scholarly journals RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review

2019 ◽  
Vol 20 (9) ◽  
pp. 2183 ◽  
Author(s):  
Peter A. van Dam ◽  
Yannick Verhoeven ◽  
Julie Jacobs ◽  
An Wouters ◽  
Wiebren Tjalma ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Uterine Cervix ◽  
Tumor Necrosis ◽  
Immune Therapy ◽  
Mrna Levels ◽  
Cervical Cancer Cells ◽  
Necrosis Factor

RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG), but also has additional more complex levels of regulation. The existing literature on RANK/RANKL signaling in cervical cancer was reviewed, particularly focusing on the effects on the microenvironment. RANKL and RANK are frequently co-expressed in cervical cancer cells lines and in carcinoma of the uterine cervix. RANKL and OPG expression strongly increases during cervical cancer progression. RANKL is directly secreted by cervical cancer cells, which may be a mechanism they use to create an immune suppressive environment. RANKL induces expression of multiple activating cytokines by dendritic cells. High RANK mRNA levels and high immunohistochemical OPG expression are significantly correlated with high clinical stage, tumor grade, presence of lymph node metastases, and poor overall survival. Inhibition of RANKL signaling has a direct effect on tumor cell proliferation and behavior, but also alters the microenvironment. Abundant circumstantial evidence suggests that RANKL inhibition may (partially) reverse an immunosuppressive status. The use of denosumab, a monoclonal antibody directed to RANKL, as an immunomodulatory strategy is an attractive concept which should be further explored in combination with immune therapy in patients with cervical cancer.

scholarly journals STAT3 activity regulates sensitivity to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in cervical cancer cells

2016 ◽  
Vol 49 (5) ◽  
pp. 2155-2162 ◽  
Author(s):  
Hiroe Nakamura ◽  
Ayumi Taguchi ◽  
Kei Kawana ◽  
Akira Kawata ◽  
Mitsuyo Yoshida ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Tumor Necrosis ◽  
Cervical Cancer Cells ◽  
Induced Apoptosis ◽  
Necrosis Factor

Polymorphism at the –308-promoter position of the tumor necrosis factor-alpha (TNF-α) gene and cervical cancer

2003 ◽  
Vol 13 (2) ◽  
pp. 148-153
Author(s):  
G. A. Stanczuk ◽  
E. N. Sibanda ◽  
S. A. Tswana ◽  
S. Bergstrom
Keyword(s):  
Cervical Cancer ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Uterine Cervix ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Healthy Women ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

The purpose of the study was to investigate the hypothesis that the genetically programmed ability to produce low, medium, or high levels of tumor necrosis factor-alpha (TNF-α), as determined by TNF-α promoter polymorphism at position 308, influenced the development of cancer of the uterine cervix. The population was recruited from patients attending gynecological clinics at two teaching hospitals in Harare, Zimbabwe. Laboratory tests were performed in the Departments of Immunology and Medical Microbiology, Medical School, University of Zimbabwe. One hundred and three patients with invasive cancer of the uterine cervix and 101 healthy women were included in the study. All patients and healthy controls were from the Shona ethnic groups that inhabit northern Zimbabwe. DNA was purified from cervical cytobrush samples obtained from women with cervical cancer. In random cases a second DNA sample was extracted from patient blood. Control DNA was extracted from urine or peripheral blood samples from the healthy women. Detection of allele A and /or G at the 308 position in the promoter region of the TNF-α gene was carried out using the amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) technique. Polymorphism in the amplified products was detected by gel electrophoresis. There was no statistically significant difference in the distribution of the low (G) or high (A) producer alleles at position 308 of the TNF-α gene between patients with cervical cancer and healthy women. The high producer haplotype AA was identified in only one patient with cervical cancer and two healthy women. These data suggest that the genetically acquired ability to produce higher levels of TNF-α is present in a minority of women with or without cervical cancer in the Zimbabwean population. Homozygosity for allele 308A is very rare. High-producer allele 308A as well as high-producer haplotypes AA is significantly less common in a Zimbabwean population than in a European population.

Kaempferol Improves TRAIL-Mediated Apoptosis in Leukemia MOLT-4 Cells by the Inhibition of Anti-apoptotic Proteins and Promotion of Death Receptors Expression

2019 ◽  
Vol 19 (15) ◽  
pp. 1835-1845
Author(s):  
Ali Hassanzadeh ◽  
Adel Naimi ◽  
Majid F. Hagh ◽  
Raedeh Saraei ◽  
Faroogh Marofi ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Cancer Cells ◽  
Tumor Necrosis ◽  
Lymphoblastic Leukemia ◽  
Annexin V ◽  
Death Receptors ◽  
Target Cells ◽  
Wide Range ◽  
Apoptotic Proteins ◽  
Necrosis Factor

Introduction: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a member of the tumor necrosis factor (TNF) superfamily, which stimulates apoptosis in a wide range of cancer cells via binding to death receptors 4 and 5 (DR4/5). Nevertheless, TRAIL has noticeable anti-cancer abilities; some cancer cells acquire resistance to TRAIL, and consequently its potential for inducing apoptosis in target cells is strongly diminished. Acute lymphoblastic leukemia MOLT-4 cell line is one of the most resistant cells to TRAIL that developed resistance to TRAIL via different pathways. We used TRAIL plus kaempferol to eliminate resistance of the MOLT-4 cells to TRAIL. Material and Methods: First, IC50 for kaempferol (95 µM) was determined by using the MTT assay. Second, the viability of the MOLT-4 cells was assayed by FACS after Annexin V/PI staining, following treatment with TRAIL (50 and 100 nM) and kaempferol (95 µM) alone and together. Finally, the expression levels of the candidate genes involved in resistance to TRAIL were assayed by real-time PCR technique. Results: Kaempferol plus TRAIL induced apoptosis robustly in MOLT-4 cells at 12, 24 and 48 hours after treatment. Additionally, we found that kaempferol could inhibit expression of the c-FLIP, X-IAP, cIAP1/2, FGF-8 and VEGF-beta, and conversely augment expression of the DR4/5 in MOLT-4 cells. Conclusion: We suggest that co-treatment of MOLT-4 cells with TRAIL plus kaempferol is a practical and attractive approach to eliminate cancers’ resistance to TRAIL via inhibition of the intracellular anti-apoptotic proteins, upregulation of DR4/5 and also by suppression of the VEGF-beta (VEGFB) and FGF-8 expressions.

Association of a variant in the tumor necrosis factor alpha gene with risk of cervical cancer

2021 ◽  
Vol 48 (2) ◽  
pp. 1433-1437
Author(s):  
Negin Behboodi ◽  
Marjaneh Farazestanian ◽  
Azam Rastgar-Moghadam ◽  
Mehrane Mehramiz ◽  
Ehsan Karimi ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Alpha Gene ◽  
Necrosis Factor
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