SGLT2 inhibition eliminates senescent cells and alleviates pathological aging.

It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.

Glycoprotein nonmetastatic melanoma protein B regulates lysosomal integrity and lifespan of senescent cells.

Accumulation of senescent cells in various tissues has been reported to have a pathological role in age-associated diseases. Elimination of senescent cells (senolysis) was recently reported to reversibly improve pathological aging phenotypes without increasing rates of cancer. We previously identified glycoprotein nonmetastatic melanoma protein B (GPNMB) as a seno-antigen specifically expressed by senescent human vascular endothelial cells and demonstrated that vaccination against Gpnmb eliminated Gpnmb-positive senescent cells, leading to an improvement of age-associated pathologies in mice. The aim of this study was to elucidate whether GPNMB plays a role in senescent cells. We examined the potential role of GPNMB in senescent cells by testing the effects of GPNMB depletion and overexpression in vitro and in vivo. Depletion of GPNMB from human vascular endothelial cells shortened their replicative lifespan and increased the expression of negative cell cycle regulators. Conversely, GPNMB overexpression protected these cells against stress-induced premature senescence. Depletion of Gpnmb led to impairment of vascular function and enhanced atherogenesis in mice, whereas overexpression attenuated dietary vascular dysfunction and atherogenesis. GPNMB was upregulated by lysosomal stress associated with cellular senescence and was a crucial protective factor in maintaining lysosomal integrity. GPNMB is a seno-antigen that acts as a survival factor in senescent cells, suggesting that targeting seno-antigens such as GPNMB may be a novel strategy for senolytic treatments.

The Association of Matrix Metalloproteinase-1 Promoter Polymorphisms with Breast Cancer.

BACKGROUND/AIM: The family of matrix metalloproteinases (MMPs) are responsible for the homeostasis of extracellular matrix components and their genetic polymorphisms may be associated with cancer susceptibility. The serum levels of MMP-1 have been reported to be lower in breast cancer patients than healthy subjects. In the current study, we aimed at investigating the contribution of a polymorphism in the promoter region of MMP-1 to breast cancer in Taiwan. MATERIALS AND METHODS: The MMP-1 rs1799705 polymorphic genotypes were genotyped among 1,232 breast cancer patients and 1,232 healthy controls by the typical polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The percentages of 2G/2G, 1G/2G, and 1G/1G for MMP1 -1607 genotypes were 35.4, 40.6 and 24.0% in the breast cancer group and 34.1, 43.6, and 22.3% in the healthy control group (p trend=0.3025), respectively. The odds ratios (ORs) after adjusting for age, smoking and alcohol drinking status for those carrying 1G/2G and 1G/1G genotypes at MMP1 -1607 were 0.93 (95%CI=0.76-1.11, p=0.2390) and 1.01 (95%CI=0.77-1.23, p=0.7377), respectively, compared to those carrying the wild-type 2G/2G genotype. Supporting this finding, the adjusted OR for those carrying the 1G allele at MMP-1 -1607 was 1.03 (95%CI=0.91-1.18, p=0.8860), compared to those carrying the wild-type 2G allele. Our findings suggest that the polymorphic genotypes at MMP1 promoter -1607 investigated in the current study, may not play a major role in determining cancer susceptibility to breast cancer in Taiwan. Other early diagnostic and predictive markers are urgently needed for personalized and precise breast cancer detection and therapy.

The Role of MTHFR Genotype in Colorectal Cancer Susceptibility in Taiwan.

AIM: To evaluate the contribution of methylenetetrahydrofolate reductase (MTHFR) genotype to the risk of colorectal cancer (CRC) in Taiwan. MATERIALS AND METHODS: In this hospital-based case-control study, the role of MTHFR C677T (rs1801133) and A1298C (rs1801131) genotypes in determining CRC risk were investigated among 362 patients with CRC and an equal number of age- and gender-matched healthy individuals. RESULTS: The percentages of CC, CT and TT genotypes for MTHFR rs1801133 were 64.1%, 29.8% and 6.1% in the CRC group and 51.1%, 37.0% and 11.9% in the control group, respectively (p for trend=0.0006). Analysis of the allelic frequency distribution showed that the variant T allele of MTHFR rs1801133 conferred a lower CRC susceptibility than did the wild-type C allele (odds ratio(OR)=0.66, 95% confidence interval(CI)=0.52-0.84, p=4.32×10-5). For the gene-lifestyle interaction, there were obvious protective effects of MTHFR rs1801133 T allele on the risk of CRC among non-smokers, ever smokers and non-alcohol drinkers, but not drinkers. CONCLUSION: MTHFR rs1801133 T allele serves as a predictive marker for CRC risk and future studies with larger samples and functional evaluation are warranted to validate the current findings.

The Association of Matrix Metalloproteinase-8 Promoter Genotypes in Breast Cancer.

BACKGROUND/AIM: The family of matrix metalloproteinases (MMPs) controls homeostasis of the extracellular matrix and their genetic polymorphisms may be associated with personal cancer susceptibility. The serum levels of MMP8 was reported to be higher in patients with breast cancer than in healthy individuals. In this study, we aimed to investigate the contribution of a polymorphism in the promoter region of MMP8 (-799C/T) and two nonsynonymous polymorphisms (Val436Ala and Lys460Thr) to breast cancer. MATERIALS AND METHODS: MMP8 -799C/T, Val436Ala and Lys460Thr polymorphic genotypes were determined for 1,232 patients with breast cancer and 1,232 healthy controls by polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The odds ratios (ORs) after adjusting for age, gender, smoking and alcohol drinking status for those carrying CT and TT genotypes at the MMP8 promoter C-799T were 1.03 (95% CI=0.88-1.23, p=0.7475) and 1.08 (95% CI=0.91-1.53, p=0.3561), respectively, compared to those carrying the wild-type CC genotype. The OR for the combined T-bearing genotypes were of a similar non-significant level (OR=1.05, 95% CI=0.90-1.26, p=0.5176). Supporting this finding, the adjusted OR for those carrying the T allele at MMP8 C-799T was 1.05 (95% CI=0.86-1.21, p=0.3797), compared to those carrying the wild-type C allele. There was also no significant association of MMP8 Lys460Thr with breast cancer. There was no polymorphic genotype at MMP8 Val436Ala found among any of the investigated individuals. CONCLUSION: MMP8 -799C/T, Val436Ala and Lys460Thr polymorphisms may only play an indirect role in determining personal cancer susceptibility to breast cancer in Taiwan.

The Contribution of Matrix Metalloproteinase-1 Promoter Genotypes in Taiwan Lung Cancer Risk.

BACKGROUND/AIM: Up-regulation of metallo-proteinase (MMP) proteins has been shown in various types of solid cancers and the genotype of MMP1 has been associated with the risk of solid cancers. The contribution of MMP1 genotype to lung cancer has been investigated in various countries, though, to our knowledge, not in Taiwan. Therefore, in this study, we focused on the contribution of a polymorphism in the promoter region of MMP1 to lung cancer risk in Taiwan population. PATIENTS AND METHODS: Genomic DNA was isolated from peripheral blood of 358 patients with lung cancer and 716 healthy individuals (non-cancer patients). MMP1 rs1799750 polymorphic genotypes of each sample were determined using the typical methodology of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The percentages of 2G/2G, 1G/2G, and 1G/1G for MMP1 -1607 genotypes were 34.4%, 41.3% and 24.3% in the disease group and 33.9%, 44.0%, and 22.1% in the control group (p trend=0.6298), respectively. The results of carrier comparisons in dominant and recessive models also support the findings that 1G or 2G appears not to be a determinant allelic biomarker for Taiwan lung cancer. CONCLUSION: The MMP1 -1607 1G allele is a non-significant protective biomarker for lung cancer in Taiwan.

The Association of Flap Endonuclease 1 Genotypes with the Susceptibility of Endometriosis.

BACKGROUND/AIM: Flap endonuclease 1 (FEN1), a protein with multiple functions in genome stability maintenance, is important in cancer prevention. The two functional germline variants of FEN1, rs174538 and rs4246215, regarding cancer susceptibility have been reported in lung, breast, liver, esophageal, gastric, colorectal cancer, glioma and leukemia, but not endometriosis. In this study, we firstly aimed at evaluating the contribution of FEN1 genotypes to endometriosis risk in a representative Taiwan population. MATERIALS AND METHODS: In total, 153 patients with endometriosis and 636 non-cancer healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. RESULTS: The genotypes of FEN1 rs174538, but not those of rs4246215, were differently distributed between the endometriosis and control groups. In detail, the AA of FEN1 rs174538 genotypes were significantly less frequently found among endometriosis patients than among controls (odds ratio [OR]=0.43, 95% confidence interval [CI]=0.24-0.78, p=0.0125). The A allele at FEN1 rs174538 was also significantly less frequent among cases than controls (OR=0.65, 95%CI=0.50-0.86, p=0.0021). As for age of first menarche, those with first menarche at the age >12.8 carrying the FEN1 rs174538 AA genotype conferred lower OR of 0.29 (95%CI=0.11-0.78, p=0.0381) for endometriosis. Regarding the full pregnancy status, those without having had a full-term pregnancy carrying the FEN1 rs174538 AA genotype were of lower risk (ORs=0.12, 95%CI=0.03-0.53, p=0.0050). CONCLUSION: The FEN1 rs174538 A allele is a novel protective biomarker for endometriosis and this genotype may have interactions with age- and hormone-related factors on the development of endometriosis.

The Contribution of Matrix Metalloproteinase-7 Promoter Genotypes in Breast Cancer in Taiwan.

BACKGROUND/AIM: The matrix metalloproteinase (MMP) family of enzymes are in charge of degradation of various components of the extracellular matrix and their functional genetic polymorphisms may be associated with cancer susceptibility. The functional polymorphisms in the promoter region of MMP7 (A-181G and C-153T) have been reported to influence the binding capacity of nuclear proteins and may contribute to genetic susceptibility to cancer. In this study, we focused on investigating the contribution of the genotypes of MMP7 (A-181G and C-153T) to breast cancer in Taiwan. MATERIALS AND METHODS: These two polymorphisms were genotyped in 1,232 patients with breast cancer and 1,232 controls by polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The odds ratios (ORs) after adjusting for age, family history of cancer, smoking and alcohol drinking status for those carrying AG and GG genotypes at MMP7 promoter A-181G were 1.22 (95%CI=0.91-1.63, p=0.2235) and 2.84 (95%CI=1.64-7.48, p=0.0007) respectively, compared to those carrying the wild-type AA genotype. Supporting this finding, the adjusted OR for those carrying the G allele at MMP7 promoter A-181G was 1.57 (95%CI=1.29-1.93, p=0.0008), compared to those carrying the wild-type A allele. There was no polymorphic genotype at MMP7 C-153T found among any of the investigated individuals. CONCLUSION: Our findings suggest that the MMP7 A-181G polymorphisms may play a role in determining personal cancer susceptibility and GG genotype at MMP7 A-181G may serve as a biomarker for early detection and prediction of breast cancer in Taiwanese.

The Contribution of MMP-8 Promoter Polymorphisms in Lung Cancer.

BACKGROUND/AIM: Accumulated evidence has supported the hypothesis that the functional polymorphisms of matrix metalloproteinases (MMP) were associated with the risk of various types of cancer. However, few reports have studied the contribution of MMP-8 genotypes to either diagnostic or prognostic potential in lung cancer. In this study, we focused on the contribution of a polymorphism in the promoter region of MMP-8 (C-799T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to lung cancer risk. PATIENTS AND METHODS: Genomic DNA was isolated from peripheral blood of 358 patients with lung cancer and 716 non-cancer healthy individuals. MMP-8 C-799T (rs11225395), Val436Ala (rs34009635) and Lys460Thr (rs35866072) polymorphic genotypes of each subject were determined using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The results showed that the three polymorphisms were not significantly associated with increased risk of lung cancer in the overall investigated population. Furthermore, when the analyses were stratified according to age, sex, status of smoking and drinking, pack-years of smoking and family history of lung cancer, there was also no significant association between these genotypes and increased lung cancer risk. CONCLUSION: The polymorphisms MMP-8 C-799T, Val436Ala and Lys460Thr may not play a major role in mediating personal susceptibility to lung cancer in Taiwan.

Contribution of matrix metalloproteinases-1 genotypes to gastric cancer susceptibility in Taiwan.

Expression of matrix metalloproteinase-1 (MMP1), an interstitial collagenase regulating the extracellular matrix, plays a major role in carcinogenesis of gastric cancer, a leading cause of death worldwide. In literature, the single-nucleotide polymorphism (SNP) promoter -1607 1G/2G (rs1799750) at the MMP1 gene promoter has been reported to alter its own transcription level. While the importance's of the genotype of MMP1 promoter -1607 has not yet been studied in gastric cancer in Taiwan, our aim was to investigate MMP1 promoter -1607 genotypes and gastric cancer (GC) susceptibility in central Taiwan population. In the current hospital-based case-control study, the contribution of MMP1 promoter -1607 genotypes to GC risk was investigated among 121 GC patients and 363 gender- and age-matched healthy controls recruited and genotyped by the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) methodology. We found that the genotypic and allelic frequencies were not differentially distributed between GC patient and control groups. The variant 1G containing genotypes have interactions with cigarrete smoking behaviors and Helicobacter pylori infection status, but not alcoholism on GC susceptibility determination. Our findings suggest that the variant 1G allele on MMP1 promoter -1607 may contribute to GC carcinogenesis and may be useful for GC early detection and prevention when combined with cigarrete smoking behaviors and Helicobacter pylori infection status.

Association of Interleukin-12A rs568408 with Susceptibility to Asthma in Taiwan.

Asthma is an inflammatory disease and interleukin 12 (IL-12) may play a regulatory role in allergen-induced inflammation. The aim of this study was to investigate the association of polymorphisms in IL-12A/IL-12B with asthma. The asthma group included 198 adult patients and the control group included 453 individuals without asthma that were frequency-matched by gender and age. The distribution of genotypic and allelic frequencies of IL-12A rs568408 demonstrated significant differences between case and control groups. Specifically, the percentages of AA genotype of IL-12A rs568408 was significantly higher among asthmatic patients in Taiwan than healthy controls, compared to GG genotype. No significant difference was observed among the IL-12A rs2243115 and IL-12B rs3212227 genotypes between case and control groups. In addition, the A allele at IL-12A rs568408 was associated with more severe symptoms (P = 0.0085) among asthmatic patients. These results suggest that IL-12A rs568408 may contribute to the etiology and symptoms severity of asthma, indicating its usefulness as a predictive and diagnostic biomarker of asthma.

The Contribution of Excision Repair Cross-complementing Group 1 Genotypes to Colorectal Cancer Susceptibility in Taiwan.

AIM: To evaluate the contribution of ERCC1 rs11615 and rs3212986 genotypes regarding the risk of colorectal cancer (CRC) in Taiwan. MATERIALS AND METHODS: In this case-control study, ERCC1 rs11615 and rs3212986 genotypes and their interaction with consumption of cigarettes and alcohol in determining CRC risk were investigated among 362 CRC patients and 362 age- and gender-matched healthy controls. RESULTS: The percentages of CC, CT and TT for ERCC1 rs11615 genotype were 44.2%, 36.2% and 19.6% in the CRC group and 49.7%, 38.4% and 11.9% in the control group, respectively (p for trend=0.0158). The allelic frequency distribution analysis showed that the variant T allele of ERCC1 rs11615 conferred increased CRC susceptibility to the wild-type C allele (odds ratio (OR)=1.34, 95% confidence interval (CI)=1.08-1.67, p=0.0079). As for the gene-lifestyle interaction, there were obvious joint effects of ERCC1 rs11615 genotype on the risk of CRC among ever smokers and alcohol drinkers, but not non-smokers or non-drinkers. There is a positive correlation of ERCC1 rs11615 genotype with lymph node metastasis, but not other CRC prognosis, including tumor size and location. CONCLUSION: ERCC1 rs11615 T allele serves as a predictive marker for CRC risk and future studies with larger samples and functional evaluation are warranted to validate these findings.

Contribution of Double-strand Break Repair Gene Nijmegen Breakage Syndrome 1 Genotypes, Gender Difference and Smoking Status to Taiwanese Lung Cancer.

BACKGROUND/AIM: Nijmegen breakage syndrome 1 (NBS1) is a component of MRE11/RAD50/NBS1 complex (MRN) that plays a critical role in the cellular response to DNA damage and maintenance of chromosomal integrity. Failure in DNA damage response affects the level of cell survival, increases the frequency of gene mutation or chromosomal instability and other cellular phenotypic abnormalities, which are the important mechanisms of carcinogenesis. However, the contribution of variant NBS1 genotypes to lung cancer is not known. The current study aimed to evaluate the contribution of the common variant NBS1 Glu185Gln (rs1805794, E185Q) genotypes to the risk of lung cancer. MATERIALS AND METHODS: The contributions of the NBS1 Glu185Gln genotypes to lung cancer risk were investigated among 358 patients with lung cancer and 716 age- and gender-matched healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: GG, CG and CC NBS1 Glu185Gln genotype percentages were 45.2%, 43.9% and 10.9% in the patient group and 46.1%, 45.1% and 8.8% in the non-cancer control group, respectively (p for trend=0.5423). Analysis of allelic frequency distributions showed that the C allele of NBS1 Glu185Gln did not increase lung cancer susceptibility (p=0.4916). Interestingly, the CC genotypes at NBS1 Glu185Gln enhanced the risk of lung cancer among the males adjusted odds ratio (aOR)=1.85, 95% confidence interval (CI)=1.12-2.83 and among the smokers (aOR=1.76, 95% CI=1.09-2.64) but not among the females and non-smokers. CONCLUSION: The CC genotype of NBS1 Glu185Gln may increase lung cancer risk only for males and smokers and may serve as a practical marker for early detective and predictive purposes of lung cancer.

Patients with uterine leiomyoma exhibit a high incidence but low mortality rate for breast cancer.

The association of uterine leiomyoma with increased risk of breast cancer is controversial. Therefore, we used the National Health Insurance Research Database of Taiwan to examine breast cancer incidence and mortality among Asian patients with and without uterine leiomyoma. We compared breast cancer incidence and mortality between 22,001 newly diagnosed uterine leiomyoma patients and 85,356 individuals without uterine leiomyoma matched by age and date of diagnosis. Adjusted hazard ratios for breast cancer were estimated using the Cox model. The incidence of breast cancer was 35% higher in the uterine leiomyoma group than the leiomyoma-free group (1.65 vs. 1.22 per 1,000 individuals, p < 0.001), with an adjusted hazard ratio of 1.31 (95% confidence interval = 1.13-1.52). Interestingly, overall mortality was lower (4.12%) in the uterine leiomyoma group (mean followed time, 3.59 ± 2.70 years) than the leiomyoma-free group (8.78%; mean followed time, 3.54 ± 2.67 years) at the endpoint of the study (p <0.05). These findings indicate the incidence of breast cancer is higher in patients with uterine leiomyoma than in those without it, but overall mortality from breast cancer was lower in the patients with uterine leiomyoma.

The Contribution of Matrix Metalloproteinase-1 Genotypes to Hepatocellular Carcinoma Susceptibility in Taiwan.

BACKGROUND/AIM: Metalloproteinases (MMPs) are a family of proteases which have been shown to be overexpressed in various types of cancers. However, the contribution of MMP1 genotype to hepatocellular carcinoma (HCC) has not been well studied. This study aimed to evaluate the contribution of MMP1 promoter 1607 genotype to the risk of HCC in Taiwan, where HCC incidence is relatively high in the world. MATERIALS AND METHODS: In this case-control study, MMP1 genotype and its interaction with consumption of cigarettes and alcohol in determining HCC risk was investigated among 298 HCC patients and 889 age- and gender-matched healthy controls. RESULTS: The percentages of ever smokers and ever alcohol drinkers were much higher in the case group than in the control group. The percentages of 2G/2G, 1G/2G and 1G/1G for MMP1 promoter 1607 genotype were 37.2%, 38.3% and 24.5% in the HCC group and 34.8%, 44.0% and 21.2% in the control group, respectively (p for trend=0.2048). The allelic frequency distribution analysis showed the variant 1G allele of MMP1 promoter 1607 conferred similar HCC susceptibility as the wild-type 2G allele (odds ratio (OR)=1.01, 95% confidence interval (CI)=0.84-1.22, p=0.8735). As for the gene-lifestyle interaction, there was an obvious protective effect of MMP1 promoter 1607 1G allele on the risk of HCC among non-smokers, but not non-smokers, even alcohol drinkers or non-drinkers. CONCLUSION: The 1G allele of MMP1 promoter 1607 may have a protective effect on HCC risk for non-smokers in Taiwan and further validations are needed in other population groups.

Matrix Metalloproteinase-1 Genotype Contributes to the Risk of Non-solid Tumor in Childhood Leukemia.

AIM: Up-regulation of metalloproteinase (MMPs) proteins have been shown in various types of solid cancers and the genotype of MMP1 has been associated with the risk of solid cancers. However, the contribution of MMP1 genotype to leukemia has never been investigated to our knowledge. Therefore, in this study we aimed to evaluate the contribution of the genotypic variants in the promoter region of MMP1 to childhood acute lymphoblastic leukemia (ALL) risk in Taiwan. MATERIALS AND METHODS: In this case-control study, 266 patients with childhood ALL and 266 non-cancer controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The distribution of 2G/2G, 1G/2G and 1G/1G for MMP1 promoter rs1799750 genotype was 49.2%, 39.5% and 11.3% in the childhood ALL group and 36.8%, 43.6% and 19.5% in the non-cancer control group, respectively (p for trend=0.0046), significantly differentially distributed between childhood ALL and control groups. The carrier comparisons in dominant and recessive models also support the findings that 1G appears to be the protective allele in childhood ALL. In genotype and gender interaction analysis, it was found that boys carrying the MMP1 rs1799750 1G/2G or 1G/1G genotypes had lower odds ratios(ORs) of 0.68 and 0.43 [95% confidence intervals (CI)=0.47-0.98 and 0.26-0.73, p=0.0395 and 0.0013, respectively] for childhood ALL than those carrying the 2G/2G genotype. Analysis of genotype inaction with age of onset age showed those aged less than 3.5 years at onset carrying the 1G/2G or 1G/1G genotypes had lower ORs (0.0183 and 0.0004, respectively) for childhood ALL, but there was no such difference for those having an age at onset of 3.5 years or more. CONCLUSION: Our results indicate that the MMP1 rs1799750 1G allele is a protective biomarker for childhood ALL.

Association of Enhancer of Zeste 2 (EZH2) Genotypes with Bladder Cancer Risk in Taiwan.

AIM: Bladder cancer is the sixth most common cancer worldwide and its incidence is particularly high in many developed regions including southwestern Taiwan. However, the genetic contribution to the etiology of bladder cancer is not well-understood. The aim of this study was to evaluate the association of the enhancer of zeste homolog 2 (EZH2) genotypes with Taiwan bladder cancer risk. MATERIALS AND METHODS: Three polymorphic variants of EZH2 were analyzed regarding their association with bladder cancer risk, and three hundred and seventy-five patients with bladder cancer and same number of age- and gender-matched healthy controls recruited were genotyped by the PCR-RFLP method. RESULTS: Among the three polymorphic sites examined, the genotypes of EZH2 rs887569 (C to T), but not rs41277434 (A to C) or rs3757441 (T to C), were positively associated with bladder cancer risk (p for trend =0.0146). Individuals with the EZH2 rs887569 TT genotypes were associated with decreased cancer risk than those with wild-type CC genotype. The stratified analyses showed that EZH2 rs887569 TT genotypes had protective effects on non-smokers but obviously not on smokers. CONCLUSION: Our findings provide evidence that the T allele of EZH2 rs887569 may be associated with the lower risk of bladder cancer development, especially among non-smokers.

Baicalin Scavenged Reactive Oxygen Species and Protected Human Keratinocytes Against UVB-induced Cytotoxicity.

Ultraviolet B (UVB), with a wavelength of 280-320 nm, represents one of the most important environmental factors for skin disorders, including sunburn, hyperpigmentation, solar keratosis, solar elastosis and skin cancer. Therefore, protection against excessive UVA-induced damage is useful for prevention of sunburn and other human diseases. Baicalin, a major component of traditional Chinese medicine Scutellaria baicalensis, has been reported to possess antioxidant and cytostatic capacities. In this study, we examined whether baicalin is also capable of protecting human keratinocytes from UVB irradiation. The results showed that baicalin effectively scavenged reactive oxygen species (ROS) elevated within 4 h after UVB radiation and reversed the UVB-suppressed cell viability and UVB-induced apoptosis after 24 h. Our results demonstrated the utility of baicalin to complement the contributions of traditional Chinese medicine in UVB-induced damage to skin and suggested their potential application as pharmaceutical agents in long-term sun-shining injury prevention.

The Contribution of Matrix Metalloproteinase-1 Genotype to Oral Cancer Susceptibility in Taiwan.

AIM: Metalloproteinases (MMPs) are a family of multifunctional proteins which have been shown to be up-regulated in various types of cancer. However, the contribution of MMP1 genotype to oral cancer has not been elucidated. This study aimed to evaluate the contribution of MMP1 promoter 1607 genotype to the risk of oral cancer. MATERIALS AND METHODS: In this case-control study, MMP1 genotype and its interaction with consumption of areca, cigarettes, and alcohol in determining oral cancer risk were investigated in 788 patients with oral cancer and 956 gender-matched healthy controls. RESULTS: The distribution of 2G/2G, 1G/2G and 1G/1G for MMP1 promoter 1607 genotype was 36.8%, 40.2% and 23.0% in the oral cancer group and 34.3%, 44.9% and 20.8% in the non-cancer control group, respectively (p for trend=0.1454). We also analyzed the allelic frequency distributions and found that the variant 1G allele of MMP1 promoter 1607 conferred similar oral cancer susceptibility as the wild-type 2G allele (odds ratio=0.99, 95% confidence interval=0.87-1.14, p=0.9199). As for the gene-lifestyle interaction, there was an obvious protective effect of MMP1 promoter 1607 1G/2G genotype on the risk of oral cancer among smokers (odds ratio=0.71, 95% confidence interval=0.55-0.91, p=0.0076), but not non-smokers. There was no interaction between MMP1 promoter 1607 genotype and areca chewing or alcohol drinking habits. CONCLUSION: The 1G/2G genotype of MMP1 promoter 1607 may have a protective effect on oral cancer risk for smokers. The detailed mechanisms involved in this require further investigation.

Matrix Metalloproteinase-1 Genetic Polymorphism in Breast Cancer in Taiwanese.

AIM: Metalloproteinases (MMPs) are a family of enzymes involved in many physiological processes, such as skeletal development, wound healing, and scar formation, as well as carcinogenesis. However, the contribution of MMP1 genotype to breast cancer has not been elucidated. This study aimed to evaluate the contribution of commonly studied MMP1 promoter 1607 genotype to breast cancer risk. MATERIALS AND METHODS: In this hospital-based case-control study, contribution of MMP1 genotype to breast cancer risk was evaluated among 1,232 patients with breast cancer and 1,232 gender-matched healthy controls. RESULTS: The distribution of 2G/2G, 1G/2G and 1G/1G for MMP1 promoter 1607 genotype was 36.0%, 41.3% and 22.7% in the breast cancer group and 34.2%, 44.5% and 21.3% in the non-cancer group, respectively (p for trend=0.2820). We also analyzed the allelic frequency distributions and found that the variant 1G allele of MMP1 promoter 1607 conferred similar breast cancer susceptibility as the wild-type 2G allele (odds ratio=0.99, 95% confidence interval=0.89-1.11, p=0.8858). There was no interaction between MMP1 promoter 1607 genotype and cigarette smoking or alcohol drinking habits. CONCLUSION: The genotype of MMP1 promoter 1607 may not be a major determining factor for breast cancer risk. The contribution of MMP1 promoter 1607 genotype to prognosis and subtypes of breast cancer needs further investigation.