scholarly journals Upregulation of fibronectin following loss of p53 function is a poor prognostic factor in ovarian carcinoma with a unique immunophenotype

2020 ◽  
Author(s):  
Ako Yokoi ◽  
Toshihide Matsumoto ◽  
Yasuko Oguri ◽  
Yoshinori Hasegawa ◽  
Masataka Tochimoto ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Biological Behavior ◽  
Clinical Samples ◽  
Cell Phenotype ◽  
Wild Type ◽  
Poor Prognostic Factor ◽  
P53 Expression ◽  
Mesenchymal Transition ◽  
Wild Type P53

Abstract Background We previously demonstrated that ovarian high grade serous carcinomas (OHGSeCa) and ovarian clear cell carcinomas (OCCCa) with an HNF-1β+/p53+/ARID1A+ immunophenotype were associated with the worst unfavorable prognosis. To clarify the molecular mechanisms underlying this finding, we focused on alterations in the p53 signaling pathway in these tumors. Methods Changes in cell phenotype and function following knockdown of wild-type p53 (p53-KD) were assessed using OCCCa cells expressing endogenous HNF-1β and ARID1A. The prognostic significance of molecules that were deregulated following p53-KD was also examined using 129 OCCCa/OHGSeCa cases. Results p53-KD cells had increased expression of Snail, phospho-Akt (pAkt), and pGSK3β, and decreased E-cadherin expression, leading to epithelial-mesenchymal transition (EMT)/cancer stem cell (CSC) features. The cells also exhibited acceleration of cell motility and inhibition of cell proliferation and apoptosis. Next generation sequencing revealed that fibronectin (FN) expression was significantly increased in the p53 KD-cells, in line with our observation that wild-type p53 (but not mutant p53) repressed FN1 promoter activity. In addition, treatment of OCCCa cells with FN significantly increased cell migration capacity and decreased cell proliferation rate, independent of induction of EMT features. In clinical samples, FN/p53 scores were significantly higher in OCCCa/OHGSeCa with the HNF-1β+/p53+/ARID1A+ immunophenotype when compared to others. Moreover, high FN/high p53 expression was associated with the worst overall survival and progression-free survival in OCCCa/OHGSeCa patients. Conclusion These findings suggest that upregulation of FN following loss of p53 function may impact the biological behavior of OCCCa/OHGSeCa, particularly in tumors with an HNF-1β+/p53+/ARID1A+ immunophenotype, through alterations in cell mobility and cell proliferation. The accompanying induction of EMT/CSC properties and inhibition of apoptosis due to p53 abnormalities also contribute to the establishment and maintenance of tumor phenotypic characteristics.

scholarly journals Upregulation of fibronectin following loss of p53 function is a poor prognostic factor in ovarian carcinoma with a unique immunophenotype

2020 ◽  
Author(s):  
Ako Yokoi ◽  
Toshihide Matsumoto ◽  
Yasuko Oguri ◽  
Yoshinori Hasegawa ◽  
Masataka Tochimoto ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Biological Behavior ◽  
Clinical Samples ◽  
Cell Phenotype ◽  
Wild Type ◽  
Poor Prognostic Factor ◽  
P53 Expression ◽  
Mesenchymal Transition ◽  
Wild Type P53

Abstract Background We previously demonstrated that ovarian high grade serous carcinomas (OHGSeCa) and ovarian clear cell carcinomas (OCCCa) with an HNF-1β+/p53+/ARID1A+ immunophenotype were associated with the worst unfavorable prognosis. To clarify the molecular mechanisms underlying this finding, we focused on alterations in the p53 signaling pathway in these tumors. Methods Changes in cell phenotype and function following knockdown of wild-type p53 (p53-KD) were assessed using OCCCa cells expressing endogenous HNF-1β and ARID1A. The prognostic significance of molecules that were deregulated following p53-KD was also examined using 129 OCCCa/OHGSeCa cases. Results p53-KD cells had increased expression of Snail, phospho-Akt (pAkt), and pGSK3β, and decreased E-cadherin expression, leading to epithelial-mesenchymal transition (EMT)/cancer stem cell (CSC) features. The cells also exhibited acceleration of cell motility and inhibition of cell proliferation and apoptosis. Next generation sequencing assay revealed that fibronectin (FN) expression was significantly increased in the p53 KD-cells, in line with our observation that wild-type p53 (but not mutant p53) repressed FN1 promoter activity. In addition, treatment of OCCCa cells with FN significantly increased cell migration capacity and decreased cell proliferation rate, independent of induction of EMT features. In clinical samples, FN/p53 scores were significantly higher in OCCCa/OHGSeCa with the HNF-1β+/p53+/ARID1A+ immunophenotype when compared to others. Moreover, high FN/high p53 expression was associated with the worst overall survival and progression-free survival in OCCCa/OHGSeCa patients. Conclusion These findings suggest that upregulation of FN following loss of p53 function may impact the biological behavior of OCCCa/OHGSeCa, particularly in tumors with HNF-1β+/p53+/ARID1A+ immunophenotype, through alterations in cell mobility and cell proliferation. The accompanying induction of EMT/CSC properties and inhibition of apoptosis due to p53 abnormalities also contribute to the establishment and maintenance of tumor phenotypic characteristics.

Wild-type p53-induced phosphatase 1 (WIP1) regulates the proliferation of swine Sertoli cells through P53

2020 ◽  
Vol 32 (18) ◽  
pp. 1350
Author(s):  
Bingyuan Wang ◽  
Mingrui Zhang ◽  
Jingjing Che ◽  
Kui Li ◽  
Yulian Mu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Sertoli Cell ◽  
Sertoli Cells ◽  
Male Reproduction ◽  
Wild Type ◽  
P53 Expression ◽  
Cancer Types ◽  
Wild Type P53 ◽  
Oncogenic Function ◽  
Sertoli Cell Line

Wild-type p53-induced phosphatase 1 (WIP1) plays an oncogenic function by increasing cell proliferation in various cancer types. Deficiency in WIP1 expression leads to male infertility, possibly by impairing the blood–testis barrier and spermatogenesis. However, how WIP1 functions in the Sertoli cells to affect male reproduction remains unclear. Thus, in the present study we used a swine Sertoli cell line to investigate whether WIP1 regulated the proliferation of Sertoli cells to participate in male reproduction. The WIP1 inhibitor GSK2830371, WIP1-short interference (si) RNAs and an upstream microRNA (miR-16) were used to inhibit the expression of WIP1, after which the proliferation of swine Sertoli cells, P53 expression and the levels of P53 phosphorylation were determined. Inhibiting WIP1 expression suppressed swine Sertoli cell proliferation, increased P53 expression and increased levels of P53 phosphorylation. In addition, overexpression of miR-16 in swine Sertoli cells resulted in a decrease in WIP1 expression and increases in both P53 expression and P53 phosphorylation. Together, these findings suggest that WIP1 positively regulates the proliferation of swine Sertoli cells by inhibiting P53 phosphorylation, and the miR-16 is likely also involved by targeting WIP1.

Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 77-96
Author(s):  
T. Jeethy Ram ◽  
Asha Lekshmi ◽  
Thara Somanathan ◽  
K. Sujathan
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Cellular Level ◽  
Clinical Samples ◽  
Innovative Strategy ◽  
Mesenchymal Transition ◽  
Galectin 3

Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.

scholarly journals An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Thao Thi Thanh Nguyen ◽  
Masato Shingyoji ◽  
Michiko Hanazono ◽  
Boya Zhong ◽  
Takao Morinaga ◽  
...  
Keyword(s):  
Wild Type ◽  
Inhibitory Effects ◽  
Cytotoxic Effects ◽  
P53 Expression ◽  
Nuclear Factor I ◽  
Infected Cells ◽  
Wild Type P53 ◽  
Mdm2 Inhibitor ◽  
P16 Expression

AbstractA majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

Adenovirus-mediated wild-type P53 expression suppresses growth of lung adeno-carcinoma cells

1998 ◽  
Vol 10 (3) ◽  
pp. 178-181
Author(s):  
Jian Li ◽  
Yongjing Xia ◽  
Lei Jiang ◽  
Hongxia Li ◽  
Yajun Hu ◽  
...  
Keyword(s):  
Carcinoma Cells ◽  
Wild Type ◽  
P53 Expression ◽  
Wild Type P53 ◽  
Adeno Carcinoma

Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells

1994 ◽  
Vol 8 (2) ◽  
pp. 171-176 ◽  
Author(s):  
Erwin G. Van Meir ◽  
Peter J. Polverini ◽  
Victoria R. Chazin ◽  
H.-J. Su Huang ◽  
Nicolas de Tribolet ◽  
...  
Keyword(s):  
Wild Type ◽  
Glioblastoma Cells ◽  
P53 Expression ◽  
Wild Type P53

scholarly journals HOXA11 Regulates Chemoresistance By Modulating p53 Gene Expression in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5182-5182
Author(s):  
Xutao Guo ◽  
Bowen Yan ◽  
Yi Qiu
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
P53 Gene ◽  
Resistant Cell ◽  
Wild Type ◽  
P53 Expression ◽  
Acute Myeloid ◽  
Resistant Cells

Acute myeloid leukemia (AML) exhibits large intrinsic variation in drug responsiveness due to its inherent heterogeneity. Therefore, it is important to understand the resistant mechanism in order to improve the treatment. In our previously study, the OCI-AML2-resistant cell lines were established to resist cytarabine (Ara-C) in the concentration of 50 µM (OCI-AML2 R50). The RNA-seq results showed that many genes changed in the resistant cells compared to wild type OCI-AML2 cells. One of the most remarkably decreased gene in resistant cells was HOXA11 (Homeobox A11). It is the part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor which regulates gene expression, morphogenesis, and differentiation. In this study, we have evaluated the importance of HOXA11 in AML chemoresistance. We found that knockdown of HOXA11 repressed the WT OCI-AML2 cell proliferation and increased the population of cells expressing CD123 and CD47 LSC (Leukemia stem cell) markers and enhanced the resistance to Ara-C in vitro, while overexpression of HOXA11 showed the reverse effect. These results support the idea that HOXA11 promotes drug sensitivity and apoptosis in AML. However, the result also showed that overexpression of HOXA11 repressed the OCI-AML2 R50 cell proliferation and enhanced the resistance. Therefore, HOXA11 plays opposite role in sensitive cells and resistant cells. We further investigated the mechanism for these effects. We found that knockdown of HOXA11 decreased the p53 gene expression and overexpression of HOXA11 increased the expression of p53 in OCI-AML2 and R50 cells. Further, in OCI-AML2 R50 cells p53 has a hotspot mutation in DNA binding site and studies have shown that p53 mutation enhance cancer cell survival and chemoresistance. Therefore, our study shows dual roles for HOXA11 in cell survival. In p53 wild type parental AML2 cells, HOXA11 induces wild type p53 expression to enhance drug sensitivity while in resistant cell, HOXA11 promotes mutant p53 expression and enhances the resistance of chemotherapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals LY75 Ablation Mediates Mesenchymal-Epithelial Transition (MET) in Epithelial Ovarian Cancer (EOC) Cells Associated with DNA Methylation Alterations and Suppression of the Wnt/β-Catenin Pathway

2020 ◽  
Vol 21 (5) ◽  
pp. 1848 ◽  
Author(s):  
Sadia Mehdi ◽  
Magdalena Bachvarova ◽  
Marie-Pier Scott-Boyer ◽  
Arnaud Droit ◽  
Dimcho Bachvarov
Keyword(s):  
Ovarian Cancer ◽  
Dna Methylation ◽  
Epithelial Ovarian Cancer ◽  
Molecular Mechanisms ◽  
Specific Inhibitor ◽  
Alternative Methods ◽  
Cell Phenotype ◽  
Mesenchymal Transition ◽  
Proteomic Approach ◽  
Mesenchymal Epithelial Transition

Growing evidence demonstrates that epithelial–mesenchymal transition (EMT) plays an important role in epithelial ovarian cancer (EOC) progression and spreading; however, its molecular mechanisms remain poorly defined. We have previously shown that the antigen receptor LY75 can modulate EOC cell phenotype and metastatic potential, as LY75 depletion directed mesenchymal–epithelial transition (MET) in EOC cell lines with mesenchymal phenotype. We used the LY75-mediated modulation of EMT as a model to investigate for DNA methylation changes during EMT in EOC cells, by applying the reduced representation bisulfite sequencing (RRBS) methodology. Numerous genes have displayed EMT-related DNA methylation patterns alterations in their promoter/exon regions. Ten selected genes, whose DNA methylation alterations were further confirmed by alternative methods, were further identified, some of which could represent new EOC biomarkers/therapeutic targets. Moreover, our methylation data were strongly indicative for the predominant implication of the Wnt/β-catenin pathway in the EMT-induced DNA methylation variations in EOC cells. Consecutive experiments, including alterations in the Wnt/β-catenin pathway activity in EOC cells with a specific inhibitor and the identification of LY75-interacting partners by a proteomic approach, were strongly indicative for the direct implication of the LY75 receptor in modulating the Wnt/β-catenin signaling in EOC cells.

Increased epidermal functioning wild-type p53 expression in vitiligo

2003 ◽  
Vol 12 (3) ◽  
pp. 268-277 ◽  
Author(s):  
Karin U. Schallreuter ◽  
Stefanie Behrens-Williams ◽  
Tahira P. Khaliq ◽  
Steven M. Picksley ◽  
Eva M. J. Peters ◽  
...  
Keyword(s):  
Wild Type ◽  
P53 Expression ◽  
Wild Type P53

scholarly journals Estrogen-Induced CCN1 Is Critical for Establishment of Endometriosis-Like Lesions in Mice

2014 ◽  
Vol 28 (12) ◽  
pp. 1934-1947 ◽  
Author(s):  
Yuechao Zhao ◽  
Quanxi Li ◽  
Benita S. Katzenellenbogen ◽  
Lester F. Lau ◽  
Robert N. Taylor ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Tissue Growth ◽  
Endometrial Tissue ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Factor C ◽  
Endothelial Growth Factor

Endometriosis is a prevalent gynecological disorder in which endometrial tissue proliferates in extrauterine sites, such as the peritoneal cavity, eventually giving rise to painful, invasive lesions. Dysregulated estradiol (E) signaling has been implicated in this condition. However, the molecular mechanisms that operate downstream of E in the ectopic endometrial tissue are unknown. To investigate these mechanisms, we used a mouse model of endometriosis. Endometrial tissue from donor mice was surgically transplanted on the peritoneal surface of immunocompetent syngeneic recipient mice, leading to the establishment of cystic endometriosis-like lesions. Our studies revealed that treatment with E led to an approximately 3-fold increase in the lesion size within a week of transplantation. E also caused a concomitant stimulation in the expression of connective tissue growth factor/Cyr61/Nov (CCN1), a secreted cysteine-rich matricellular protein, in the lesions. Interestingly, CCN1 is highly expressed in human ectopic endometriotic lesions. To address its role in endometriosis, endometrial tissue from Ccn1-null donor mice was transplanted in wild-type recipient mice. The resulting ectopic lesions were reduced up to 75% in size compared with wild-type lesions due to diminished cell proliferation and cyst formation. Notably, loss of CCN1 also disrupted the development of vascular networks in the ectopic lesions and reduced the expression of several angiogenic factors, such as vascular endothelial growth factor-A and vascular endothelial growth factor-C. These results suggest that CCN1, acting downstream of E, critically controls cell proliferation and neovascularization, which support the growth and survival of endometriotic tissue at ectopic sites. Blockade of CCN1 signaling during the early stages of lesion establishment may provide a therapeutic avenue to control endometriosis.

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