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1.
Zhonghua Bing Li Xue Za Zhi ; 53(6): 541-545, 2024 Jun 08.
Article Zh | MEDLINE | ID: mdl-38825897

Objective: To investigate the clinicopathological features, diagnosis and differential diagnosis of pseudocarcinomatous hyperplasia of the fallopian tubes. Methods: Sixteen cases of pseudocarcinomatous hyperplasia of the fallopian tubes diagnosed at Obstetrics and Gynecology Hospital of Fudan University from January 2011 to January 2024 were collected.The pathological sections were reviewed, the clinical and pathological data were consulted, and immunohistochemical examination was conducted along with follow-up. Results: The patients were aged from 19 to 57 years, with an average age of 41 and a median age of 38. Among the 16 cases, 4 were located in the right fallopian tubes, 6 in the left fallopian tubes, while the remaining cases presented bilaterally. The general manifestations were tubal edema, crispness and purulent secretion in the lumen. Morphologically, the fallopian tube mucosa exhibited a significant infiltration of neutrophils, lymphocytes and plasma cells. The epithelial cells of the fallopian tube displayed evident proliferation, stratification and disorganized arrangement leading to formation of small glandular cavity with back-to-back, fissure-like and sieve-like structures. Immunohistochemical analysis revealed positivity for CK7 and WT1, along with wild-type p53 expression, Ki-67 index ranged from 5% to 20%. During the follow-up period ranging from 1 to 156 months, all the patients remained free of disease. Conclusions: Pseudocarcinomatous hyperplasia of the fallopian tube is a rare non-neoplastic lesion, which can lead to epithelial hyperplasia and atypical hyperplasia. The most important significance of recognizing this lesion lies in avoiding misdiagnosis of fallopian tube cancer during intraoperative and postoperative pathological examination. This ensures that clinicians can administer correct clinical interventions.


Fallopian Tubes , Hyperplasia , Humans , Female , Adult , Hyperplasia/pathology , Middle Aged , Fallopian Tubes/pathology , Fallopian Tubes/metabolism , Diagnosis, Differential , Tumor Suppressor Protein p53/metabolism , Keratin-7/metabolism , Fallopian Tube Neoplasms/pathology , Fallopian Tube Neoplasms/metabolism , Fallopian Tube Neoplasms/surgery , Fallopian Tube Neoplasms/diagnosis , Ki-67 Antigen/metabolism , WT1 Proteins/metabolism , Young Adult , Epithelial Cells/pathology , Epithelial Cells/metabolism , Immunohistochemistry , Fallopian Tube Diseases/pathology , Fallopian Tube Diseases/metabolism , Fallopian Tube Diseases/diagnosis
2.
Zhonghua Bing Li Xue Za Zhi ; 53(6): 546-551, 2024 Jun 08.
Article Zh | MEDLINE | ID: mdl-38825898

Objective: To investigate the clinical and pathological characteristics of primary mucinous gland lesions of the fallopian tubes. Methods: The clinical data, pathomorphological characteristics and immunophenotype of 14 cases of primary mucinous gland lesions of the fallopian tube diagnosed at Obstetrics and Gynecology Hospital of Fudan University from 2015 to 2023 were analyzed retrospectively. In addition, a comprehensive review of relevant literature was conducted. Results: The age of 14 patients ranged from 53 to 83 years, with an average of 65 years. Among them, 13 cases exhibited unilateral involvement while one case showed bilateral presentation. Nine cases were mucinous metaplasia of the fallopian tube, four cases were invasive mucinous adenocarcinoma and one case was mucinous carcinoma in situ. Morphologically, mucinous metaplasia of the fallopian tube was focal, with or without inflammation. The cells of mucinous adenocarcinoma or mucinous carcinoma in situ exhibited characteristics indicative of gastrointestinal differentiation. Immunohistochemical analysis revealed diffuse positive expression of CK7, and negative expression of SATB2. CDX2 demonstrated positive staining in two cases. One case exhibited diffuse and strongly positive mutant expression of p53, whereas the remaining cases displayed wild-type expression. MUC6 showed diffuse or focally positive staining in mucinous gland lesions characterized by gastric differentiation. Some cases of mucinous adenocarcinoma of fallopian tube were subject to AB-PAS staining, resulting in red to purple cytoplasmic staining. Conclusions: Primary mucinous lesions of the fallopian tube are exceedingly uncommon. All cases of mucinous adenocarcinoma of fallopian tubes in this study exhibit the morphology and immunohistochemical characteristics of gastrointestinal differentiation. Mucinous metaplasia of the fallopian tube is a benign lesion of incidental finding, which is closely related to inflammation or gastric differentiation. Mucinous lesions of cervix, ovary and digestive tract are excluded in all patients, confirming the independent existence of mucinous lesions within fallopian tubes.


Adenocarcinoma, Mucinous , Fallopian Tube Neoplasms , Fallopian Tubes , Metaplasia , Tumor Suppressor Protein p53 , Humans , Female , Fallopian Tube Neoplasms/pathology , Fallopian Tube Neoplasms/metabolism , Adenocarcinoma, Mucinous/pathology , Adenocarcinoma, Mucinous/metabolism , Aged , Middle Aged , Retrospective Studies , Fallopian Tubes/pathology , Aged, 80 and over , Tumor Suppressor Protein p53/metabolism , Metaplasia/pathology , Keratin-7/metabolism , CDX2 Transcription Factor/metabolism , CDX2 Transcription Factor/genetics , Mucin-6/metabolism , Matrix Attachment Region Binding Proteins/metabolism , Matrix Attachment Region Binding Proteins/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Carcinoma in Situ/pathology , Immunohistochemistry
3.
Proc Natl Acad Sci U S A ; 121(24): e2320867121, 2024 Jun 11.
Article En | MEDLINE | ID: mdl-38838015

O-GlcNAcase (OGA) is the only human enzyme that catalyzes the hydrolysis (deglycosylation) of O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) from numerous protein substrates. OGA has broad implications in many challenging diseases including cancer. However, its role in cell malignancy remains mostly unclear. Here, we report that a cancer-derived point mutation on the OGA's noncatalytic stalk domain aberrantly modulates OGA interactome and substrate deglycosylation toward a specific set of proteins. Interestingly, our quantitative proteomic studies uncovered that the OGA stalk domain mutant preferentially deglycosylated protein substrates with +2 proline in the sequence relative to the O-GlcNAcylation site. One of the most dysregulated substrates is PDZ and LIM domain protein 7 (PDLIM7), which is associated with the tumor suppressor p53. We found that the aberrantly deglycosylated PDLIM7 suppressed p53 gene expression and accelerated p53 protein degradation by promoting the complex formation with E3 ubiquitin ligase MDM2. Moreover, deglycosylated PDLIM7 significantly up-regulated the actin-rich membrane protrusions on the cell surface, augmenting the cancer cell motility and aggressiveness. These findings revealed an important but previously unappreciated role of OGA's stalk domain in protein substrate recognition and functional modulation during malignant cell progression.


Cytoskeleton , LIM Domain Proteins , Tumor Suppressor Protein p53 , Humans , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , LIM Domain Proteins/metabolism , LIM Domain Proteins/genetics , Cytoskeleton/metabolism , Acetylglucosamine/metabolism , Neoplasms/metabolism , Neoplasms/genetics , Neoplasms/pathology , Cell Line, Tumor , Glycosylation , Hydrolysis , Mutation , Cell Movement , Antigens, Neoplasm , Hyaluronoglucosaminidase , Histone Acetyltransferases
4.
BMC Cancer ; 24(1): 673, 2024 Jun 03.
Article En | MEDLINE | ID: mdl-38825709

Hepatocellular carcinoma (HCC) genomic research has discovered actionable genetic changes that might guide treatment decisions and clinical trials. Nonetheless, due to a lack of large-scale multicenter clinical validation, these putative targets have not been converted into patient survival advantages. So, it's crucial to ascertain whether genetic analysis is clinically feasible, useful, and whether it can be advantageous for patients. We sequenced tumour tissue and blood samples (as normal controls) from 111 Chinese HCC patients at Qingdao University Hospital using the 508-gene panel and the 688-gene panel, respectively. Approximately 95% of patients had gene variations related to targeted treatment, with 50% having clinically actionable mutations that offered significant information for targeted therapy. Immune cell infiltration was enhanced in individuals with TP53 mutations but decreased in patients with CTNNB1 and KMT2D mutations. More notably, we discovered that SPEN, EPPK1, and BRCA2 mutations were related to decreased median overall survival, although MUC16 mutations were not. Furthermore, we found mutant MUC16 as an independent protective factor for the prognosis of HCC patients after curative hepatectomy. In conclusion, this study connects genetic abnormalities to clinical practice and potentially identifies individuals with poor prognoses who may benefit from targeted treatment or immunotherapy.


Carcinoma, Hepatocellular , Liver Neoplasms , Mutation , Humans , Liver Neoplasms/genetics , Liver Neoplasms/therapy , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Male , Female , Prognosis , Middle Aged , Aged , Adult , Biomarkers, Tumor/genetics , Genomics/methods , BRCA2 Protein/genetics , Molecular Targeted Therapy , Hepatectomy , Gene Expression Profiling , Tumor Suppressor Protein p53/genetics , DNA-Binding Proteins , Neoplasm Proteins , beta Catenin
5.
J Cell Mol Med ; 28(11): e18442, 2024 Jun.
Article En | MEDLINE | ID: mdl-38842135

Epithelial-mesenchymal transition (EMT) and its reversal process are important potential mechanisms in the development of HCC. Selaginella doederleinii Hieron is widely used in Traditional Chinese Medicine for the treatment of various tumours and Amentoflavone is its main active ingredient. This study investigates the mechanism of action of Amentoflavone on EMT in hepatocellular carcinoma from the perspective of bioinformatics and network pharmacology. Bioinformatics was used to screen Amentoflavone-regulated EMT genes that are closely related to the prognosis of HCC, and a molecular prediction model was established to assess the prognosis of HCC. The network pharmacology was used to predict the pathway axis regulated by Amentoflavone. Molecular docking of Amentoflavone with corresponding targets was performed. Detection and evaluation of the effects of Amentoflavone on cell proliferation, migration, invasion and apoptosis by CCK-8 kit, wound healing assay, Transwell assay and annexin V-FITC/propidium iodide staining. Eventually three core genes were screened, inculding NR1I2, CDK1 and CHEK1. A total of 590 GO enrichment entries were obtained, and five enrichment results were obtained by KEGG pathway analysis. Genes were mainly enriched in the p53 signalling pathway. The outcomes derived from both the wound healing assay and Transwell assay demonstrated significant inhibition of migration and invasion in HCC cells upon exposure to different concentrations of Amentoflavone. The results of Annexin V-FITC/PI staining assay showed that different concentrations of Amentoflavone induces apoptosis in HCC cells. This study revealed that the mechanism of Amentoflavone reverses EMT in hepatocellular carcinoma, possibly by inhibiting the expression of core genes and blocking the p53 signalling pathway axis to inhibit the migration and invasion of HCC cells.


Apoptosis , Biflavonoids , Carcinoma, Hepatocellular , Cell Movement , Cell Proliferation , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Liver Neoplasms , Signal Transduction , Tumor Suppressor Protein p53 , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Epithelial-Mesenchymal Transition/drug effects , Humans , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Biflavonoids/pharmacology , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Signal Transduction/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Apoptosis/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Cell Line, Tumor , Molecular Docking Simulation , Computational Biology/methods
6.
Vopr Virusol ; 69(2): 127-133, 2024 May 06.
Article En | MEDLINE | ID: mdl-38843019

OBJECTIVES: The HTLV-1 infection persists for life, remaining as asymptomatic viral reservoirs in most patients, ensuring the chain of transmission, but around 4% develop adult T-cell leukemia/lymphoma (ATLL). HTLV-1 is an oncogenic retrovirus that transforms CD4+ T lymphocytes and deregulates the lymphoproliferative pathways that contribute to the development of ATLL. To achieve cell transformation, most oncogenic retroviruses use proto-oncogene capture transduction, with proviral integration disrupting the expression of tumor suppressors or proto-oncogenes. THE AIM: We conducted this study on the prevalence of HTLV-1 infection in blood donors to expand the HTLV-1 database, assess the risk of transmission via blood products, as well as evaluate the risk of persistent infection or development of neoplastic diseases in HTLV-1 carriers. MATERIALS AND METHODS: This is a cross-sectional study of blood donors of all categories. For this study, 265 blood donors were recruited at the Centre National de Transfusion Sanguine in Brazzaville. After testing for HTLV-1 antibodies by ELISA, proviral DNA was extracted from all ELISA-positive samples for detection by nested PCR, followed by RT qPCR using specific primers p53 and c-myc for gene expression. RESULTS: 20/265 were positive for anti-HTLV-1 antibody, 5 donors were positive for proviral DNA. The prevalence of HTLV-1 was 1.8%. All HTLV-1-positive donors were male (1.8%), with a positive correlation (p = 0.05); the 1.1% of positive donors were regular, with the majority aged between 31 and 45 years (1.5%), and concubine donors were the most frequent (1.1%). All samples showed normal expression of the p53 and c-myc genes. CONCLUSION: The prevalence, though low, remains a serious problem. No abnormal p53 or c-myc gene expression was detected in HTLV-1-positive donors, which could mean that none of the T lymphocytes in these donors had been transformed by HTLV-1.


Blood Donors , HTLV-I Infections , Human T-lymphotropic virus 1 , Proto-Oncogene Proteins c-myc , Tumor Suppressor Protein p53 , Humans , Human T-lymphotropic virus 1/genetics , Male , HTLV-I Infections/epidemiology , HTLV-I Infections/virology , HTLV-I Infections/genetics , HTLV-I Infections/blood , Adult , Female , Tumor Suppressor Protein p53/genetics , Middle Aged , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Mas , Cross-Sectional Studies , Gene Expression Profiling , Leukemia-Lymphoma, Adult T-Cell/virology , Leukemia-Lymphoma, Adult T-Cell/epidemiology , Leukemia-Lymphoma, Adult T-Cell/genetics , Leukemia-Lymphoma, Adult T-Cell/blood , Proviruses/genetics , Adolescent
7.
Med Oncol ; 41(7): 167, 2024 Jun 04.
Article En | MEDLINE | ID: mdl-38831079

Cancer stem cells (CSCs) are mainly responsible for tumorigenesis, chemoresistance, and cancer recurrence. CSCs growth and progression are regulated by multiple signaling cascades including Wnt/ß-catenin and Hh/GLI-1, which acts independently or via crosstalk. Targeting the crosstalk of signaling pathways would be an effective approach to control the CSC population. Both Wnt/ß-catenin and Hh/GLI-1 signaling cascades are known to be regulated by p53/p21-dependent mechanism. However, it is interesting to delineate whether p21 can induce apoptosis in a p53-independent manner. Therefore, utilizing various subtypes of oral CSCs (SCC9-PEMT p53+/+p21+/+, SCC9-PEMT p53-/-p21+/+, SCC9-PEMT p53+/+p21-/- and SCC9-PEMT p53-/-p21-/-), we have examined the distinct roles of p53 and p21 in Resveratrol nanoparticle (Res-Nano)-mediated apoptosis. It is interesting to see that, besides the p53/p21-mediated mechanism, Res-Nano exposure also significantly induced apoptosis in oral CSCs through a p53-independent activation of p21. Additionally, Res-Nano-induced p21-activation deregulated the ß-catenin-GLI-1 complex and consequently reduced the TCF/LEF and GLI-1 reporter activities. In agreement with in vitro data, similar experimental results were obtained in in vivo mice xenograft model.


Apoptosis , Cyclin-Dependent Kinase Inhibitor p21 , Mouth Neoplasms , Nanoparticles , Neoplastic Stem Cells , Resveratrol , Tumor Suppressor Protein p53 , Zinc Finger Protein GLI1 , beta Catenin , Apoptosis/drug effects , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Resveratrol/pharmacology , Zinc Finger Protein GLI1/metabolism , Zinc Finger Protein GLI1/genetics , beta Catenin/metabolism , Tumor Suppressor Protein p53/metabolism , Humans , Mouth Neoplasms/pathology , Mouth Neoplasms/drug therapy , Mouth Neoplasms/metabolism , Animals , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinase Inhibitor p21/genetics , Mice , Cell Line, Tumor , Xenograft Model Antitumor Assays
8.
Life Sci Alliance ; 7(8)2024 Aug.
Article En | MEDLINE | ID: mdl-38843934

RNA-binding proteins are frequently deregulated in cancer and emerge as effectors of the DNA damage response (DDR). The non-POU domain-containing octamer-binding protein NONO/p54nrb is a multifunctional RNA-binding protein that not only modulates the production and processing of mRNA, but also promotes the repair of DNA double-strand breaks (DSBs). Here, we investigate the impact of Nono deletion in the murine KP (KRas G12D , Trp53 -/- ) cell-based lung cancer model. We show that the deletion of Nono impairs the response to DNA damage induced by the topoisomerase II inhibitor etoposide or the radiomimetic drug bleomycin. Nono-deficient KP (KPN) cells display hyperactivation of DSB signalling and high levels of DSBs. The defects in the DDR are accompanied by reduced RNA polymerase II promoter occupancy, impaired nascent RNA synthesis, and attenuated induction of the DDR factor growth arrest and DNA damage-inducible beta (Gadd45b). Our data characterise Gadd45b as a putative Nono-dependent effector of the DDR and suggest that Nono mediates a genome-protective crosstalk of the DDR with the RNA metabolism via induction of Gadd45b.


DNA Damage , DNA Repair , RNA-Binding Proteins , Animals , Mice , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , DNA Breaks, Double-Stranded , Antigens, Differentiation/metabolism , Antigens, Differentiation/genetics , Bleomycin/pharmacology , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Etoposide/pharmacology , Signal Transduction , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Cell Line, Tumor , RNA Polymerase II/metabolism , Humans , GADD45 Proteins
9.
Sci Rep ; 14(1): 13058, 2024 06 06.
Article En | MEDLINE | ID: mdl-38844774

The incidence of vulvar carcinoma varies by race; however, it is a rare disease, and its genomic profiles remain largely unknown. This study examined the characteristics of vulvar squamous cell carcinoma (VSCC) in Japanese patients, focusing on genomic profiles and potential racial disparities. The study included two Japanese groups: the National Cancer Center Hospital (NCCH) group comprised 19 patients diagnosed between 2015 and 2023, and the Center for Cancer Genomics and Advanced Therapeutics group comprised 29 patients diagnosed between 2019 and 2022. Somatic mutations were identified by targeted or panel sequencing, and TP53 was identified as the most common mutation (52-81%), followed by HRAS (7-26%), CDKN2A (21-24%), and PIK3CA (5-10%). The mutation frequencies, except for TP53, were similar to those of Caucasian cohorts. In the NCCH group, 16 patients of HPV-independent tumors were identified by immunohistochemistry and genotyping. Univariate analysis revealed that TP53-mutated patients were associated with a poor prognosis (log-rank test, P = 0.089). Japanese VSCC mutations resembled those of Caucasian vulvar carcinomas, and TP53 mutations predicted prognosis regardless of ethnicity. The present findings suggest potential molecular-targeted therapies for select VSCC patients.


Carcinoma, Squamous Cell , Mutation , Tumor Suppressor Protein p53 , Vulvar Neoplasms , Humans , Female , Vulvar Neoplasms/genetics , Vulvar Neoplasms/pathology , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Middle Aged , Aged , Tumor Suppressor Protein p53/genetics , Japan/epidemiology , Aged, 80 and over , Cyclin-Dependent Kinase Inhibitor p16/genetics , Class I Phosphatidylinositol 3-Kinases/genetics , Prognosis , Adult , Asian People/genetics , Genomics/methods , Proto-Oncogene Proteins p21(ras)/genetics , East Asian People
10.
Breast Cancer Res ; 26(1): 91, 2024 Jun 04.
Article En | MEDLINE | ID: mdl-38835038

BACKGROUND: The aberrant amplification of mammary luminal progenitors is at the origin of basal-like breast cancers associated with BRCA1 mutations. Integrins mediate cell-matrix adhesion and transmit mechanical and chemical signals that drive epithelial stem cell functions and regulate tumor progression, metastatic reactivation, and resistance to targeted therapies. Consistently, we have recently shown that laminin-binding integrins are essential for the expansion and differentiation of mammary luminal progenitors in physiological conditions. As over-expression of the laminin-binding α6 integrin (Itgα6) is associated with poor prognosis and reduced survival in breast cancer, we here investigate the role of Itgα6 in mammary tumorigenesis. METHODS: We used Blg-Cre; Brca1F/F; Trp53F/F mice, a model that phenocopies human basal-like breast cancer with BRCA1 mutations. We generated mutant mice proficient or deficient in Itgα6 expression and followed tumor formation. Mammary tumors and pretumoral tissues were characterized by immunohistochemistry, flow cytometry, RT-qPCR, Western blotting and organoid cultures. Clonogenicity of luminal progenitors from preneoplastic glands was studied in 3D Matrigel cultures. RESULTS: We show that Itga6 deletion favors activation of p16 cell cycle inhibitor in the preneoplastic tissue. Subsequently, the amplification of luminal progenitors, the cell of origin of Brca1-deficient tumors, is restrained in Itgα6-deficient gland. In addition, the partial EMT program operating in Brca1/p53-deficient epithelium is attenuated in the absence of Itgα6. As a consequence of these events, mammary tumor formation is delayed in Itgα6-deficient mice. After tumor formation, the lack of Itgα6 does not affect tumor growth but rather alters their differentiation, resulting in reduced expression of basal cell markers. CONCLUSIONS: Our data indicate that Itgα6 has a pro-tumorigenic role in Blg-Cre; Brca1F/F; Trp53F/F mice developing basal-like mammary tumors. In particular, we reveal that Itgα6 is required for the luminal progenitor expansion and the aberrant partial EMT program that precedes the formation of BRCA1 deficient tumors.


BRCA1 Protein , Breast Neoplasms , Integrin alpha6 , Tumor Suppressor Protein p53 , Animals , Integrin alpha6/metabolism , Integrin alpha6/genetics , Female , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Mice , BRCA1 Protein/genetics , BRCA1 Protein/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Humans , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Cell Proliferation , Stem Cells/metabolism , Gene Deletion , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism
11.
PLoS One ; 19(6): e0303134, 2024.
Article En | MEDLINE | ID: mdl-38837975

In recent years, a cancer research trend has shifted towards identifying novel therapeutic compounds from natural assets for the management of cancer. In this study, we aimed to assess the cytotoxic activity of Kigelia Africana (KA) extracts on breast cancer (MDA-MB-231 and MCF-7) and noncancerous kidney cells (HEK-293T) to develop an efficient anticancer medication. We used gas chromatography mass spectrometry (GC-MS to analyze the constituents of EKA and HKA extracts meanwhile the crystal violet and the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assays were used to examine the possible cytotoxic effects of plant extracts on our cancer cell lines along with non-cancerous control. The quantitative real-time PCR (RT-PCR) was run on cell samples to evaluate the differential expression of cell proliferative markers of cancer (BCL-2 and TP53). These phytochemicals have been reported to have binding affinity for some other growth factors and receptors as well which was evaluated by the in-silico molecular docking against Bcl2, EGFR, HER2, and TP53. Our Morphological observation showed a significant difference in the cell morphology and proliferation potential which was decreased under the effect of plant extracts treatment as compared to the control samples. The ethanol extract exhibited a marked antiproliferative activity towards MDA-MB-231 and MCF-7 cell lines with IC50 = 20 and 32 µg/mL, respectively. Quantitative RT-PCR gene expression investigation revealed that the IC50 concentration of ethanolic extract regulated the levels of mRNA expression of apoptotic genes. With the target and active binding site amino acids discovered in the molecular docking investigation, TP53/Propanoic acid, 3-(2, 3, 6-trimethyl-1, 4-dioxaspiro [4.4] non-7-yl)-, methyl ester (-7.1 kcal/mol) is the best-docked ligand. The use of this plant in folk remedies justifies its high in vitro anti-cancer capabilities. This work highlights the role of phytochemicals in the inhibition of cancer proliferation. Based on all these findings, it can be concluded that EKA extract has promising anti-proliferative effect on cancerous cells but more study is required in future to further narrow down the active ingredients of total crude extract with specific targets in cancer cells.


Molecular Docking Simulation , Plant Extracts , Tumor Suppressor Protein p53 , Humans , Plant Extracts/pharmacology , Plant Extracts/chemistry , MCF-7 Cells , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Cell Proliferation/drug effects , Cell Line, Tumor , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Female , HEK293 Cells , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism
12.
Saudi Med J ; 45(6): 560-564, 2024 Jun.
Article En | MEDLINE | ID: mdl-38830650

OBJECTIVES: To analyze the immunohistochemical staining pattern of mismatch repair (MMR) proteins and p53 in endometrial carcinoma cases, including different subtypes and stages, to gain insights into their role in the pathogenesis and clinical behaviour of this malignancy. METHODS: In this study, we investigate the association between MMR deficiency, p53 mutational status, and clinical outcomes in various subtypes of endometrial carcinoma. The immunohistochemical staining pattern of MMR proteins in 96 cases of endometrial carcinoma have been analyzed, including 72 endometrioid, 14 papillary serous, 5 clear cell, and 5 mixed Müllerian tumor. RESULTS: The results showed that 36 cases were MMR deficient, with the majority being of endometrioid subtype. The p53 immunostain showed a mutational pattern in a subset of cases, with a documented dismal prognosis. However, aforementioned stains failed to predict synchronous or metachronous cancers in 5 patients. CONCLUSION: These findings highlight the importance of MMR and p53 immunohistochemical staining in the classification, and prognosis of endometrial carcinoma.


DNA Mismatch Repair , Endometrial Neoplasms , Immunohistochemistry , Tumor Suppressor Protein p53 , Humans , Female , Endometrial Neoplasms/pathology , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/genetics , Tumor Suppressor Protein p53/metabolism , Middle Aged , Aged , Adult , Prognosis , Carcinoma, Endometrioid/pathology , Carcinoma, Endometrioid/metabolism , Mutation , Aged, 80 and over
13.
J Cell Mol Med ; 28(9): e18295, 2024 May.
Article En | MEDLINE | ID: mdl-38722284

The RNA-binding protein PNO1 plays an essential role in ribosome biogenesis. Recent studies have shown that it is involved in tumorigenesis; however, its role in hepatocellular carcinoma (HCC) is not well understood. The purpose of this study was to examine whether PNO1 can be used as a biomarker of HCC and also examine the therapeutic potential of PNO1 knockout for the treatment of HCC. PNO1 expression was upregulated in HCC and associated with poor prognosis. PNO1 expression was positively associated with tumour stage, lymph node metastasis and poor survival. PNO1 expression was significantly higher in HCC compared to that in fibrolamellar carcinoma or normal tissues. Furthermore, HCC tissues with mutant Tp53 expressed higher PNO1 than those with wild-type Tp53. PNO1 knockout suppressed cell viability, colony formation and EMT of HCC cells. Since activation of Notch signalling pathway promotes HCC, we measured the effects of PNO1 knockout on the components of Notch pathway and its targets. PNO1 knockout suppressed Notch signalling by modulating the expression of Notch ligands and their receptors, and downstream targets. PNO1 knockout also inhibited genes involved in surface adhesion, cell cycle, inflammation and chemotaxis. PNO1 knockout also inhibited colony and spheroid formation, cell migration and invasion, and markers of stem cells, pluripotency and EMT in CSCs. Overall, our data suggest that PNO1 can be used as a diagnostic and prognostic biomarker of HCC, and knockout of PNO1 by CRISPR/Cas9 can be beneficial for the management of HCC by targeting CSCs.


Biomarkers, Tumor , Carcinoma, Hepatocellular , Gene Expression Regulation, Neoplastic , Liver Neoplasms , RNA-Binding Proteins , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Humans , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/genetics , Male , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Cell Line, Tumor , Female , Prognosis , Middle Aged , Signal Transduction , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Receptors, Notch/metabolism , Receptors, Notch/genetics , Cell Movement/genetics , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Epithelial-Mesenchymal Transition/genetics , Cell Proliferation , Clinical Relevance
14.
Mol Biol Rep ; 51(1): 603, 2024 May 02.
Article En | MEDLINE | ID: mdl-38698270

BACKGROUND: Drug combination studies help to improve new treatment approaches for colon cancer. Tumor spheroids (3D) are better models than traditional 2-dimensional cultures (2D) to evaluate cellular responses to chemotherapy drugs. The cultivation of cancer cells in 2D and 3D cultures affects the apoptotic process, which is a major factor influencing the response of cancer cells to chemotherapeutic drugs. In this study, the antiproliferative effects of 5-fluorouracil (5-FU) and doxorubicin (DOX) were investigated separately and in combination using 2D and 3D cell culture models on two different colon cancer cell lines, HT-29 (apoptosis-resistant cells) and Caco-2 2 (apoptosis-susceptible cells). METHODS: The effect of the drugs on the proliferation of both colon cancer cells was determined by performing an MTT assay in 2D culture. The apoptotic effect of 5-FU and DOX, both as single agents and in combination, was assessed in 2D and 3D cultures through quantitative real-time polymerase chain reaction analysis. The expression of apoptotic genes, such as caspases, p53, Bax, and Bcl-2, was quantified. RESULTS: It was found that the mRNA expression of proapoptotic genes was significantly upregulated, whereas the mRNA expression of the antiapoptotic Bcl-2 gene was significantly downregulated in both colon cancer models treated with 5-FU, DOX, and 5-FU + DOX. CONCLUSION: The results indicated that the 5-FU + DOX combination therapy induces apoptosis and renders 5-FU and DOX more effective at lower concentrations compared to their alone use. This study reveals promising results in reducing the potential side effects of treatment by enabling the use of lower drug doses.


Apoptosis , Cell Proliferation , Colorectal Neoplasms , Doxorubicin , Fluorouracil , Spheroids, Cellular , Humans , Fluorouracil/pharmacology , Spheroids, Cellular/drug effects , Spheroids, Cellular/pathology , Doxorubicin/pharmacology , Apoptosis/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , HT29 Cells , Cell Proliferation/drug effects , Caco-2 Cells , Gene Expression Regulation, Neoplastic/drug effects , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Cell Line, Tumor , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , bcl-2-Associated X Protein/metabolism , bcl-2-Associated X Protein/genetics
15.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(4): 727-738, 2024 Apr 20.
Article Zh | MEDLINE | ID: mdl-38708507

OBJECTIVE: To identify the key genes differentially expressed in Wilms tumor and analyze their potential impacts on prognosis and immune responses of the patients. METHODS: High-throughput RNA sequencing was used to identify the differentially expressed mRNAs in clinical samples of Wilms tumor and paired normal tissues, and their biological functions were analyzed using GO, KEGG and GSEA enrichment analyses. The hub genes were identified using STRING database, based on which a prognostic model was constructed using LASSO regression. The mutations of the key hub genes were analyzed and their impacts on immunotherapy efficacy was predicted using the cBioPortal platform. RT-qPCR was used to verify the differential expressions of the key hub genes in Wilms tumor. RESULTS: Of the 1612 differentially expressed genes identified in Wilms tumor, 1030 were up-regulated and 582 were down-regulated, involving mainly cell cycle processes and immune responses. Ten hub genes were identified, among which 4 genes (TP53, MED1, CCNB1 and EGF) were closely related to the survival of children with Wilms tumor. A 3-gene prognostic signature was constructed through LASSO regression analysis, and the patients stratified into with high- and low-risk groups based on this signature had significantly different survival outcomes (HR=1.814, log-rank P=0.002). The AUCs of the 3-, 5- and 7-year survival ROC curves of this model were all greater than 0.7. The overall mutations in the key hub genes or the individual mutations in TP53/CCNB1 were strongly correlated with a lower survival rates, and a high TP53 expression was correlated with a poor immunotherapy efficacy. RT-qPCR confirmed that the key hub genes had significant differential expressions in Wilms tumor tissues and cells. CONCLUSION: TP53 gene plays an important role in the Wilms tumor and may potentially serve as a new immunotherapeutic biomarker as well as a therapeutic target.


High-Throughput Nucleotide Sequencing , Wilms Tumor , Humans , Wilms Tumor/genetics , Wilms Tumor/immunology , Prognosis , Sequence Analysis, RNA , Gene Expression Regulation, Neoplastic , Kidney Neoplasms/genetics , Kidney Neoplasms/immunology , Gene Expression Profiling , RNA, Messenger/genetics , Mutation , Tumor Suppressor Protein p53/genetics , Immunotherapy , Cyclin B1/genetics , Child
16.
Oncotarget ; 15: 275-284, 2024 May 03.
Article En | MEDLINE | ID: mdl-38709242

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 infection has led to worsened outcomes for patients with cancer. SARS-CoV-2 spike protein mediates host cell infection and cell-cell fusion that causes stabilization of tumor suppressor p53 protein. In-silico analysis previously suggested that SARS-CoV-2 spike interacts with p53 directly but this putative interaction has not been demonstrated in cells. We examined the interaction between SARS-CoV-2 spike, p53 and MDM2 (E3 ligase, which mediates p53 degradation) in cancer cells using an immunoprecipitation assay. We observed that SARS-CoV-2 spike protein interrupts p53-MDM2 protein interaction but did not detect SARS-CoV-2 spike bound with p53 protein in the cancer cells. We further observed that SARS-CoV-2 spike suppresses p53 transcriptional activity in cancer cells including after nutlin exposure of wild-type p53-, spike-expressing tumor cells and inhibits chemotherapy-induced p53 gene activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2. The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity. In fact, cisplatin-treated tumor cells expressing spike were found to have increased cell viability as compared to control cells. Further observations on γ-H2AX expression in spike-expressing cells treated with cisplatin may indicate altered DNA damage sensing in the DNA damage response pathway. The preliminary observations reported here warrant further studies to unravel the impact of SARS-CoV-2 and its various encoded proteins including spike on pathways of tumorigenesis and response to cancer therapeutics. More efforts should be directed at studying the effects of the SARS-CoV-2 spike and other viral proteins on host DNA damage sensing, response and repair mechanisms. A goal would be to understand the structural basis for maximal anti-viral immunity while minimizing suppression of host defenses including the p53 DNA damage response and tumor suppression pathway. Such directions are relevant and important including not only in the context of viral infection and mRNA vaccines in general but also for patients with cancer who may be receiving cytotoxic or other cancer treatments.


Cell Survival , Cyclin-Dependent Kinase Inhibitor p21 , Proto-Oncogene Proteins c-mdm2 , Receptors, TNF-Related Apoptosis-Inducing Ligand , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Tumor Suppressor Protein p53 , Humans , Proto-Oncogene Proteins c-mdm2/metabolism , Tumor Suppressor Protein p53/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Spike Glycoprotein, Coronavirus/genetics , Cell Survival/drug effects , Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism , Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics , SARS-CoV-2/physiology , Cell Line, Tumor , Neoplasms/metabolism , Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Transfection , COVID-19/virology , COVID-19/metabolism
17.
Cell Biochem Funct ; 42(4): e4027, 2024 Jun.
Article En | MEDLINE | ID: mdl-38715184

Bioactive phytocompounds are crucial components in all plants. Since the time of traditional medicine, the utilization of plants has been grounded in the potential of these bioactive compounds to treat or manage specific illnesses. These natural bioactive compounds have sparked growing interest in employing medicinal plants for addressing various conditions, such as inflammatory diseases, diabetes, and cancer. This study focuses on assessing the qualitative phytochemical composition, antioxidant potential, and cytotoxic effects of blueberry (Vaccinium sect. Cyanococcus) extract using three different solvents, namely water, ethanol, and methanol. The extract exhibited notable antioxidant activities, as evidenced by DPPH and H2O2 free radical scavenging assays. The cell viability assay also demonstrated cell growth inhibition in A549 cells. Furthermore, nine specific phytocompounds sourced from existing literature were selected for molecular docking studies against CDK6 and, AMPK key protein kinases which enhance the cancer progression. The molecular docking results also revealed favorable binding scores, with a high score of -9.5 kcal/mol in CDK6 protein and a maximum score of AMPK with targets of -8.8 kcal/mol. The selected phytocompounds' pharmacodynamic properties such as ADMET also supported the study. Furthermore, rutin stated that pre-dominantly present in blueberry plants shows a potent cytotoxicity effect in A549 cells. Functional annotations by bioinformatic analysis for rutin also revealed the strong enrichment in the involvement of PI3K/AKT1/STAT, and p53 signaling pathways. Based on this analysis, the identified rutin and other compounds hold a promising anticancer activity. Overall, the comprehensive evaluation of both in vitro and in silico data suggests that the Vaccinium sect. Cyanococcus extract could serve as a valuable source of pharmaceutical agents and may prove effective in future therapeutic applications.


Blueberry Plants , Cell Proliferation , ErbB Receptors , Oxidative Stress , Plant Extracts , STAT3 Transcription Factor , Signal Transduction , Tumor Suppressor Protein p53 , Humans , Plant Extracts/pharmacology , Plant Extracts/chemistry , Blueberry Plants/chemistry , Oxidative Stress/drug effects , STAT3 Transcription Factor/metabolism , Tumor Suppressor Protein p53/metabolism , A549 Cells , Signal Transduction/drug effects , Cell Proliferation/drug effects , ErbB Receptors/metabolism , Interleukin-6/metabolism , Molecular Docking Simulation , Lung Neoplasms/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Cell Survival/drug effects , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/metabolism , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Drug Screening Assays, Antitumor
18.
Clin Lab ; 70(5)2024 May 01.
Article En | MEDLINE | ID: mdl-38747915

BACKGROUND: As a tumor mass, a myeloid sarcoma consists of myeloid blasts and presents at an anatomical site other than the bone marrow. In about one quarter of cases, myeloid sarcoma happens without an underlying acute myeloid leukemia or other myeloid neoplasm, and it may precede or coincide with AML or form acute blastic transformation of MDSs, MPNs, or MDS/MPNs. METHODS: Herein, we described a rare case of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), with WT1 mutation and high expression of TP53 after isolated myeloid sarcoma of lymph nodes showing a higher proportion of blasts, dysplasia of both megakaryocytes and granulocytes. CONCLUSIONS: The case highlights the importance of a bone marrow examination, including morphology, immunophenotyping, cytogenetic, and molecular examination in all cases to exclude the possibility of myeloid sarcoma, especially the morphological feature of bone marrow dysplasia in the early stage before AML.


Leukemia, Myeloid, Acute , Mutation , Myelodysplastic Syndromes , Sarcoma, Myeloid , Humans , Sarcoma, Myeloid/genetics , Sarcoma, Myeloid/diagnosis , Sarcoma, Myeloid/pathology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/diagnosis , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/pathology , Myelodysplastic Syndromes/diagnosis , Tumor Suppressor Protein p53/genetics , WT1 Proteins/genetics , Male , Bone Marrow/pathology , Middle Aged , Immunophenotyping
19.
Nat Commun ; 15(1): 4002, 2024 May 11.
Article En | MEDLINE | ID: mdl-38734692

Precise genome editing is crucial for establishing isogenic human disease models and ex vivo stem cell therapy from the patient-derived hPSCs. Unlike Cas9-mediated knock-in, cytosine base editor and prime editor achieve the desirable gene correction without inducing DNA double strand breaks. However, hPSCs possess highly active DNA repair pathways and are particularly susceptible to p53-dependent cell death. These unique characteristics impede the efficiency of gene editing in hPSCs. Here, we demonstrate that dual inhibition of p53-mediated cell death and distinct activation of the DNA damage repair system upon DNA damage by cytosine base editor or prime editor additively enhanced editing efficiency in hPSCs. The BE4stem system comprised of p53DD, a dominant negative p53, and three UNG inhibitor, engineered to specifically diminish base excision repair, improves cytosine base editor efficiency in hPSCs. Addition of dominant negative MLH1 to inhibit mismatch repair activity and p53DD in the conventional prime editor system also significantly enhances prime editor efficiency in hPSCs. Thus, combined inhibition of the distinct cellular cascades engaged in hPSCs upon gene editing could significantly enhance precise genome editing in these cells.


CRISPR-Cas Systems , DNA Damage , DNA Repair , Gene Editing , Tumor Suppressor Protein p53 , Gene Editing/methods , Humans , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , Cell Line , MutL Protein Homolog 1/genetics , MutL Protein Homolog 1/metabolism , Cytosine/metabolism
20.
Stomatologiia (Mosk) ; 103(2): 5-11, 2024.
Article Ru | MEDLINE | ID: mdl-38741528

OBJECTIVE: The aim of the study. Improving the efficiency of diagnosis and detailing the features of the clinic of «potentially malignant¼ diseases of the oral mucosa. MATERIALS AND METHODS: Clinical and laboratory examination of 124 patients of the department of oral mucosa diseases aged 35 to 80 years, among whom there were 75 women and 49 men, with diseases such as erythroplakia - 12 patients, verrucous leukoplakia - 52 patients, erosive form of leukoplakia - 35 patients, cheilitis Manganotti - 25 patients. Histological and immunohistochemical methods of investigation were used as diagnostics. To assess the proliferative activity of epithelial cells, the determination of the Ki-67 index was used. The synthesis of keratin 15 (K15) in epithelial layers was determined as a diagnostic criterion for the severity of neoplasia. The expression of human papillomavirus type 16 (HPV 16) antigens and p16INK4a protein in epithelial cells was studied, as well as the expression of p53 protein. RESULTS: A high prevalence of p53 mutations was observed in patients with erythroplakia. In leukoplakia, the expression of the Ki-67 protein was detected in the cell nuclei in both the basal and parabasal layers of the multilayer squamous epithelium, in 77% of cases, the expression of the p16INK4a protein in the epithelial nuclei with varying degrees of dysplastic changes was noted, and a positive reaction to HPV16 was also observed in the cell nuclei and cytoplasm of epithelial cells in the basal, parabasal and spiny epithelial layers. The appearance of K15 in the cytoplasm of cells above the basal layer with abrasive precancerous cheilitis was found in 48% of cases. CONCLUSION: To diagnose early manifestations of neoplastic processes in «potentially malignant¼ diseases of the oral mucosa, it is necessary to use both classical histological and immunohistochemical methods of investigation with various markers.


Ki-67 Antigen , Mouth Mucosa , Precancerous Conditions , Humans , Middle Aged , Male , Female , Aged , Adult , Mouth Mucosa/pathology , Aged, 80 and over , Ki-67 Antigen/analysis , Precancerous Conditions/pathology , Precancerous Conditions/diagnosis , Mouth Neoplasms/pathology , Mouth Neoplasms/diagnosis , Leukoplakia, Oral/pathology , Leukoplakia, Oral/diagnosis , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Protein p53/metabolism , Cheilitis/pathology , Cheilitis/diagnosis , Human papillomavirus 16/isolation & purification , Human papillomavirus 16/genetics , Cyclin-Dependent Kinase Inhibitor p16/analysis , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Erythroplasia/pathology , Erythroplasia/diagnosis
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