Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nasopharyngeal carcinoma (NPC) is a malignancy with remarkable racial and geographic distribution. The development of this EBV-associated cancer likely involves cumulative genetic and epigenetic changes in a background of predisposed genetic and environmental factors. Genome-wide studies have unravelled multiple chromosomal abnormalities with involvement of specific oncogenes and tumour suppressor genes. Alterations of genes such as Ras association domain family 1A (RASSF1A), p16/INK4A, p14/ARF suggest that multiple cellular pathways were dysregulated in the NPC cells. Studies on the precancerous lesions revealed early genetic changes and a critical role of EBV latent infection in the development of this cancer. Based on the existing findings, a pathogenetic model for NPC is proposed.
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PMID:Genetic and epigenetic changes in nasopharyngeal carcinoma. 1245 Jul 31

Nasopharyngeal carcinoma (NPC) is the most tightly Epstein-Barr virus (EBV)-associated tumour. The EBV oncoprotein latent membrane protein 1 (LMP1) is frequently expressed in NPC tumours and may play a role in the genesis of the disease. NPC tumours often exhibit loss of expression (by deletion or methylation) of the INK4a locus, which encodes the tumour suppressor genes p16INK4a and p14ARF. To investigate the contribution of LMP1 and INK4a loss to tumourigenesis, skin chemical carcinogenesis was conducted using PyLMP1 and INK4a null mice. Surprisingly, INK4a null mice developed significantly fewer papillomas than wild-type mice, nevertheless, the papillomas that did develop grew faster and converted more rapidly to carcinoma than controls. This indicates that while loss of the INK4a locus plays an important role in the later stages of tumourigenesis, initially its loss inhibits papilloma formation. Conversely, LMP1 promoted papilloma formation but paradoxically inhibited papilloma growth. Using cross-breeds, it was found that LMP1 cooperates with loss of the INK4a locus during epithelial tumourigenesis. The expression of LMP1 overcame the inhibition of papilloma formation observed in INK4a null mice, whilst the loss of the INK4a locus counteracted the inhibition of papilloma growth rate found in PyLMP1 mice. This suggests that LMP1 mediates the inhibition of papilloma growth via one or both of the INK4a locus products. Intriguingly, mice heterozygous for INK4a loss showed lesion growth rates intermediate between wild-type and null, demonstrative of haploinsufficiency. We propose that LMP1 acts at the early stages in carcinogenesis to promote the development of benign tumours and that early reduction of INK4a locus expression allows these lesions to expand in size. In addition, loss of the INK4a locus accelerates the development of a more aggressive lesion. Conversely, complete loss of the INK4a locus in an otherwise normal cell might inhibit lesion formation.
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PMID:The latent membrane protein 1 of Epstein-Barr virus and loss of the INK4a locus: paradoxes resolve to cooperation in carcinogenesis in vivo. 1280 17

Nasopharyngeal carcinoma (NPC) is a prevalent tumour in southern China and southeast Asia, particularly in the Cantonese population, where its incidence has remained high for decades. Recent studies have demonstrated that the aetiology of NPC is complex, involving multiple factors including genetic susceptibility, infection with the Epstein-Barr virus (EBV) and exposure to chemical carcinogens. During development of the disease, viral infection and multiple somatic genetic and epigenetic changes synergistically disrupt normal cell function, thus contributing to NPC pathogenesis. NPC is highly radiosensitive and chemosensitive, but treatment of patients with locoregionally advanced disease remains problematic. New biomarkers for NPC, including EBV DNA copy number or methylation of multiple tumour suppressor genes, which can be detected in serum and nasopharyngeal brushings, have been developed for the molecular diagnosis of this tumour. Meanwhile, new therapeutic strategies such as intensity-modulated radiation therapy and immuno- and epigenetic therapies might lead to more specific and effective treatments.
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PMID:Nasopharyngeal carcinoma: molecular pathogenesis and therapeutic developments. 1747 89

Nasopharyngeal carcinoma (NPC) is characterized by a high rate of local invasion and early distant metastasis. Increasing evidence indicates that epigenetic abnormalities play important roles in NPC development. However, the epigenetic mechanisms underlying NPC metastasis remain unclear. Here we investigate aberrantly methylated transcription factors in NPC tissues, and we identify the HOP homeobox HOPX as the most significantly hypermethylated gene. Consistently, we find that HOXP expression is downregulated in NPC tissues and NPC cell lines. Restoring HOPX expression suppresses metastasis and enhances chemosensitivity of NPC cells. These effects are mediated by HOPX-mediated epigenetic silencing of SNAIL transcription through the enhancement of histone H3K9 deacetylation in the SNAIL promoter. Moreover, we find that patients with high methylation levels of HOPX exhibit poor clinical outcomes in both the training and validation cohorts. In summary, HOPX acts as a tumour suppressor via the epigenetic regulation of SNAIL transcription, which provides a novel prognostic biomarker for NPC metastasis and therapeutic target for NPC treatment.
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PMID:HOPX hypermethylation promotes metastasis via activating SNAIL transcription in nasopharyngeal carcinoma. 2814 49

Thioridazine (THZ) has been identified as a potential regulator of tumour progression, and programmed cell death 4 (PDCD4) has been reported as a novel tumour suppressor. This study aimed to investigate the link between PDCD4 and THZ in the regulation of nasopharyngeal cancer (NPC) cell proliferation. The effect of THZ on NPC cells was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays. Then, the involvement of apoptosis and cell cycle in the THZ-mediated regulation of cell viability was assessed by flow cytometry. Related mRNAs and proteins were subsequently examined by real-time PCR and western blot, respectively. After transfection with the PDCD4-siRNA, pGC-FU-GFP-PDCD4 vector and phosphoinositide 3-kinase (PI3K) inhibitor Ly294002, we investigated the antagonistic effects of THZ and PDCD4 on NPC-related protein expression. MTT assays showed that THZ treatment suppressed cell viability. THZ-treated cells were arrested at the G1/G0 phase and showed a significantly increased apoptotic fraction. Furthermore, PDCD4-siRNA antagonized THZ treatment and promoted NPC cell proliferation. Western blot analysis showed that PDCD4 overexpression or PI3K inhibition by LY294002 significantly reduced the expression of phospho-PI3K, phospho-Akt, phospho-mammalian target of rapamycin and phospho-p70s6k, but not their total protein levels. In conclusion, our findings show that THZ and PDCD4 exert antagonistic effects on NPC cell proliferation, probably through the PI3K/Akt pathway. Moreover, these results provide an insight into the mechanism by which THZ targets PDCD4 in NPC cell lines and suggest that the ectopic expression of PDCD4 is a potential therapeutic strategy.
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PMID:Thioridazine upregulates programmed cell death 4 to induce apoptosis in nasopharyngeal carcinoma through the PI3K/Akt signalling pathway. 3305 35