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author:("Liu, chaotian")
1.  WISP1 Polymorphisms Contribute to Platinum-Based Chemotherapy Toxicity in Lung Cancer Patients 
Platinum-based chemotherapy toxicity is always one of the serious problems from which lung cancer patients suffer. The genetic polymorphism of WISP1 was revealed to be associated with susceptibility and platinum-based chemotherapy response in our previous studies. In this study, we aimed to investigate the relationship of WISP1 genetic polymorphisms with platinum-based chemotherapy toxicity in lung cancer patients. A total of 412 lung cancer patients were enrolled in this study, and 28 polymorphisms of the WISP1 gene were genotyped by SequenomMassARRAY. We found that WISP1 polymorphisms (rs2929965, rs2929969, rs2929970, rs2929973 and rs754958) were related to the overall chemotherapy toxicity of lung cancer in subgroup analyses. Rs16904853, rs2929970, rs2977549 and rs2977551 (p = 0.021, 0.028, 0.024, 0.048, respectively) polymorphisms were significantly associated with hematologic toxicity. Rs2929946, rs2929970, rs2977519, rs2977536, rs3739262 and rs754958 (p = 0.031, 0.046, 0.029, 0.016, 0.042, 0.035, respectively) polymorphisms were significantly associated with the gastrointestinal toxicity of lung cancer. Genotypes of WISP1 may be novel and useful biomarkers for predicting platinum-based chemotherapy toxicity in lung cancer patients.
PMCID: PMC4264209  PMID: 25405734
WISP1; lung cancer; genetic polymorphism; chemotherapy toxicity
2.  Overexpression of HMGB1 in melanoma predicts patient survival and suppression of HMGB1 induces cell cycle arrest and senescence in association with p21 (Waf1/Cip1) up-regulation via a p53-independent, Sp1-dependent pathway 
Oncotarget  2014;5(15):6387-6403.
Although laboratory studies have implicated the high mobility group box 1 (HMGB1) in melanoma, its clinical relevance remains unclear. We analyzed nearly 100 cases of human melanoma and found that HMGB1 was highly overexpressed in melanoma samples relative to normal skin and nevi tissues. Significantly, higher levels of HMGB1 correlated with more advanced disease stages and with poorer survival in melanoma patients. Unlike the well-documented pro-inflammatory role of the extracellular HMGB1, we found that its intracellular activity is necessary for melanoma cell proliferation. An absolute dependency of melanoma cell proliferation on HMGB1 was underscored by the marked response of cell cycle arrest and senescence to HMGB1 knockdown. We demonstrated that HMGB1 deficiency-induced inhibition of cell proliferation was mediated by p21, which was induced via a Sp1-dependent mechanism. Taken together, our data demonstrate a novel oncogenic role of HMGB1 in promoting human melanoma cell proliferation and have important implications in melanoma patient care.
PMCID: PMC4171638  PMID: 25051367
high mobility group box 1; p53; p21; Sp1; melanoma
3.  Genetic Variants of Pregnane X Receptor (PXR) and CYP2B6 Affect the Induction of Bupropion Hydroxylation by Sodium Ferulate 
PLoS ONE  2013;8(6):e62489.
This study investigated the effects of pregnane X receptor (PXR/NR1I2) and CYP2B6 genetic variants on sodium ferulate (SF)-mediated induction of bupropion hydroxylation. The pharmacokinetics of bupropion and hydroxybupropion were evaluated after an oral dose of bupropion (150 mg) administered with and without SF pretreatment for 14 days in 33 healthy subjects. The area under the time-concentration curve (AUC) ratio of AUC_hyd (AUC(0-∞) of hydroxybupropion)/AUC_bup (AUC(0-∞) of bupropion) represents the CYP2B6 hydroxylation activity, which was significantly lower in CYP2B6*6 carriers (NR1I2 TGT noncarriers or carriers) than in noncarriers in both the basal and SF-induced states (p-value<0.05). AUC ratio and AUC_hyd of NR1I2 -24113AA variant were markedly lower than GA and GG genotypes (7.5±2.1 versus 14.5±3.3 and 20.6±1.1, and 8873±1431 versus 14,504±2218 and 17,586±1046) in the induced states. However, -24020(-)/(-) variant didn't show significant difference in the induction of CYP2B6 hydroxylation activity by SF compared with other -24020[GAGAAG]/(-) genotypes. NR1I2 TGT haplotype (-25385T+g.7635G+g.8055T) carriers exhibited a significantly decreased AUC ratio, compared with TGT noncarriers, in the basal states (7.6±1.0 versus 9.7±1.0), while this result wasn't observed in CYP2B6*6 noncarriers. Moreover, individuals with complete mutation-type [CYP2B6*6/*6+NR1I2 TGT+ -24113AA+ -24020 (-)/(-)] showed even lower percent difference of AUC ratio (8.7±1.2 versus 39.5±8.2) than those with complete wild-type. In conclusion, it is suggested that NR1I2 variants decrease the bupropion hydroxylation induced by SF treatment, particularly in CYP2B6*6 carriers.
Trial Registration ChiCTR-TRC-11001285
PMCID: PMC3686783  PMID: 23840296
4.  Ethnopharmacokinetic- and Activity-Guided Isolation of a New Antidepressive Compound from Fructus Aurantii Found in the Traditional Chinese Medicine Chaihu-Shugan-San: A New Approach and Its Application 
Aims. We aimed to identify an antidepressive compound found in traditional Chinese medicine (TCM) by a new approach called ethnopharmacokinetic- and activity-guided isolation (EAGI). Methods. The new approach targets an unknown chromatographic peak produced by an absorbed compound found in oral Chaihu-Shugan-San (CSS) taken by patients with depression. Once the compound was isolated from Fructus Aurantii (FA), spectral data was employed to identify the compound. The effects of this compound, FA, and CSS on depressive behaviors were investigated. Results. The identified compound was merazin hydrate (MH) according to the new approach. MH, FA, and CSS significantly reduced immobility time and increased locomotor activity. The effects of MH, FA and CSS were similar to Fluoxetine at high doses. Conclusion. MH, a compound whose antidepressive effect is similar to FA and CSS, was isolated for the first time from FA via targeting its corresponding unknown chromatographic peak, and its antidepressive effect was compared with FA or CSS. These findings highlight the potential for drug R&D and pharmacological research of ∼100,000 TCMs.
PMCID: PMC3291166  PMID: 22454671
5.  Regulation of expression by promoters versus internal ribosome entry site in the 5′-untranslated sequence of the human cyclin-dependent kinase inhibitor p27kip1 
Nucleic Acids Research  2005;33(12):3763-3771.
p27kip1 regulates cell proliferation by binding to and inhibiting the activity of cyclin-dependent kinases and its expression oscillates with cell cycle. Recently, it has been suggested from studies using the traditional dicistronic DNA assay that the expression of p27kip1 is regulated by internal ribosome entry site (IRES)-mediated translation initiation, and several RNA-binding protein factors were thought to play some role in this regulation. Considering the inevitable drawbacks of the dicistronic DNA assay, which could mislead a promoter activity or alternative splicing to IRES as previously demonstrated, we decided to reanalyze the 5′-untranslated region (5′-UTR) sequence of p27kip1 and test whether it contains an IRES element or a promoter using more stringent methods, such as dicistronic RNA and promoterless dicistronic and monocistronic DNA assays. We found that the 5′-UTR sequence of human p27kip1 does not have any significant IRES activity. The previously observed IRES activities are likely generated from the promoter activities present in the 5′-UTR sequences of p27kip1. The findings in this study indicate that transcriptional regulation likely plays an important role in p27kip1 expression, and the mechanism of regulation of p27 expression by RNA-binding factors needs to be re-examined. The findings in this study also further enforce the importance that more stringent studies, such as promoterless dicistronic and monocistronic DNA and dicistronic RNA tests, are required to safeguard any future claims of cellular IRES.
PMCID: PMC1174905  PMID: 16006622

Results 1-5 (5)