritoneal metastasis and TNM stage. Moreover, miR-1286 was lowly expressed in GC patients with peritoneal metastasis, and independently predicted the occurrence of peritoneal metastasis in GC. miR-1286 acts as a tumor suppressor and a biomarker in GC, and is closely associated with HP infection and peritoneal metastasis onset. The methods to regulate miR-1286 may be novel strategies to improve the treatment of GC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Primary effusion lymphoma (PEL) is a malignant B-cell lymphoma attributable to Kaposi sarcoma-associated herpesvirus (KSHV) infection. PEL is characterized by invasive behavior, showing recurrent effusions in body cavities. The clinical outcome and typical prognosis in patients with PEL are poor and potentially lethal. Clarification of the pathogenesis in PEL is urgently needed in order to develop novel therapies. PEL cells generally lack B-cell surface markers, and we therefore hypothesized that the B-cell transcription factor, PAX5, would be down-regulated in PEL. The expression of PAX5 is detected from the pro-B to the mature B-cell stage and is indispensable for the differentiation of B-cells. PAX5 was silenced in PEL cells via its promoter methylation. Up-regulation of PAX5 induced several genes coding for B-cell surface marker mRNA, but not protein level. PAX5 inhibited cell growth via G1 cell cycle arrest. PAX5 bound to RB and increased its protein expression. RB/E2F-regulated genes were significantly down-regulated in microarray analysis and PCR experiments. To elucidate the in vivo role of PAX5, we examined the restoration of PAX5 in a PEL mouse model. The ascites volume and organ invasions were significantly suppressed by PAX5 restoration. Reduction of PAX5 has played a crucial role in the oncogenesis of PEL, and PAX5 is a tumor suppressor in PEL. Targeting PAX5 could represent a novel therapeutic strategy for patients with PEL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Alpha T-catenin has recently been identified as a crucial tumor suppressor in various cancer types, with roles that go beyond just providing structural support in adherens junctions. This review brings together recent findings on alpha T-catenin's important involvement in key signaling pathways related to cancer progression. We present strong evidence of its regulatory role in Wnt signaling, a pathway often disrupted in colorectal cancer, and explain how it inhibits cell proliferation and tumor growth. We also discuss the significant downregulation of alpha T-catenin in colorectal cancers and its potential as a prognostic marker. Moreover, this review looks at how increasing alpha T-catenin levels can reduce tumor growth and spread, suggesting new therapeutic strategies. Additionally, we reveal alpha T-catenin's unexpected impact on NF-κB signaling in basal E-cadherin-negative breast cancer, expanding its importance across different cancer types. By bringing these findings together, we provide a thorough understanding of alpha T-catenin's tumor-suppressing actions, setting the stage for new targeted therapies and diagnostic tools in cancer treatment., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Zic family member ZIC4 is a transcription factor that has been shown to be silenced in several cancers. However, understanding the regulation and function of ZIC4 in pediatric choroid plexus tumors (CPTs) remained limited. This study employed data mining and bioinformatics analysis to investigate the DNA methylation status of ZIC4 in CPTs and its correlation with patient survival. Our results unveiled ZIC4 methylation as a segregating factor, dividing CPT cohorts into two clusters, with hyper-methylation linked to adverse prognosis. Hyper-methylation of ZIC4 was confirmed in a choroid plexus carcinoma-derived cell line (CCHE-45) by bisulfite sequencing. Furthermore, our study demonstrated that demethylating agent and a histone methyltransferase inhibitor could reverse ZIC4 silencing. RNA sequencing and proteomic analysis showed that ZIC4 over-expression influenced genes and proteins involved in immune response, antigen processing and presentation, endoplasmic reticulum stress, and metabolism. Functionally, re-expressing ZIC4 negatively impacted cell proliferation and migration. Ultimately, these findings underscore ZIC4 hyper-methylation as a prognostic marker in CPTs and shed light on potential mechanisms underlying its tumor suppressor role in CPC. This insight paves the way for novel therapeutic targets in treating aggressive CPTs., (© 2024. The Author(s).)

Uterine cancer is the most common gynecologic malignancy in the United States, with endometrioid endometrial adenocarcinoma (EC) being the most common histologic sub-type. Considering the molecular classifications of EC, efforts have been made to identify additional biomarkers that can assist in diagnosis, prognosis, and individualized therapy. We sought to explore the relationship of Repressor Element 1 (RE1) silencing transcription factor (REST), which downregulates neuronal genes in non-neuronal tissue, along with matrix metalloproteinase-24 (MMP24) and EC. We analyzed the expression of REST and MMP24 in 31 cases of endometrial cancer and 16 controls. We then explored the baseline expression of REST and MMP24 in two EC cell lines (Ishikawa and HEC-1-A) compared to a benign cell line (t-HESC) and subsequently evaluated proliferation, migration, and invasion in the setting of loss of REST gene expression. REST and MMP24 expression were significantly lower in human EC samples compared to control samples. REST was highly expressed in EC cell lines, but decreasing REST gene expression increased proliferation (FC: 1.13X, p < 0.0001), migration (1.72X, p < 0.0001), and invasion (FC: 7.77X, p < 0.05) in Ishikawa cells, which are hallmarks of cancer progression and metastasis. These findings elicit a potential role for REST as a putative tumor suppressor in EC.

The selenoenzyme type I iodothyronine deiodinase (DIO1) catalyzes removal of iodine atoms from thyroid hormones. Although DIO1 action is reported to be disturbed in several malignancies, no work has been conducted in high-grade serous ovarian carcinoma (HGSOC), the most lethal gynecologic cancer. We studied DIO1 expression in HGSOC patients [The Cancer Genome Atlas (TCGA) data and tumor tissues], human cell lines (ES-2 and Kuramochi), normal Chinese hamster ovarian cells (CHO-K1), and normal human fallopian tube cells (FT282 and FT109). To study its functional role, DIO1 was overexpressed, inhibited [by propylthiouracil (PTU)], or knocked down (KD), and cell count, proliferation, apoptosis, cell viability, and proteomics analysis were performed. Lower DIO1 levels were observed in HGSOC compared to normal cells and tissues. TCGA analyses confirmed that low DIO1 mRNA expression correlated with worse survival and therapy resistance in patients. Silencing or inhibiting the enzyme led to enhanced ovarian cancer proliferation, while an opposite effect was shown following DIO1 ectopic expression. Proteomics analysis in DIO1-KD cells revealed global changes in proteins that facilitate tumor metabolism and progression. In conclusion, DIO1 expression and ovarian cancer progression are inversely correlated, highlighting a tumor suppressive role for this enzyme and its potential use as a biomarker in this disease., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Copyright of Lijecnicki Vjesnik is the property of Croatian Medical Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background/Aims Overwhelming evidence suggests that inflammatory bowel disease (IBD) is caused by a complicated interplay between the multiple genes and abnormal epigenetic regulation in response to environmental factors. It is becoming apparent that epigenetic factors are significantly associated with the development of the disease. DNA methylation remains the most studied epigenetic modification, and hypermethylation of gene promoters is associated with gene silencing. Methods DNA methylation alterations may contribute to the many complex diseases development by regulating the interplay between external and internal environmental factors and gene transcriptional expression. In this study, we used 15 tumor suppressor genes (TSGs), originally identified in colon cancer, to detect promoter methylation in patients with Crohn’s disease (CD). Methylation specific polymerase chain reaction and bisulfite sequencing analyses were performed to assess methylation level of TSGs in CD patients. Results We found 6 TSGs (sFRP1, sFRP2, sFRP5, TFPI2, Sox17, and GATA4) are robustly hypermethylated in CD patient samples. Bisulfite sequencing analysis confirmed the methylation levels of the sFRP1, sFRP2, sFRP5, TFPI2, Sox17, and GATA4 promoters in the representative CD patient samples. Conclusions In this study, the promoter hypermethylation of the TSGs observed indicates that CD exhibits specific DNA methylation signatures with potential clinical applications for the noninvasive diagnosis of IBD and the prognosis for patients with IBD.

Objective Several studies have examined biological markers during the first trimester to predict the maintenance of a healthy pregnancy. One such marker is kisspeptin, which is encoded by the KISS-1 gene. We aimed to determine whether first-trimester pregnancy losses were associated with levels of placental KISS-1 expression. Methods This prospective case control study was conducted at a tertiary center. The study group included 27 and 24 patients who underwent dilation and curettage at

Tumor suppressor genes play critical roles in normal tissue homeostasis, and their dysregulation underlies human diseases including cancer. Besides human genetics, model organisms such as Drosophila have been instrumental in discovering tumor suppressor pathways that were subsequently shown to be highly relevant in human cancer. Here we show that hyperplastic disc (Hyd), one of the first tumor suppressors isolated genetically in Drosophila and encoding an E3 ubiquitin ligase with hitherto unknown substrates, and Lines (Lin), best known for its role in embryonic segmentation, define an obligatory tumor suppressor protein complex (Hyd-Lin) that targets the zinc finger-containing oncoprotein Bowl for ubiquitin-mediated degradation, with Lin functioning as a substrate adaptor to recruit Bowl to Hyd for ubiquitination. Interestingly, the activity of the Hyd-Lin complex is directly inhibited by a micropeptide encoded by another zinc finger gene, drumstick ( drm ), which functions as a pseudosubstrate by displacing Bowl from the Hyd-Lin complex, thus stabilizing Bowl. We further identify the epigenetic regulator Polycomb repressive complex1 (PRC1) as a critical upstream regulator of the Hyd-Lin-Bowl pathway by directly repressing the transcription of the micropeptide drm Consistent with these molecular studies, we show that genetic inactivation of Hyd, Lin, or PRC1 resulted in Bowl-dependent hyperplastic tissue overgrowth in vivo. We also provide evidence that the mammalian homologs of Hyd (UBR5, known to be recurrently dysregulated in various human cancers), Lin (LINS1), and Bowl (OSR1/2) constitute an analogous protein degradation pathway in human cells, and that OSR2 promotes prostate cancer tumorigenesis. Altogether, these findings define a previously unrecognized tumor suppressor pathway that links epigenetic program to regulated protein degradation in tissue growth control and tumorigenesis., (© 2024 Wen et al.; Published by Cold Spring Harbor Laboratory Press.)

Abstract: Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Family with sequence similarity 122a (FAM122A), identified as an endogenous inhibitor of protein phosphatase 2A (PP2A) previously, is involved in multiple important physiological processes, and essential for the growth of acute myeloid leukemia and hepatocellular carcinoma cells. However, the function of FAM122A in oral squamous cell carcinoma (OSCC) is undetermined. In this study, by analyzing TCGA and GEO databases, we found that the expression of FAM122A was significantly down-regulated in head and neck squamous cell carcinoma and OSCC patients, meanwhile this low expression was tightly associated with the poor prognosis and advanced clinical stage during OSCC development. The similar low expression pattern of FAM122A could also been seen in OSCC cell lines compared with normal human oral keratinocytes. Further, we demonstrated that FAM122A knockdown significantly promoted the growth, clonogenic potential as well as migration capabilities of OSCC cells, while these alterations could be rescued by the re-expression of FAM122A. Over-expression of FAM122A suppressed OSCC cell proliferation and migration. FAM122A also inhibited the epithelial-mesenchymal transition (EMT) in OSCC cells by the up-regulation of epithelial marker E-cadherin and down-regulation of mesenchymal markers Fibronectin and Vimentin, which is presumably mediated by transforming growth factor β receptor 3 (TGFBR3), a novel tumor suppressor. In addition, FAM122A could induce T cell infiltration in OSCC, indicating that FAM122A might influence the immune cell activity of tumor environment and further interfere the tumor development. Collectively, our results suggest that FAM122A functions as a tumor suppressor in OSCC and possibly acts as a predictive biomarker for the diagnosis and/or treatment of OSCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: While melanomas commonly harbor losses of 9p21, on which CDKN2A resides, the presence of additional tumor suppressor elements at this locus is incompletely characterized. Here we assess the expression levels and functional role of microRNA-876-3p (miR-876), whose gene also maps to 9p21., Methods: Expression of miR-876 was assessed in human tissues and cell lines using quantitative miRNA reverse transcriptase polymerase chain reaction (qRT-PCR). MIR876 copy number was determined in The Cancer Genome Atlas (TCGA) melanoma cohort. The consequences of regulation of miR-876 expression were assessed on melanoma cell colony formation, migration, invasion, apoptosis, cell cycle progression, and drug sensitivity in culture, and on in vivo tumor growth in a xenograft model. Genome-wide transcriptomic changes induced by miR-876 overexpression were determined using RNA sequencing (RNA-Seq)., Results: miR-876 expression was significantly decreased in primary melanoma samples when compared with nevi, and in human melanoma cell lines when compared with human melanocytes. Analysis of the TCGA cohort revealed deletions in MIR876 in > 50% of melanomas. miR-876 overexpression resulted in decreased melanoma cell colony formation, migration, and invasion, which was accompanied by cell cycle arrest and increased apoptosis. Intra-tumoral injections of miR-876 significantly suppressed melanoma growth in vivo. RNA-Seq analysis of miR-876-treated tumors revealed downregulation of several growth-promoting genes, along with upregulation of tumor suppressor genes, which was confirmed by qRT-PCR analysis. Computational analyses identified MAPK1 (or ERK2) as a possible target of miR-876 action. Overexpression of miR-876 significantly suppressed luciferase expression driven by the MAPK1/ERK2 3' UTR, and resulted in decreased ERK protein expression in melanoma cells. MAPK1/ERK2 cDNA overexpression rescued the effects of miR-876 on melanoma colony formation. miR-876 overexpression sensitized melanoma cells to treatment with the BRAF inhibitor vemurafenib., Conclusions: These studies identify miR-876 as a distinct tumor suppressor on 9p21 that is inactivated in melanoma and suggest miR-876 loss as an additional mechanism to activate ERK and the mitogen activated protein kinase (MAPK) pathway in melanoma. In addition, they suggest the therapeutic potential of combining miR-876 overexpression with BRAF inhibition as a rational therapeutic strategy for melanoma., (© 2024. The Author(s).)

Background: Identification of driver mutations and development of targeted therapies has considerably improved outcomes for lung cancer patients. However, significant limitations remain with the lack of identified drivers in a large subset of patients. Here, we aimed to assess the genomic landscape of lung adenocarcinomas (LUADs) from individuals without a history of tobacco use to reveal new genetic drivers of lung cancer., Methods: Integrative genomic analyses combining whole-exome sequencing, copy number, and mutational information for 83 LUAD tumors was performed and validated using external datasets to identify genetic variants with a predicted functional consequence and assess association with clinical outcomes. LUAD cell lines with alteration of identified candidates were used to functionally characterize tumor suppressive potential using a conditional expression system both in vitro and in vivo., Results: We identified 21 genes with evidence of positive selection, including 12 novel candidates that have yet to be characterized in LUAD. In particular, SNF2 Histone Linker PHD RING Helicase (SHPRH) was identified due to its frequency of biallelic disruption and location within the familial susceptibility locus on chromosome arm 6q. We found that low SHPRH mRNA expression is associated with poor survival outcomes in LUAD patients. Furthermore, we showed that re-expression of SHPRH in LUAD cell lines with inactivating alterations for SHPRH reduces their in vitro colony formation and tumor burden in vivo. Finally, we explored the biological pathways associated SHPRH inactivation and found an association with the tolerance of LUAD cells to DNA damage., Conclusions: These data suggest that SHPRH is a tumor suppressor gene in LUAD, whereby its expression is associated with more favorable patient outcomes, reduced tumor and mutational burden, and may serve as a predictor of response to DNA damage. Thus, further exploration into the role of SHPRH in LUAD development may make it a valuable biomarker for predicting LUAD risk and prognosis., (© 2024. The Author(s).)

Mutually exclusive loss-of-function alterations in gene pairs are those that occur together less frequently than may be expected and may denote a synthetically lethal relationship (SSL) between the genes. SSLs can be exploited therapeutically to selectively kill cancer cells. Here, we analysed mutation, copy number variation, and methylation levels in samples from The Cancer Genome Atlas, using the hypergeometric and the Poisson binomial tests to identify mutually exclusive inactivated genes. We focused on gene pairs where one is an inactivated tumour suppressor and the other a gene whose protein product can be inhibited by known drugs. This provided an abundance of potential targeted therapeutics and repositioning opportunities for several cancers. These data are available on the MexDrugs website, https://bioinformaticslab.sussex.ac.uk/mexdrugs., (© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Glioblastomas derived from malignant astrocytes are the most common primary tumors of the central nervous system in humans, exhibiting very bad prognosis. Treatment with surgery, radiotherapy, and chemotherapy (mainly using temozolomide), generates as much one-year survival. The circadian clock controls different aspects of tumor development, and its role in GBM is beginning to be explored. Here, the role of the canonic circadian clock gene bmal1 was studied in vivo in a nude mice model bearing human GBMs from LN229 cells xenografted orthotopically in the dorsal striatum. For that aim, a bmal1 knock-down was generated in LN229 cells by CRISPR/Cas9 gene editing tool, and tumor progression was followed in male mice by measuring survival, tumor growth, cell proliferation and prognosis with CD44 marker, as well as astrocyte activation in the tumor microenvironment with GFAP and nestin markers. Disruption of bmal1 in the tumor decreased survival, increased tumor growth and CD44 expression, worsened motor performance, as well as increased GFAP expression in astrocytes at tumor microenvironment. In addition, survival and tumor progression was not affected in mice bearing LN229 wild type GBM that underwent circadian disruption by constant light, as compared to mice synchronized to 12:12 light-dark cycles. These results consistently demonstrate in an in vivo orthotopic model of human GBM, that bmal1 has a key role as a tumor suppressor gene regulating GBM progression., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Recent research indicates a positive correlation between DEP structural domain-containing 1B (DEPDC1B) and the cell cycle in various tumors. However, the role of DEPDC1B in the infiltration of the tumor immune microenvironment (TIME) remains unexplored., Methods: We analyzed the differential expression and prognostic significance of DEPDC1B in colon adenocarcinoma (COAD) using the R package "limma" and the Gene Expression Profiling Interactive Analysis (GEPIA) website. Gene set enrichment analysis (GSEA) was employed to investigate the functions and interactions of DEPDC1B expression in COAD. Cell Counting Kit-8 (CCK-8) assays and colony formation assays were utilized to assess the proliferative function of DEPDC1B. Correlations between DEPDC1B expression and tumor-infiltrating immune cells, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI) status were examined using Spearman correlation analysis and CIBERSORT., Results: DEPDC1B was highly expressed in COAD. Elevated DEPDC1B expression was associated with lower epithelial-to-mesenchymal transition (EMT) and TNM stages, leading to a favorable prognosis. DEPDC1B mRNA was prominently expressed in COAD cell lines. CCK-8 and colony formation assays demonstrated that DEPDC1B inhibited the proliferation of COAD cells. Analysis using the CIBERSORT database and Spearman correlation revealed that DEPDC1B correlated with four types of tumor-infiltrating immune cells. Furthermore, high DEPDC1B expression was linked to the expression of PD-L1, CTLA4, SIGLEC15, PD-L2, TMB, and MSI-H. High DEPDC1B expression also indicated responsiveness to anti-PD-L1 immunotherapy., Conclusions: DEPDC1B inhibits the proliferation of COAD cells and positively regulates the cell cycle, showing a positive correlation with CCNB1 and PBK expression. DEPDC1B expression in COAD is associated with tumor-infiltrating immune cells, immune checkpoints, TMB, and MSI-H in the tumor immune microenvironment. This suggests that DEPDC1B may serve as a novel prognostic marker and a potential target for immunotherapy in COAD., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Transmembrane proteins play key roles in the development of lung cancer. The family with sequence similarity 189 member A2 (FAM189A2) gene encodes a transmembrane structural protein, yet its involvement in lung adenocarcinoma remains largely unexplored. This study elucidated its role in lung adenocarcinoma and its possible molecular mechanism. Our findings revealed diminished expression levels of FAM189A2 in LUAD tissues. Additionally, the activity of LUAD cells was significantly inhibited by overexpression of FAM189A2. Following FAM189A2 overexpression, the expression of OCLN and TJP2 was upregulated in LUAD cells, while CXCR4 expression experiences a notable decrease. Moreover, the coimmunoprecipitation experiment confirmed the direct interaction between FAM189A2 and CXCR4. The infiltration levels of T cells (CD4+ memory resting, CD8+, regulatory), NK cells, B memory cells, endothelial cells and cancer-associated fibroblasts were significantly correlated with FAM189A2 expression. These results indicate FAM189A2 may act as a tumour suppressor in LUAD through tight junction protein (TJP) and CXCR4 regulation. Moreover, FAM189A2 is significantly correlated with the immune microenvironment of LUAD, which may be involved in prognosis and immunotherapeutic efficacy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To explore the role of ferroptosis-related genes in regulating ferroptosis of esophageal squamous cell carcinoma (ESCC)., Methods: ESCC datasets GSE161533 and GSE20347 were downloaded from the Gene Expression Omnibus (GEO) to identify the differentially expressed genes (DEGs) using R software. ESCC ferroptosis-related genes obtained by intersecting the DEGs with ferroptosis-related genes from FerrDb were analyzed using GO and KEGG analyses, protein-protein interaction (PPI) network analysis, and core gene identification through Cytoscape. The identified ferroptosis suppressor genes were validated using TCGA database, and their expression levels were detected using RT-qPCR in cultured normal esophageal cells and ESCC cells. Six ferroptosis suppressor genes (RRM2, GCLC, TFRC, TXN, SLC7A11, and EZH2) were downregulated with siRNA in ESCC cells, and the changes in cell proliferation and apoptosis were assessed with CCK8 assay and flow cytometry; Western blotting was performed to examine the changes in ferroptosis progression of the cells., Results: We identified a total of 58 ESCC ferroptosis-related genes, which involved such biological processes as glutathione transmembrane transport, iron ion transport, and apoptosis and the ferroptosis, glutathione metabolism, and antifolate resistance pathways. The PPI network included 54 nodes and 74 edges with a clustering coefficient of 0.522 and PPI enrichment P <0.001. Cytoscape identified 6 core ferroptosis suppressor genes (RRM2, TFRC, TXN, EZH2, SLC7A11, and GCLC), which were highly expressed in ESCC tissues in the TCGA dataset and in ESCC cell lines. Downregulating these genes in ESCC TE1 cells significantly inhibited cell proliferation, promoted cell apoptosis, reduced the expression levels of ferroptosis markers GPX4 and FIH1, and increased the expression of ACSL4., Conclusion: High expression of ferroptosis suppressor genes in ESCC may cause arrest of ferroptosis progression to facilitate tumor development, and inhibiting these genes can restore ferroptosis and promote cell apoptosis, suggesting their value as potential therapeutic targets for ESCC.

Cancer driver genes can undergo positive selection for various types of genetic alterations, including gain-of-function or loss-of-function mutations and copy number alterations (CNA). We investigated the landscape of different types of alterations affecting driver genes in 17,644 cancer exomes and genomes. We find that oncogenes may simultaneously exhibit signatures of positive selection and also negative selection in different gene segments, suggesting a method to identify additional tumor types where an oncogene is a driver or a vulnerability. Next, we characterize the landscape of CNA-dependent selection effects, revealing a general trend of increased positive selection on oncogene mutations not only upon CNA gains but also upon CNA deletions. Similarly, we observe a positive interaction between mutations and CNA gains in tumor suppressor genes. Thus, two-hit events involving point mutations and CNA are universally observed regardless of the type of CNA and may signal new therapeutic opportunities. An analysis with focus on the somatic CNA two-hit events can help identify additional driver genes relevant to a tumor type. By a global inference of point mutation and CNA selection signatures and interactions thereof across genes and tissues, we identify 9 evolutionary archetypes of driver genes, representing different mechanisms of (in)activation by genetic alterations., (© 2024. The Author(s).)

MDS1 and EVI1 complex locus (MECOM), a transcription factor encoding several variants, has been implicated in progression of ovarian cancer. The function of regulatory regions in regulating MECOM expression in ovarian cancer is not fully understood. In this study, MECOM expression was evaluated in ovarian cancer cell lines treated with bromodomain and extraterminal (BET) inhibitor JQ-1. Oncogenic phenotypes were assayed using assays of CCK-8, colony formation, wound-healing and transwell. Oncogenic phenotypes were estimated in stable sgRNA-transfected OVCAR3 cell lines. Xenograft mouse model was assayed via subcutaneous injection of enhancer-deleted OVCAR3 cell lines. The results displayed that expression of MECOM is downregulated in cell lines treated with JQ-1. Data from published ChIP-sequencing (H3K27Ac) in 3 ovarian cancer cell lines displayed a potential enhancer around the first exon. mRNA and protein expression were downregulated in OVCAR3 cells after deletion of the MECOM enhancer. Similarly, oncogenic phenotypes both in cells and in the xenograft mouse model were significantly attenuated. This study demonstrates that JQ-1 can inhibit the expression of MECOM and tumorigenesis. Deletion of the enhancer activity of MECOM has an indispensable role in inhibiting ovarian cancer progress, which sheds light on a promising opportunity for ovarian cancer treatment through the application of this non-coding DNA deletion., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Breast invasive carcinoma (BRCA) is the most malignant and leading cause of death in women. Global efforts are ongoing for improvement in early detection, prevention, and treatment. In this milieu, a comprehensive analysis of RNA-sequencing data of 1097 BRCA samples and 114 normal adjacent tissues is done to identify dysregulated genes in major molecular classes of BRCA in various clinical stages. Significantly enriched pathways in distinct molecular classes of BRCA have been identified. Pathways such as interferon signaling, tryptophan degradation, granulocyte adhesion & diapedesis, and catecholamine biosynthesis were found to be significantly enriched in Estrogen/Progesterone Receptor positive/Human Epidermal Growth Factor Receptor 2 negative, pathways such as RAR activation, adipogenesis, the role of JAK1/2 in interferon signaling, TGF-β and STAT3 signaling intricated in Estrogen/Progesterone Receptor negative/Human Epidermal Growth Factor Receptor 2 positive and pathways as IL-1/IL-8, TNFR1/TNFR2, TWEAK, and relaxin signaling were found in triple-negative breast cancer. The dysregulated genes were clustered based on their mutation frequency which revealed nine mutated clusters, some of which were well characterized in cancer while others were less characterized. Each cluster was analyzed in detail which led to the identification of NLGN3, MAML2, TTN, SYNE1, ANK2 as candidate genes in BRCA. They are central hubs in the protein-protein-interaction network, indicating their important regulatory roles. Experimentally, the Real-Time Quantitative Reverse Transcription PCR and western blot confirmed our computational predictions in cell lines. Further, immunohistochemistry corroborated the results in ~ 100 tissue samples. We could experimentally show that the NLGN3 & ANK2 have tumor-suppressor roles in BRCA as shown by cell viability assay, transwell migration, colony forming and wound healing assay. The cell viability and migration was found to be significantly reduced in MCF7 and MDA-MB-231 cell lines in which the selected genes were over-expressed as compared to control cell lines. The wound healing assay also demonstrated a significant decrease in wound closure at 12 h and 24 h time intervals in MCF7 & MDA-MB-231 cells. These findings established the tumor suppressor roles of NLGN3 & ANK2 in BRCA. This will have important ramifications for the therapeutics discovery against BRCA., (© 2024. The Author(s).)

Neuroblastoma is a childhood developmental cancer; however, its embryonic origins remain poorly understood. Moreover, in-depth studies of early tumor-driving events are limited because of the lack of appropriate models. Herein, we analyzed RNA sequencing data obtained from human neuroblastoma samples and found that loss of expression of trunk neural crest-enriched gene MOXD1 associates with advanced disease and worse outcome. Further, by using single-cell RNA sequencing data of human neuroblastoma cells and fetal adrenal glands and creating in vivo models of zebrafish, chick, and mouse, we show that MOXD1 is a determinate of tumor development. In addition, we found that MOXD1 expression is highly conserved and restricted to mesenchymal neuroblastoma cells and Schwann cell precursors during healthy development. Our findings identify MOXD1 as a lineage-restricted tumor-suppressor gene in neuroblastoma, potentiating further stratification of these tumors and development of novel therapeutic interventions.

Background: TMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. However, its association with lung cancer remains insufficiently unexplored., Methods: In five bulk transcriptomics datasets, one single-cell RNA sequencing (scRNA-seq) dataset and one proteomics dataset for lung adenocarcinoma (LUAD), we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, genomic features, and clinical prognosis in LUAD by the bioinformatics approach. Furthermore, we performed experimental validation of the bioinformatics findings., Results: TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios of immune-stimulatory/immune-inhibitory signatures. It indicated that TMPRSS2 levels had a stronger negative correlation with immune-inhibitory than with immune-stimulatory signatures. TMPRSS2 downregulation correlated with increased proliferation, stemness, genomic instability, tumor progression, and worse survival in LUAD. We further validated that TMPRSS2 was downregulated with tumor progression in the LUAD cohort we collected from Jiangsu Cancer Hospital, China. In vitro and in vivo experiments verified the association of TMPRSS2 deficiency with increased tumor cell proliferation and invasion and antitumor immunity in LUAD. Moreover, in vivo experiments demonstrated that TMPRSS2-knockdown tumors were more sensitive to BMS-1, an inhibitor of PD-1/PD-L1., Conclusions: TMPRSS2 is a tumor suppressor, while its downregulation is a positive biomarker of immunotherapy in LUAD. Our data provide a potential link between lung cancer and pneumonia caused by SARS-CoV-2 infection., (© 2024. The Author(s).)

Cells of multicellular organisms generate heterogeneity in a controlled and transient fashion during embryogenesis, which can be reactivated in pathologies such as cancer. Although genomic heterogeneity is an important part of tumorigenesis, continuous generation of phenotypic heterogeneity is central for the adaptation of cancer cells to the challenges of tumorigenesis and response to therapy. Here I discuss the capacity of generating heterogeneity, hereafter called cell hetness, in cancer cells both as the activation of hetness oncogenes and inactivation of hetness tumor suppressor genes, which increase the generation of heterogeneity, ultimately producing an increase in adaptability and cell fitness. Transcriptomic high hetness states in therapy-tolerant cell states denote its importance in cancer resistance to therapy. The definition of the concept of hetness will allow the understanding of its origins, its control during embryogenesis, its loss of control in tumorigenesis and cancer therapeutics and its active targeting., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To uncover the mechanisms underlying the development of colorectal cancer (CRC), we applied bioinformatic analyses to identify key genes and experimentally validated their possible roles in CRC onset and progression., Methods: We performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis on differentially expressed genes (DEGs), constructed a protein-protein interaction (PPI) network to find the top 10 hub genes, and analyzed their expression in colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ). We also studied the correlation between these genes and immune cell infiltration and prognosis and validated the expression of SLC9A2 in CRC tissues and cell lines using qRT-PCR and Western blotting. Functional experiments were conducted in vitro to investigate the effects of SLC9A2 on tumor growth and metastasis., Results: We found 130 DEGs, with 45 up-regulated and 85 down-regulated in CRC. GO analysis indicated that these DEGs were primarily enriched in functions related to the regulation of cellular pH, zymogen granules, and transmembrane transporter activity. KEGG pathway analysis revealed that the DEGs played pivotal roles in pancreatic secretion, rheumatoid arthritis, and the IL-17 signaling pathway. We identified 10 hub genes: CXCL1, SLC26A3, CXCL2, MMP7, MMP1, SLC9A2, SLC4A4, CLCA1, CLCA4, and ZG16. GO enrichment analysis showed that these hub genes were predominantly involved in the positive regulation of transcription. Gene expression analysis revealed that CXCL1, CXCL2, MMP1, and MMP7 were highly expressed in CRC, whereas CLCA1, CLCA4, SLC4A4, SLC9A2, SLC26A3, and ZG16 were expressed at lower levels. Survival analysis revealed that 5 key genes were significantly associated with the prognosis of CRC. Both mRNA and protein expression levels of SLC9A2 were markedly reduced in CRC tissues and cell lines. Importantly, SLC9A2 overexpression in SW480 cells led to a notable inhibition of cell proliferation, migration, and invasion. Western blotting analysis revealed that the expression levels of phosphorylated ERK (p-ERK) and phosphorylated JNK (p-JNK) proteins were significantly increased, whereas there were no significant changes in the expression levels of ERK and JNK following SLC9A2 overexpression. Correlation analysis indicated a potential link between SLC9A2 expression and the MAPK signaling pathway., Conclusion: Our study suggests that SLC9A2 acts as a tumor suppressor through the MAPK pathway and could be a potential target for CRC diagnosis and therapy., (© 2024. Huazhong University of Science and Technology.)

Background/aim: Gastric cancer, with its high global incidence and mortality rates, poses a significant challenge due to the rapid decline in patient survival upon metastasis. Understanding and combating metastasis are crucial in improving outcomes. The metastasis suppressor gene CD82 has demonstrated efficacy in inhibiting metastasis across various carcinomas but is frequently down-regulated. However, its role and regulatory mechanisms in gastric cancer remain elusive., Materials and Methods: Utilizing public data, we assessed patient survival in relation to CD82 expression. CD82 expression in gastric cancer cell lines was evaluated via western blotting, and its impact on cell mobility was assessed through wound healing and Transwell assays. The demethylation of CD82 was induced using 5-aza-deoxycytidine, while methylation levels were detected via methylation-specific PCR., Results: Low CD82 expression correlated with poor prognosis in patients, and down-regulation and over-expression of CD82 significantly affected cell mobility. Treatment with 5-aza-deoxycytidine restored CD82 expression in low-expressing cell lines, highlighting its methylation-dependent regulation., Conclusion: CD82 serves as a pivotal regulator of cell mobility in gastric cancer by suppressing metastasis. Its expression is attenuated in gastric cancer cells through promoter hypermethylation., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Cervical cancer (CC) is a key contributor to cancer-related mortality in several countries. The identification of molecular markers and the underlying mechanism may help improve CC management. We studied the regulation and biological function of the chromosome 14 microRNA cluster (C14MC; miR-379/miR-656) in CC. Most C14MC members exhibited considerably lower expression in CC tissues and cell lines in The Cancer Genome Atlas (TCGA) cervical squamous cell carcinoma and endocervical adenocarcinoma patient cohorts. Bisulfite Sanger sequencing revealed hypermethylation of the C14MC promoter in CC tissues and cell lines. 5-aza-2 deoxy cytidine treatment reactivated expression of the C14MC members. We demonstrated that C14MC is a methylation-regulated miRNA cluster via artificial methylation and luciferase reporter assays. C14MC downregulation correlated with poor overall survival and may promote metastasis. C14MC activation via the lentiviral-based CRISPRa approach inhibited growth, proliferation, migration, and invasion; enhanced G2/M arrest; and induced senescence. Post-transcriptional regulatory network analysis of C14MC transcriptomic data revealed enrichment of key cancer-related pathways, such as metabolism, the cell cycle, and phosphatidylinositol 3-kinase (PI3K)-AKT signaling. Reduced cell proliferation, growth, migration, invasion, and senescence correlated with the downregulation of active AKT, MYC, and cyclin E1 (CCNE1) and the overexpression of p16, p21, and p27. We showed that C14MC miRNA activation increases reactive oxygen species (ROS) levels, intracellular Ca 2+ levels, and lipid peroxidation rates, and inhibits epithelial-mesenchymal transition (EMT). C14MC targets pyruvate dehydrogenase kinase-3 (PDK3) according to the luciferase reporter assay. PDK3 is overexpressed in CC and is inversely correlated with C14MC. Both miR-494-mimic transfection and C14MC activation inhibited PDK3 expression. Reduced glucose uptake and lactate production, and upregulation of PDK3 upon C14MC activation suggest the potential role of these proteins in metabolic reprogramming. Finally, we showed that C14MC activation may inhibit EMT signaling. Thus, C14MC is a tumor-suppressive and methylation-regulated miRNA cluster in CC. Reactivation of C14MC can be useful in the management of CC., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Cervical cancer is one of the malignant tumors in women, and the pathogenesis and related pathway molecules have been studied more and more deeply. Among them, the research on Wnt/β-catenin signaling pathway has attracted great attention. The Wnt/β-catenin signaling pathway involves a wide range of physiological and pathological processes, including cell growth, differentiation, ontogeny, migration, genetic stability, apoptosis, stem cell self-renewal, and maintenance of adult tissue homeostasis. Stable β-catenin is accumulated in the cytoplasm and transferred to the nucleus, which activates the Wnt/ β-catenin signaling pathway and is one of the inducing factors of multiple cancers. The accumulation of β-catenin occupies a core position in the Wnt/β-catenin signaling pathway. β-catenin drives target genes through Wnt/β-catenin signaling pathway and participates in the multi -step occurrence and development of cervical cancer. DKK3 may inhibit the Wnt/β -catenin signaling pathway by degrading β-catenin, blocking the nuclear transport of β-catenin, and thus become a potential key role in the inhibition of cervical cancer. Therefore, it is particularly important to study the relationship between DKK3, Wnt/β-catenin signaling pathway and cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1's clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing.Methods: To estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1's National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes' overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data.Results: In our cohort the utility of NF1's clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes' diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist.Conclusions: Early diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge. [ABSTRACT FROM AUTHOR]

BackgroundWe previously reported the frequent neurofibromatosis 2 (NF2) gene mutations in anaplastic thyroid cancers in association with the BRAFV600E mutation. We aimed to investigate the role of NF2 in thyroid cancer with BRAF mutation.MethodsTo identify the function of NF2 in thyroid cancers, we investigated the changes in cell proliferation, colon formation, migration and invasion of thyroid cancer cells (8505C, BHT101, and KTC-1) with BRAFV600E mutation after overexpression and knock-down of NF2. We also examined how cell proliferation changed when NF2 was mutagenized. Human NF2 expression in papillary thyroid carcinoma (PTC) was analyzed using the The Cancer Genome Atlas (TCGA) data.ResultsFirst, NF2 was overexpressed in 8505C and KTC-1 cells. Compared to control, NF2 overexpressed group of both thyroid cancer cells showed significant inhibition in cell proliferation and colony formation. These results were also confirmed by cell migration and invasion assay. After knock-down of NF2 in 8505C cells, there were no significant changes in cell proliferation and colony formation, compared with the control group. However, after mutagenized S288* and Q470* sites of NF2 gene, the cell proliferation increased compared to NF2 overexpression group. In the analysis of TCGA data, the mRNA expression of NF2 was significantly decreased in PTCs with lateral cervical lymph node (LN) metastasis compared with PTCs without LN metastasis.ConclusionOur study suggests that NF2 might play a role as a tumor suppressor in thyroid cancer with BRAF mutation. More studies are needed to elucidate the mechanism how NF2 acts in thyroid cancer with BRAF mutation.

To investigate the role of Linc00891 in osteosarcoma (OS) and its mechanism. Methods The expressions of Linc00891 in different OS cell lines U-2 OS, Saos-2, MG-63, SW 1353 and human osteoblast cell line hFOB 1.19 were detected by qPCR. Saos-2 and MG-63 OS cell lines were transfected with Linc00891 vector. CCK-8 method, plate cloning method and Transwell chamber were used to detect the effects of Linc00891 overexpression on the proliferation, colony forming ability and migration ability. Western blot assay was used to detect the expressions of E-cadherin (E-cad) and N-cadherin (N-cad) related to epithelial-mesenchymal transition. RNA pulldown assay was used to detect the binding relationship between Linc00891 and miR-27a-3p in OS cells. TCF/LEF Reporter Kit was used to detect the effects of overexpression of Linc00891 and up-regulation of miR-27a-3p on Wnt/β-catenin signaling pathway in different OS cell lines. Results The expression levels of Linc00891 in different OS cell lines U-2 OS, Saos-2, MG-63 and SW 1353 were significantly lower than those in normal osteoblast cell line hFOB 1.19 (P＜0.05). The overexpression of Linc00891 could inhibit the proliferation, clone formation, migration and epithelial mesenchymal transition of human OS cell lines Saos-2 and MG-63 (P＜0.05). There was a binding relationship between Linc00891 and miR-27a-3p in OS cells. The overexpression of Linc00891 could reverse the activation of miR-27a-3p on Wnt/β -catenin signaling pathway (P＜0.05). Conclusion Linc00891 plays an anti-tumor role in OS by competitively binding and inhibiting miR-27a-3p. [ABSTRACT FROM AUTHOR]

The detection of DNA methylation at cytosine/guanine dinucleotide (CpG) islands in promoter regions of tumor suppressor genes has great potential for early cancer screening, diagnosis, and prognosis monitoring. Nevertheless, achieving accurate, sensitive, cost-effective, and quantitative detection of target methylated DNA remains challenging. Herein, we propose a novel piezoelectric sensor (series piezoelectric quartz crystal (SPQC)) based on transcription activator-like effectors (TALEs) for detecting DNA methylation of Ras association domain family 1 isoform A (RASSF1A) tumor suppressor genes (R-5mC). The sensor employs TALEs-Ni magnetic beads to specifically recognize and separate the R-5mC, thereby improving the detection selectivity. The TALEs-Ni magnetic beads-R-5mC complex is sheared by a nucleic acid enzyme (DNAzyme) to release the single-stranded DNA (ST). ST initiates a catalyzed hairpin assembly (CHA) reaction on the surface of the electrode, which in turn triggers the hybridization chain reaction (HCR) and silver staining for enhanced detection sensitivity. The strategy exhibits a linear response in the detection of R-5mC in the range of 1 fM to 1 nM with a detection limit of 0.79 fM. R-5mC as low as 0.01% can be detected, even in the presence of large numbers of unmethylated DNA. The detection of R-5mC in circulating cell-free DNA (cfDNA) derived from clinical plasma specimens of lung cancer patients yielded satisfactory results.

Li-Fraumeni syndrome is caused by inherited TP53 tumor suppressor gene mutations. MicroRNA miR-34a is a p53 target and modifier gene. Interestingly, miR-34 triple-null mice exhibit normal p53 responses and no overt cancer development, but the lack of miR-34 promotes tumorigenesis in cancer-susceptible backgrounds. miR-34 genes are highly conserved and syntenic between zebrafish and humans. Zebrafish miR-34a and miR-34b/c have similar expression timing in development, but miR-34a is more abundant. DNA damage by camptothecin led to p53-dependent induction of miR-34 genes, while miR-34a mutants were adult-viable and had normal DNA damage-induced apoptosis. Nevertheless, miR-34a-/- compound mutants with a gain-of-function tp53R217H/ R217H or tp53-/- mutants were more cancer-prone than tp53 mutants alone, confirming the tumor-suppressive function of miR-34a. Through transcriptomic comparisons at 28 hours post-fertilization (hpf), we characterized DNA damage-induced transcription, and at 8, 28 and 72 hpf we determined potential miR-34a-regulated genes. At 72 hpf, loss of miR-34a enhanced erythrocyte levels and up-regulated myb-positive hematopoietic stem cells. Overexpression of miR-34a suppressed its reporter mRNA, but not p53 target induction, and sensitized injected embryos to camptothecin but not to γ-irradiation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Prykhozhij et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recent studies have revealed that arginine is the most favorable target of amino acid alteration in most cancer types and it has been suggested that the high preference for arginine mutations reflects the critical roles of this amino acid in the function of proteins. High rates of mutations of arginine residues in cancer, however, might also be due to increased mutability of arginine codons of the CGN family as the CpG dinucleotides of these codons may be methylated. In the present work we have analyzed spectra of single base substitutions of cancer genes (oncogenes, tumor suppressor genes) and passenger genes in cancer tissues to assess the contributions of CpG hypermutability and selection to arginine mutations. Our studies have shown that arginines encoded by the CGN codon family display higher rates of mutation in both cancer genes and passenger genes than arginine codons AGA and AGG that are devoid of CpG dinucleotide, suggesting that the predominance of arginine mutations in cancer is primarily due to CpG hypermutability, rather than selection for arginine replacement. Nevertheless, our results also suggest that CGN codons for arginines may serve as Achilles' heels of cancer genes. CpG hypermutability of key arginines of proto-oncogenes, leading to high rates of recurrence of driver mutations, contributes significantly to carcinogenesis. Similarly, our results indicate that hypermutability of the CpG dinucleotide of CGA codons (converting them to TGA stop codons) contributes significantly to recurrent truncation and inactivation of tumor suppressor genes., (© 2024. The Author(s).)