| SECTION ?TNF-?-308 G/A polymorphism with colorectal cancer and breast cancer riskObjectives:Tumor necrosis factor a(TNFa)is an important factor in systematic inflammation.It has been shown to be involved in several types of cancer.The association between TNF-a-308 G/A polymorphism and colorectal cancer(CRC)breast cancer(BRC)are not fully understood,especially on the connections between TNF-a-308 G/A polymorphism and clinical features of CRC and BRC.Therfore we conducted a case-control study to investigate the association between TNFa poly-morphism and CRC&BRC clinical risk,expecting to find potential molecular marker to guide individualized treatment.Methods:This case-control study included 570 CRCs,490 BRCs and relevant cancer-free controls.All subjects were from southwestern Chinese individuals.Patients were recruited from January 2010 to December 2015 at the First Affiliated Hospital of Kunming Medical University&Yunnan Tumor Hospital and had been diagnosed with histologically confirmed CRC and BRC.In this study,we classified the CRC and BRC subtypes according to their histopathological classification and genetic profile.The controls were selected based on a physical examination in the same region during the same period as patient recruitment.The selection criteria included no history of cancer and frequency matching to cases by age and gender.At recruitment,demographic information and clinical characteristics of each participant were collected.Genotyping of TNFa(rs1800629)polymorphism was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry(MALDI-TOF MS).Results:TNFa(rs1800629)polymorphism were detected three genotypes:GQ GA and AA.In this case-control study,the distributions of age and gender have been investigated consistently among all the cases and controls of CRC(P=0.46&0.77)and age has been investigated consistently among all the cases and controls of BRC(P=0.065).The genotype frequency of TNF-?-308 G and A alleles in the controls and cases was in concordance with Hardy-Weinberg equilibrium(HWE)(P=0.85&0.67 in CRC,0.87&0.96 in BRC).By analyzing the correlations between TNF-a-308 G>A polymorphism and clinical features of CRC,firstly,we found that TNF-a-308 A allele was associated with higher BMI(body mass index),bigger tumor size,higher neutrophil(%)and distant tumor metastasis in all CRC patients.Notably,the rectal cancer(a subtype of CRC)patients with TNF-?-308 A allele had very high risk of distant tumor metastasis(OR = 4.481,95%CI:2.072-9.693,P= 0.00025).The association between TNF-?-308 A allele and distant tumor metastasis still exists after adjusting by all clinical characteristics(OR=7.099,95%CI:2.482-20.301,P=0.000256)in rectal cancer patients.Secondly,we found that TNF-?-308 G>A polymorphism had a high correlation with smaller tumor size(OR = 0.137,95%CI:0.019-1.013,P=0.023),higher cholesterol status(OR= 7.75,95%CI:0.842-69.708,P=0.041)and lower albumin(OR= 2.571,95%CI:1.194-5.535,P=0.013).In TNBC,GA and AA genotypes were more frequent in patients with high blood pressure(OR=8,95%CI:1.02-62.737,P=0.025)and in patients who were 15 years old or more at menarche(OR ? 11.75,95%CI:1.761-78.416,P= 0.003).In Luminal A subtype,TNF-a-308 A allele was significantly associated with right breast tumors(OR= 5.073,95%CI:1.022-25.194,P=0.031),and more frequent in patients who were 48 older diagnosed with tumor in HER-2 subtype.Conclusions:Our results suggest that TNF-a-308 A allele is significantly associated with distant tumor metastasis in rectal cancer patients,which would be a prognostic factor for CRC.TNFa(rs1800629)GA and AA genotypes were risk foctors of obesity,large tumor size and inflammation response in CRC.TNF-a-308 G>A polymorphism was risk factors of albumin and cholesterol status in BRC,significantly associated with hytension risk in TNBC and right breast tumor risk in Luminal-A subtype,which would predict primary tumor site,tumor size and evaluate the nutritional status of the BRC.SECTION ?The mechanism of dexamethasone mediated chemo-resistant in triple-negative breast cancerObjectives:Dexamethasone(Dex),a glucocorticoid(GC),is used as a pretreatment drug in cancer patients undergoing chemotherapy.Dex functions by binding to the glucocorticoid receptor(GR)to prevent allergic reactions and severe chemo-therapeutic side effects such as nausea and vomiting.However,the mechanisms by which Dex causes chemoresistance remain unknown.Methods:Using docetaxel and cisplatin to treat triple-negative breast cancer(TNBC)cells with or without Dex and assessed cell proliferation using a sulforhodamine B colorimetric(SRB)assay;Additionally,Western blotting was employed to measure Kriippel-like factor 5(KLF5),GR and several apoptosis-related proteins.To deter-mine how the GR regulates KLF5,we used qRT-PCR,luciferase reporter assays and ChIP assays.Finally,we detected the involvement of Dex in TNBC chemothera-peutic resistance using HCC1806 xenograft model in vivo.Results:In this study,we demonstrated that Dex induces docetaxel and cisplatin resistance in TNBC cells in vitro and in vivo.Dex up-regulates pro-survival transcription factor KLF5 expression at both mRNA and protein levels dependent on GR.Importantly,Dex failed to promote cancer cell survival and tumor growth when KLF5 induction was blocked.Conclusions:We conclude that KLF5 is a Dex-induced gene that contributes to Dex-mediated drug chemoresistance,providing a potential novel target for TNBC treatment. |
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