Biomedical subjects

Guolin Tan

Publications and source records attributed to Guolin Tan.

5 recordsLinked to original sources

PubMed2006

Genomic instability in the progression of sporadic nasopharyngeal carcinoma.

OBJECTIVE: Genomic instability reflecting the susceptibility of the genome to acquire multiple genetic alterations plays a major role in tumorigenesis and tumor progression. We evaluated the prognostic significance of the extent of genomic instability in nasopharyngeal carcinoma. STUDY DESIGN AND SETTING: Genomic instability was assessed by inter-simple sequence repeats polymerase chain reaction (inter-SSR PCR) in 38 patients with nasopharyngeal carcinoma. Characterization and verification of band alterations shared in different tumors were carried out by sequencing and nest PCR. RESULTS: 31 (81.6%) of 38 patients showed genomic alterations, and genomic instability index ranged from 0 to 16.2%. A gain-based genomic damage shared in 6 tumors was identified on chromosome 6q27, a new mutator phenotype in nasopharyngeal carcinoma. Significantly more genomic alteration was found in patients without 5-year survival than that with 5-year survival (P<0.05), suggesting that higher genomic instability predicts a poor prognosis in nasopharyngeal carcinoma. CONCLUSIONS AND SIGNIFICANCE: Our data suggests that genomic instability can be an early event marker in carcinogenesis of nasopharyngeal carcinoma. Also, aggravation of genomic alterations is a poor prognosis for cancer recovery.

Carcinoma↗

PubMed2005

Isolation of transcriptomal changes attributable to LHON mutations and the cybridization process.

Leber's hereditary optic neuropathy (LHON) is thought to be the most common disease resulting from mitochondrial DNA (mtDNA) point mutations, and transmitochondrial cytoplasmic hybrid (cybrid) cell lines are the most frequently used model for understanding the pathogenesis of mitochondrial disorders. We have used oligonucleotide microarrays and a novel study design based on shared transcripts to allocate transcriptomal changes into rho-zero-dependent, cybridization-dependent and LHON-dependent categories in these cells. The analysis indicates that the rho-zero process has the largest transcriptomal impact, followed by the cybridization process, and finally the LHON mutations. The transcriptomal impacts of the rho-zero and cybridization processes preferentially and significantly affect the mitochondrial compartment, causing upregulation of many transcripts involved in oxidative phosphorylation, presumably in response to the mtDNA depletion that occurs at the rho-zero step. Nine LHON-specific transcriptional alterations were shared among osteosarcoma cybrids and lymphoblasts bearing LHON mutations. Notably, the aldose reductase transcript was overexpressed in LHON cybrids and lymphoblasts. Aldose reductase is also overexpressed in diabetic retinopathy, leading to optic nerve and retinal complications. The LHON-specific increase in transcript level was confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR), and a western blot confirmed a higher level of aldose reductase in mutant mitochondria. One product of aldose reductase is sorbitol, which has been linked to osmotic stress, oxidative stress and optic neuropathy, and sorbitol levels were increased in LHON cybrids. If these results are confirmed in patient tissues, aldose reductase inhibitors could have some therapeutic value for LHON.

Aldehyde Reductase↗

PubMed2003

Decreased expression of genes involved in sulfur amino acid metabolism in frataxin-deficient cells.

Inherited deficiency of the mitochondrial protein frataxin causes neural and cardiac cell degeneration, and Friedreich's ataxia. Five hypotheses for frataxin's mitochondrial function have been generated, largely from work in non-human cells: iron transporter, iron-sulfur cluster assembler, iron-storage protein, antioxidant and stimulator of oxidative phosphorylation. We analyzed gene expression in three human cell types using microarrays, and identified just 48 transcripts whose expression was significantly frataxin-dependent in at least two cell types. Significant decreases in seven transcripts occurred in the sulfur amino acid (SAA) biosynthetic pathway and the iron-sulfur cluster (ISC) biosynthetic pathway to which it is connected. By contrast, we did not observe a single frataxin-dependent transcript that fits with the other four current hypotheses. Quantitative reverse-transcriptase PCR analysis of ISC-S and rhodanese transcripts confirmed that the expression of these genes involved in ISC metabolism was lower in mutants. Amino acid analysis confirmed the defect in SAA metabolism: homocystine, cysteine, cystathionine and serine were significantly decreased in frataxin-deficient cell extracts and mitochondria. An ISC defect was further confirmed by observing decreases in succinate dehydrogenase and aconitase activities, whose activities require ISCs. The ISC-U scaffold protein was specifically decreased in frataxin-deficient cells, suggesting a role for frataxin in its expression or maintenance, and sodium sulfide partially rescued the oxidant-sensitivity of the FRDA cells. Also, multiple transcripts involved in the Fas/TNF/INF apoptosis pathway were up-regulated in frataxin-deficient cells, consistent with a multi-step mechanism of Friedreich's ataxia pathophysiology, and suggesting alternative possibilities for therapeutic intervention.

Amino Acids, Sulfur↗

PubMed2002

Apoptosis induced by low-dose paclitaxel is associated with p53 upregulation in nasopharyngeal carcinoma cells.

Paclitaxel exerts its cytotoxic effect by kinetic suppression of microtubules that block cells in the G2/M phase of the cell cycle and trigger apoptosis. To investigate apoptosis induced by paclitaxel in nasopharyngeal carcinoma (NPC), and its possible molecular mechanism of action, the human NPC cell lines HNE-1 (bearing wild-type p53) and CNE-2 (bearing mutant p53) were treated with different concentrations of paclitaxel. Apoptosis was determined by staining with propidium iodide and also by DNA fragmentation. Protein expression levels of p53, bcl-2 and bcl-xl were examined by Western blotting. Activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP) were also studied in paclitaxel-induced apoptosis. We showed that paclitaxel inhibited growth and induced apoptosis in both cell lines but that the p53 mutant line (CNE-2) was less sensitive to treatment with low-dose paclitaxel. Caspase-3 activity and cleavage of death substrate PARP were significantly increased in a dose-dependent manner, both in parallel with the induction of apoptosis and growth inhibition of NPC cells. We observed a striking increase of p53 protein levels in NPC cells exposed to 1 and 10 nM paclitaxel but a marked inhibition at 100 nM paclitaxel treatment. An inhibitor of caspase, zVAD.fmk, blocked the apoptotic morphologic changes and DNA fragmentation but did not change the rate of cell death or the protein levels of p53, bcl-2 and bcl-xl. In summary, low-dose paclitaxel inhibited cell growth in NPC cells and induced apoptosis possibly by upregulation of p53. In contrast, cell growth and apoptosis induced by a high dose of the drug occurred in a p53-independent manner, which may directly initiate downstream events of apoptosis.

Amino Acid Chloromethyl Ketones↗

PubMed2002

Microsatellite analyses of loci at 7q31.3-q36 reveal a minimum of two common regions of deletion in nasopharyngeal carcinoma.

OBJECTIVE: Our goal was to better define the extent and specificity of deletion in the 7q32-qter chromosomal region in nasopharyngeal carcinoma (NPC). DESIGN AND SETTING: Polymerase chain reaction-based deletion analysis was performed on DNA samples from 24 paired NPCs and corresponding germlines using 13 microsatellite markers mapped to chromosome subbands 7q31.3-q36. RESULTS: Loss of heterozygosity of at least 1 marker in this interval was found in 18 (75%) of 24 tumor specimens. Particularly frequent allelic losses were identified at 5 loci: D7S495 (46%), D7S509 (42%), D7S500 (45%), D7S631 (30%), and D7S514 (35%). Two shortest regions of overlap could be identified in this interval, although the most common shortest region of overlap appeared to lie around D7S500 between but not including D7S631 and D7S495, on chromosome subband 7q32. CONCLUSION: These results suggest that at least 2 putative tumor suppressor genes important in the pathogenesis of NPC are present in the examined interval, an interval that has also been found to harbor deletions in breast and prostate carcinomas.

Carcinoma↗