Residential mobility and liver cancer risk: findings from a prospective cohort study in Chinese women.

BACKGROUND: Residential mobility is believed to influence the occurrence and development of cancer; however, the results are inconclusive. Furthermore, limited studies have been conducted on Asian populations. This study aimed to evaluate the relationship between residential mobility and liver cancer risk among Chinese women. METHODS: We enrolled 72,818 women from urban Shanghai between 1996 and 2000, and then followed them until the end of 2016. Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to assess the association between residential mobility and liver cancer risk. A linear trend test was conducted by ranking variables. A sensitivity analysis was also conducted, excluding participants with follow-up times of less than 2 years, to prevent potential bias. RESULTS: During the 1,269,765 person-years of follow-up, liver cancer was newly diagnosed in 259 patients. Domestic migration (HR = 1.47, 95% CI, 1.44-1.50), especially immigration to Shanghai (HR = 1.47, 95% CI, 1.44-1.50) was associated with an increased risk of liver cancer. In addition, migration frequency, age at initial migration and first immigration to Shanghai had linear trends with an increased liver cancer risk (Ptrend <0.001). The results were similar when excluding participants with less than two years of follow-up. CONCLUSIONS: The possible association between residential mobility and a higher risk of liver cancer in women could suggest the need for effective interventions to reduce adverse environmental exposures and enhance people's health.

Sex-specific impact of dietary patterns on liver cancer incidence: updated results from two population-based cohort studies in China.

PURPOSE: The associations between dietary patterns and liver cancer risk have received much attention, but evidence among the Chinese population is scarce. This study aims to update the results of two cohort studies and provide the sex-specific associations in the Chinese population. METHODS: This study was based on two cohorts from the Shanghai Men's Health Study (SMHS) and the Shanghai Women's Health Study (SWHS). Diet information was collected by validated food frequency questionnaires. Dietary patterns were derived by factor analysis. Cox regression model was utilized to estimate the hazard ratio (HR) and 95% confidence interval (CI) for associations between dietary patterns and liver cancer risk. RESULTS: During median follow-up years of 11.2 (male) and 17.1 (female) years, 427 males and 252 females were identified as incident primary liver cancer cases. In males, vegetable-based dietary pattern was inversely associated with liver cancer (HRQ4-Q1: 0.67, 95%CI 0.51-0.88, Ptrend < 0.001). Interaction analysis indicated that in males lower vegetable-based dietary pattern score and older age/medical history of chronic hepatitis combined increase the hazard of liver cancer more than the sum of them, with a 114% and 1061% higher risk, respectively. In females, the fruit-based dietary pattern was associated with a reduced risk of liver cancer (HRQ4-Q1: 0.63, 95%CI 0.42-0.95, Ptrend = 0.03). In both males and females, null associations were observed between the meat-based dietary pattern and the risk of liver cancer. CONCLUSION: A vegetable-based dietary pattern in males and a fruit-based dietary pattern in females tended to have a protective role on liver cancer risk. This study provided updated information that might be applied to guide public health action for the primary prevention of liver cancer.

Prediagnostic plasma metabolite concentrations and liver cancer risk: a population-based study of Chinese men.

BACKGROUND: Previous metabolic profiling of liver cancer has mostly used untargeted metabolomic approaches and was unable to quantitate the absolute concentrations of metabolites. In this study, we examined the association between the concentrations of 186 targeted metabolites and liver cancer risk using prediagnostic plasma samples collected up to 14 years prior to the clinical diagnosis of liver cancer. METHODS: We conducted a nested case-control study (n = 322 liver cancer cases, n = 322 matched controls) within the Shanghai Men's Health Study. Conditional logistic regression models adjusted for demographics, lifestyle factors, dietary habits, and related medical histories were used to estimate the odds ratios. Restricted cubic spline functions were used to characterise the dose-response relationships between metabolite concentrations and liver cancer risk. FINDINGS: After adjusting for potential confounders and correcting for multiple testing, 28 metabolites were associated with liver cancer risk. Significant non-linear relationships were observed for 22 metabolites. The primary bile acid biosynthesis and phenylalanine, tyrosine and tryptophan biosynthesis were found to be important pathways involved in the aetiology of liver cancer. A metabolic score consisting of 10 metabolites significantly improved the predictive ability of traditional epidemiological risk factors for liver cancer, with an optimism-corrected AUC increased from 0.84 (95% CI: 0.81-0.87) to 0.89 (95% CI: 0.86-0.91). INTERPRETATION: This study characterised the dose-response relationships between metabolites and liver cancer risk, providing insights into the complex metabolic perturbations prior to the clinical diagnosis of liver cancer. The metabolic score may serve as a candidate risk predictor for liver cancer. FUNDING: National Key Project of Research and Development Program of China [2021YFC2500404, 2021YFC2500405]; US National Institutes of Health [subcontract of UM1 CA173640].

A diet-wide association study for liver cancer risk: findings from a prospective cohort study in Chinese men.

Dietary factors have been extensively investigated as possible risk factors for liver cancer, but the evidence is inconclusive. Our study systematically assessed the association between 142 foods and nutrients and liver cancer risk in a Chinese population using a diet-wide association study. Based on data from 59,844 men in the Shanghai Men's Health Study (SMHS), we assessed the diet intake by dietary questionnaires. Cox regression was used to quantify the association between each food and nutrient and liver cancer risk. A false discovery rate (FDR) of 0.05 was used to select the foods and nutrients for validation. In the cohort, 431 liver cancer cases were identified during 712,373 person-years of follow-up. Retinol (HR per 1 SD increment = 1.09, 95% CI: 1.03-1.14) was associated with a higher risk of liver cancer, whereas onions (HR per 1 SD increment = 0.67, 95% CI: 0.54-0.84) and manganese (HR per 1 SD increment = 0.85, 95% CI: 0.78-0.94) were inversely associated with liver cancer risk. In the replication analysis, estimates for these foods and nutrients were similar in magnitude and direction. Our findings confirm that retinol, onions and manganese were associated with liver cancer risk, which provides reliable evidence between diet and liver cancer development.

Sex-Specific Correlation Analysis of Branched-Chain Amino Acids in Dietary Intakes and Plasma among Chinese Adults.

BACKGROUND: Previous findings about the influence of dietary intakes of the branched-chain amino acid (BCAA) on their plasma concentrations have been limited and inconsistent, and evidence from the Chinese population was lacking. OBJECTIVES: This study aimed to investigate the diet-plasma BCAA correlations in Chinese male and female adults. METHODS: This cross-sectional study was based on a nested case-control study within 2 prospective population-based cohorts in Shanghai, China. Diet information was collected by the food frequency questionnaires. Plasma BCAA concentrations were measured by ultraperformance liquid chromatography coupled with tandem mass spectrometry. Spearman correlations and linear regression models were conducted to examine the relationships between dietary BCAA intakes and plasma BCAA. The multivariable model was adjusted for age at the interview, total energy intake, time of blood collection from last meal, dietary patterns, body mass index (in kg/m2), type 2 diabetes, and physical activity. RESULTS: A total of 322 males (median age of 57.0 y) and 187 females (median age of 60.0 y) were included in this cross-sectional study. The geometric means of dietary intake of leucine, isoleucine, valine, and BCAA were 4937.7, 3029.6, 3268.5, and 11237.4 mg/d in males, and 4125.7, 2567.8, 2754.3, and 9449.4 mg/d in females. The geometric means of plasma concentrations of leucine, isoleucine, valine, and BCAA were 181.9, 65.0, 219.8, and 469.4 µM/L in males and 161.6, 61.1, 206.5, and 431.6 µM/L in females. Only leucine (r = 0.1660, P = 0.0028) and total BCAA (r = 0.1348, P = 0.0155) in males exhibited weak positive correlation coefficients. After adjustment for the covariates, leucine, isoleucine, valine, and total BCAA in dietary intakes and plasma were not correlated in both males and females. CONCLUSIONS: In Chinese male and female adults, dietary intakes are not major determinants of plasma concentrations of BCAA, and plasma concentrations might not be reflected by usual dietary intakes of BCAA.

Cumulative consumption of tea is associated with lower risk of liver cancer: Updated results from the Shanghai Women's Health Study.

Prospective epidemiological studies have provided limited evidence for an association between tea consumption and liver cancer risk. Based on a population-based prospective cohort study in middle-aged Chinese women, we investigated the association between tea consumption and the risk of primary liver cancer. Detailed information on tea drinking habits and other potential confounders was obtained at the baseline interview. Incident liver cancer cases were identified through record linkage with the population-based cancer registry and verified through home visits and review of medical charts by medical experts. Multiple aspects of tea drinking habits including starting age, duration, intensity and cumulative consumption of any type of tea and green tea were considered. Multivariable-adjusted hazard ratios (aHRs) and their 95% confidence intervals (CIs) were derived from the Cox regression models. After a median follow-up time of 18.12 (interquartile range = 1.59) years, 253 incident liver cancer cases were identified from 71 841 cohort members. Compared with never tea drinkers, the risk of liver cancer for participants who have consumed over 30 kg of dried tea leaves cumulatively was 0.56 (95% CI: 0.32-0.97). For those who drank green tea only, the aHR was 0.54 (95% CI: 0.30-0.98). This updated study suggested an inverse association between cumulative consumption of tea, especially green tea and the risk of primary liver cancer.

A prospective cohort study of cigarette smoking, alcohol drinking and liver cancer incidence in Chinese men.

OBJECTIVES: Population-based prospective studies on the associations of cigarette smoking, alcohol drinking, and primary liver cancer remain limited in Mainland China. Our study was designed to evaluate such relationships in middle-aged Chinese men. METHODS: Self-reported habits of cigarette smoking and alcohol drinking were obtained from all cohort members at the baseline survey. The outcomes were identified through in-person follow-up and annual record linkage to multiple statistics of vital and cancer registration. Age-adjusted and multivariable-adjusted hazard ratio (HR) and their corresponding 95% confidence interval (CI) were estimated utilizing the Cox regression model. RESULTS: After a median follow-up of 12.31 years, 329 cases of incident primary liver cancer occurred among 45 266 male participants. Compared with never smoker, former smoker was positively associated with liver cancer risk, with a multivariable-adjusted HR of 1.42 (95% CI 1.02-1.98). Individuals who had smoked for more than 40 years had a 49% increased risk of liver cancer (HR≥40 years  1.49, 95% CI 1.04-2.14). The association of alcohol drinking with liver cancer showed no statistical significance. CONCLUSIONS: Our study provided evidence that cigarette smoking was positively associated with an increased liver cancer risk among Chinese men. Attention to such non-viral modifiable risk factors to prevent liver cancer effectively is needed.

Incidence, Mortality Features and Lifetime Risk Estimation of Digestive Tract Cancers in an Urban District of Shanghai, China.

Digestive tract cancers are the common cause of cancer deaths in both China and worldwide. This study aimed to describe the burden, recent trends and lifetime risks in the incidence and mortality of digestive tract cancers in an urban district of Shanghai, China. Our study extracted data on stomach, colon, rectum and liver cancers diagnosed in Changning District between 2010 and 2019 from the Shanghai Cancer Registry. We calculated age-standardized incidence and mortality rates, the risks of developing and dying from cancer, and the estimated annual percent changes. Between 2010 and 2019, 8619 new cases and 5775 deaths were registered with digestive tract cancers in the district. The age-standardized incidence rates (ASIRs) of liver cancer decreased steadily, whereas the ASIRs of stomach, colon and rectum cancers remained stable from 2010 to 2019. The age-standardized mortality rates (ASMRs) of stomach and liver cancers showed significant declining changes from 2010 to 2019 in both sexes, but that of colon and rectum cancers remained stable during the entire period. The risks of developing and dying from digestive tract cancers were substantially higher in men than women. The burden of digestive tract cancer and its disparities between sex and age group remain major public health challenges in urban Shanghai. To reduce the burden of digestive tract cancers, the government and researchers should develop and promote a healthy diet, organize a screening, and reduce the prevalence of smoking, alcohol drinking, and hepatitis B virus and hepatitis C virus infections.

Dose-response relationship between fat distribution and liver cancer incidence: A prospective cohort study in Chinese men.

BACKGROUND: Based on a prospective cohort study in middle-aged Chinese men, the current study characterized the dose-response relationships between fat distribution measurements and the incidence of primary liver cancer. METHODS: Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by Cox regression models for the association between waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), a body shape index (ABSI), and body roundness index (BRI) with liver cancer incidence. Dose-response curves were characterized using a restricted cubic spline function. RESULTS: After a mean follow-up time of 11.9 (SD = 2.4) years, 440 liver cancer cases were identified from 60,625 participants. WC, WHtR, ABSI, and BRI were found to be associated with an increased risk of liver cancer at a given level of body mass index (BMI), with multivariable-adjusted HRs of 1.19 (95% CI: 1.01-1.41), 1.26 (95% CI: 1.02-1.50), 1.12 (95% CI: 1.05-1.23) and 1.28 (95% CI: 1.08-1.53) for per SD increment, respectively. Dose-response curves suggested that the risk increased rapidly above the median levels of WC, WHtR, and BRI. For ABSI, the risk decreased from the minimum level to about the 35th percentile and increased slowly thereafter. CONCLUSIONS: The current study suggested an association between abdominal obesity in middle age and increased risk of primary liver cancer at a given level of BMI. WHtR and BRI were better predictors of liver cancer risk compared with WC and ABSI.

Joint impact of BMI, physical activity and diet on type 2 diabetes: Findings from two population-based cohorts in China.

AIMS: Limited epidemiological data on the combined impact of several lifestyle factors on type 2 diabetes (T2D) incidence was reported in Chinese population. This study aimed to examine how combinations of BMI, physical activity and diet relate to T2D incidence and estimate corresponding population attributable risk in the general population. METHODS: A total of 56,691 male and 70,849 female participants aged 40-74 years old in two population-based cohorts from the Shanghai Men's and Women's Health Studies were used for analysis. The Cox regression model was used to estimate the association between lifestyle factors collected at baseline and T2D incidence. Multivariable-adjusted population attributable risks were calculated for specific combinations of lifestyle factors. RESULTS: There were 3315 male and 5925 female incident T2D, with corresponding density incidence rates of 6.39 and 6.04 per 1000 person-years. If the healthiest group of healthy lifestyle index (HLI) was used as a reference, the hazard ratios (95% confidence intervals) of T2D increased monotonically in men [2.04 (1.75, 2.38); 2.94 (2.53, 3.42); 4.31 (3.66, 5.07)] and women [1.85 (1.64, 2.08); 2.79 (2.49, 3.13); 4.14 (3.66, 4.67)]. One point increase of HLI was related to 35% and 35% lower risk in men and women. About 52.7% and 58.4% cases in men and women could have been avoided if participants had been adherent to a healthy lifestyle of maintaining healthy body weight, eating a healthy diet and keeping physically active. CONCLUSIONS: An increased number of healthy lifestyle factors were associated with a decreased risk of T2D in the Chinese population. Future interventions targeted at combined healthy lifestyle factors are needed to reduce the burden of T2D.

Dose-Response Association between Adiposity and Liver Cancer Incidence: A Prospective Cohort Study among Non-Smoking and Non-Alcohol-Drinking Chinese Women.

BACKGROUND: Based on a population with very low prevalence of smoking and alcohol drinking, we examined the associations between overall obesity and fat distribution in middle age, obesity in early adulthood, and adult weight gain with the risk of liver cancer incidence. METHODS: The associations between body mass index (BMI) at study enrollment and at age 20, waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), adult weight gain, and annual average weight gain with the risk of liver cancer were estimated using Cox regression models. Multivariable-adjusted HRs and 95% confidence intervals (CIs) were calculated. RESULTS: After a mean follow-up time of 17.5 years, 241 liver cancer cases were identified from 69,296 participants. The HRs for per 5-kg/m2 increment of BMI, per 10-cm increment of WC and HC, and per 0.1-unit increment of WHtR in middle age were 1.29 (95% CI, 1.07-1.57), 1.23 (95% CI, 1.05-1.43), 1.30 (95% CI, 1.10-1.55), and 1.37 (95% CI, 1.07-1.75), respectively. The HRs for per 5-kg increment of absolute adult weight gain and per 0.5-kg/year increment of annual average weight gain were 1.15 (95% CI, 1.06-1.25) and 1.44 (95% CI, 1.08-1.92). CONCLUSIONS: Overall and abdominal obesity in middle age and weight gain through adulthood were positively associated with liver cancer risk among non-smoking and non-alcohol-drinking women. IMPACT: Based on a cohort of non-smoking and non-alcohol-drinking women, the current study confirmed the association between obesity in middle age and increased liver cancer risk and suggested weight gain through adulthood as a risk factor for liver cancer.

Population attributable risk of excess weight, abdominal obesity and physical inactivity for type 2 diabetes in Chinese men and women.

BACKGROUND: Given the high prevalence of type 2 diabetes mellitus (T2DM) in the Chinese population, it is necessary to estimate the T2DM incident attributable to obesity and physical inactivity. METHODS: We analyzed the data from the Shanghai Men's and Women's Health Studies, including 56,691 men and 70,849 women aged 40-74. The hazard ratios (HRs) and the population attributable risks (PARs) were calculated by Cox regression model and model-based estimation. RESULTS: A total of 3,315 male and 5,925 female cases were identified during 519,157 and 981,504 person-years, up to 31 December 2017. Excess weight, abdominal obesity were associated with the increased risks of T2DM both in women and men, while physical inactivity was only associated with an increased risk in men. A large proportion of T2DM incident cases can be attributed to excess body weight (women: 48.6%; men: 41.5%) and abdominal obesity (women: 50.4%; men: 30.3%). Physical activity was negatively associated with the risk of T2DM (Ptrend<0.01). The PARs adjusted for confounders were 3.6% for physical inactivity in men and 1.7% in women. CONCLUSIONS: Excess weight and abdominal obesity accounted for a large proportion of T2DM incident cases in men and women; a small part of T2DM cases were attributed to physical inactivity in men. Weight control is of great significance in curbing the epidemic of diabetes.

Dietary fat intake and liver cancer incidence: A population-based cohort study in Chinese men.

To date, limited studies have focused on the association between dietary fat and liver cancer risk, especially in China. Our study aims to evaluate the association between dietary fat intake and liver cancer incidence risk in men. Dietary fat intake was obtained through a validated food frequency questionnaire in a Chinese prospective cohort. The Cox regression model was utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). After exclusion, 59 998 recruitments were finally analyzed with a total follow-up time of 714 339 person-years, 431 incident liver cancer cases were newly identified among them. The adjusted HRs (95% CIs) for the highest vs lowest quartile of total fat, saturated fat, monounsaturated fat (MUFA), and polyunsaturated fat (PUFA) were 1.33 (1.01-1.75), 1.50 (1.13-1.97), 1.26 (0.96-1.65), and 1.41 (1.07-1.86), and the corresponding P-trend values were .008, .005, .034, and .005, respectively. In the secondary analysis among participants tested for hepatitis B virus, we found that higher intakes of saturated fat and PUFA were also associated with increased liver cancer risks. Besides, high risks of per standard deviation alterations of the total fat, saturated fat and MUFA were detected in liver cancer, and these results were similar to those concluded from the full-cohort analysis. In conclusion, dietary intakes of total fat, saturated fat, PUFA, and probably MUFA might increase liver cancer risks. Our study provides suggestive advice to public administration on dietary suggestions, and related measures taken from managing dietary fat intake might reduce liver cancer incidence.

Tea Drinking and Risk of Cancer Incidence: A Meta-Analysis of Prospective Cohort Studies and Evidence Evaluation.

Here we provide a comprehensive meta-analysis to summarize and appraise the quality of the current evidence on the associations of tea drinking in relation to cancer risk. PubMed, Embase, and the Cochrane Database of Systematic Reviews were searched up to June 2020. We reanalyzed the individual prospective studies focused on associations between tea drinking and cancer risk in humans. We conducted a meta-analysis of prospective studies and provided the highest- versus lowest-category analyses, dose-response analyses, and test of nonlinearity of each association by modeling restricted cubic spline regression for each type of tea. We graded the evidence based on the summary effect size, its 95% confidence interval, 95% prediction interval, the extent of heterogeneity, evidence of small-study effects, and excess significance bias. We identified 113 individual studies investigating the associations between tea drinking and 26 cancer sites including 153,598 cancer cases. We assessed 12 associations for the intake of black tea with cancer risk and 26 associations each for the intake of green tea and total tea with cancer risk. Except for an association between lymphoid neoplasms with green tea, we did not find consistent associations for the highest versus lowest categories and dose-response analyses for any cancer. When grading current evidence for each association (number of studies ≥2), weak evidence was detected for lymphoid neoplasm (green tea), glioma (total tea, per 1 cup), bladder cancer (total tea, per 1 cup), and gastric and esophageal cancer (tea, per 1 cup). This review of prospective studies provides little evidence to support the hypothesis that tea drinking is associated with cancer risk. More well-designed studies are still needed to identify associations between tea intake and rare cancers.

Coffee drinking and cancer risk: an umbrella review of meta-analyses of observational studies.

BACKGROUND: Epidemiological studies on the association between coffee intake and cancer risk have yielded inconsistent results. To summarize and appraise the quality of the current evidence, we conducted an umbrella review of existing findings from meta-analyses of observational studies. METHODS: We searched PubMed, Embase, Web of Science and the Cochrane database to obtain systematic reviews and meta-analyses of associations between coffee intake and cancer incidence. For each association, we estimated the summary effect size using the fixed- and random-effects model, the 95% confidence interval, and the 95% prediction interval. We also assessed heterogeneity, evidence of small-study effects, and excess significance bias. RESULTS: Twenty-eight individual meta-analyses including 36 summary associations for 26 cancer sites were retrieved for this umbrella review. A total of 17 meta-analyses were significant at P ≤ 0.05 in the random-effects model. For the highest versus lowest categories, 4 of 26 associations had a more stringent P value (P ≤ 10- 6). Associations for five cancers were significant in dose-response analyses. Most studies (69%) showed low heterogeneity (I2 ≤ 50%). Three and six associations had evidence of excessive significance bias and publication bias, respectively. Coffee intake was inversely related to the risk of liver cancer and endometrial cancer and was characterized by dose-response relationships. There were no substantial changes when we restricted analyses to meta-analysis of cohort studies. CONCLUSIONS: There is highly suggestive evidence for an inverse association between coffee intake and risk of liver and endometrial cancer. Further research is needed to provide more robust evidence for cancer at other sites.

Panax notoginseng saponins decrease cholesterol ester via up-regulating ATP-binding cassette transporter A1 in foam cells.

AIM: Accumulating evidence has indicated that Panax notoginseng saponins (PNS), the major ingredients in Panax notoginseng (Burk.) F.H. Chen which could be found widely in Asia, can attenuate atherogenesis in vivo. This study was designed to examine the relationship of PNS with cholesterol ester in foam cells sourced from macrophages and the effect of PNS on the expression of ATP-binding cassette transporter A1 (ABCA1). MATERIALS AND METHODS: Foam cells sourced from macrophages were cultured with PNS. The content of cholesterol ester in foam cells was analyzed and expressions of ABCA1 and liver X receptor α (LXRα) in foam cells were measured by real-time PCR and western blotting methods. RESULTS: The results showed that PNS could significantly decrease the level of cholesterol ester in foam cells at middle and high dosages. The real-time PCR and western blotting assays indicated that the expression of ABCA1 was up-regulated by PNS in a dose-dependent manner. Analysis based on these results showed that the cholesterol ester level was negatively correlated with ABCA1 expression. CONCLUSIONS: As a result, we conclude that by up-regulating the expression of ABCA1, PNS could lower the cholesterol ester level, which resulted in the attenuation of the foam cell formation. This bioactivity might be associated with the special chemical structures of PNS that are similar to the natural agonist of LXRα.

[The effect of cyclooxygenase-2 on lymphangiogenesis in breast cancer].

OBJECTIVE: To study the effect of cyclooxygenase-2 (COX-2) on lymphangiogenesis in breast cancer. METHODS: By the means of immunohistochemistry, COX-2, vascular endothelial growth factor-C (VEGF-C) and D2-40 were examined in the tissue samples of primary tumors from 94 patients underwent surgical resections for breast cancer from November 1998 to March 2002. Eighty-three patients were followed-up. The expressions of VEGF-C mRNA and protein were detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot in MDA-MB-231 cell lines by the treatment of selective COX-2 inhibitor Nimesulide at different doses. The expressions of VEGF-C protein were evaluated in MDA-MB-231 cells treated by PGE2 (1 microg/ml) and Trastuzumab (1 microg/ml), respectively. RESULTS: COX-2 over-expression was observed in 46.8% of surgical specimens (44/94), while VEGF-C overexpression occurred in 51.1% of tumor samples (48/94). COX-2 was strongly correlated with VEGF-C expression (P < 0.01), micro-lymphatic vessels (P = 0.032) and metastatic lymph nodes (P = 0. 035). Patients with COX-2 positive tumors had a significant shorter survival time than those with negative tumors did, including disease-free survival (P = 0.010) and overall survival (P = 0.040). Nimesulide could down-regulate the expressions of VEGF-C mRNA and protein in a does-dependent manner, while PGE2 could up-regulate the expressions. The expression of VEGF-C protein up-regulated by PGE2 treatment was decreased by Trastuzumab. CONCLUSIONS: COX-2 over-expression can up-regulate the expression of VEGF-C. VEGF-C might promote lymph node metastasis by a lymph-angiogenic pathway, then affect the prognosis of the patients with breast cancer.