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Kensler T.W.,University of Pittsburgh | Chen J.-G.,Qidong Liver Cancer Institute | Chen T.-Y.,Qidong Liver Cancer Institute
Topics in Current Chemistry | Year: 2013

Sulforaphane is a promising agent under preclinical evaluation in many models of disease prevention. This bioactive phytochemical affects many molecular targets in cellular and animal models; however, amongst the most sensitive is Keap1, a key sensor for the adaptive stress response system regulated through the transcription factor Nrf2. Keap1 is a sulfhydryl-rich protein that represses Nrf2 signaling by facilitating the polyubiquitination of Nrf2, thereby enabling its subsequent proteasomal degradation. Interaction of sulforaphane with Keap1 disrupts this function and allows for nuclear accumulation of Nrf2 and activation of its transcriptional program. Enhanced transcription of Nrf2 target genes provokes a strong cytoprotective response that enhances resistance to carcinogenesis and other diseases mediated by exposures to electrophiles and oxidants. Clinical evaluation of sulforaphane has been largely conducted by utilizing preparations of broccoli or broccoli sprouts rich in either sulforaphane or its precursor form in plants, a stable β-thioglucose conjugate termed glucoraphanin. We have conducted a series of clinical trials in Qidong, China, a region where exposures to food-and air-borne carcinogens has been considerable, to evaluate the suitability of broccoli sprout beverages, rich in either glucoraphanin or sulforaphane or both, for their bioavailability, tolerability, and pharmacodynamic action in population-based interventions. Results from these clinical trials indicate that interventions with well characterized preparations of broccoli sprouts may enhance the detoxication of aflatoxins and air-borne toxins, which may in turn attenuate their associated health risks, including cancer, in exposed individuals. © 2013 Springer-Verlag Berlin Heidelberg.


Guo W.,Fudan University | Guo W.,Shanghai JiaoTong University | Qiu Z.,Shanghai JiaoTong University | Wang Z.,Fudan University | And 11 more authors.
Hepatology | Year: 2015

Cancer cells possess a unique metabolic phenotype that allows them to preferentially utilize glucose through aerobic glycolysis. This phenomenon is referred to as the "Warburg effect." Accumulating evidence suggests that microRNAs (miRNAs), a class of small noncoding regulatory RNAs, interact with oncogenes/tumor suppressors and induce such metabolic reprograming in cancer cells. To systematically study the metabolic roles of miRNAs in cancer cells, we developed a gain-of-function miRNA screen in HeLa cells. Subsequent investigation of the characterized miRNAs indicated that miR-199a-5p acts as a suppressor for glucose metabolism. Furthermore, miR-199a-5p is often down-regulated in human liver cancer, and its low expression level was correlated with a low survival rate, large tumor size, poor tumor differentiation status, high tumor-node-metastasis stage and the presence of tumor thrombus of patients. MicroRNA-199a-5p directly targets the 3'-untranslated region of hexokinase 2 (HK2), an enzyme that catalyzes the irreversible first step of glycolysis, thereby suppressing glucose consumption, lactate production, cellular glucose-6-phosphate and adenosine triphosphate levels, cell proliferation, and tumorigenesis of liver cancer cells. Moreover, HK2 is frequently up-regulated in liver cancer tissues and associated with poor patient outcomes. The up-regulation of hypoxia-inducible factor-1α under hypoxic conditions suppresses the expression of miR-199a-5p and promotes glycolysis, whereas reintroduction of miR-199a-5p interferes with the expression of HK2, abrogating hypoxia-enhanced glycolysis. Conclusion: miR-199a-5p/HK2 reprograms the metabolic process in liver cancer cells and provides potential prognostic predictors for liver cancer patients. © 2015 by the American Association for the Study of Liver Diseases.


Hu L.,Nanjing Medical University | Zhai X.,U.S. Center for Disease Control and Prevention | Liu J.,Nantong Tumor Hospital | Chu M.,Nanjing Medical University | And 7 more authors.
Hepatology | Year: 2012

Recent genome-wide association studies showed that four single-nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA)-DP (rs3077and rs9277535) and HLA-DQ (rs2856718 and rs7453920) were associated with chronic hepatitis B virus (HBV) infection in Japanese populations. More than 75% of hepatocellular carcinoma (HCC) patients are attributable to persistent infection of hepatitis B virus (HBV), especially in China. We genotyped these four SNPs in 1,300 HBV-positive HCC patients, 1,344 persistent HBV carriers, and 1,344 persons with HBV natural clearance from Southeast China to further test the associations of HLA-DP/DQ variants and with risk of both HBV clearance and HCC development. Logistic regression analyses showed that HLA-DQ rs2856718 significantly decreased host HCC risk, whereas three SNPs were associated with HBV clearance (HLA-DP rs9277535 as well as HLA-DQ rs7453920 and rs2856718). In addition, HLA-DP rs3077 showed an approaching significant effect on susceptibility to HBV persistent infection and HCC development when considering multiple testing adjustments. Taken together, we report, for the first time, that genetic variants in the HLA-DP and HLA-DQ loci may be marker SNPs for risk of both HBV clearance and HCC development. © 2011 American Association for the Study of Liver Diseases.


Tolstov Y.L.,University of Pittsburgh | Knauer A.,University of Pittsburgh | Chen J.G.,Qidong Liver Cancer Institute | Kensler T.W.,University of Pittsburgh | And 4 more authors.
Emerging Infectious Diseases | Year: 2011

Merkel cell polyomavirus (MCV) is a recently discovered virus that causes 80% of Merkel cell carcinomas. We examined data for 564 gay/bisexual male participants >18 years of age in the Multicenter AIDS Cohort Study in Pittsburgh, Pennsylvania, USA, and found that 447 (79.3%) were MCV-antibody positive at initial enrollment. Of the 117 MCV-seronegative men, 31 subsequently seroconverted over a 4-year follow-up period, corresponding to a 6.6% annual conversion rate. MCV immunoglobulin G levels remained detectable up to 25 years after exposure. No signs, symptoms, or routine diagnostic test results were associated with MCV infection, and no correlation between HIV infection or AIDS progression and MCV infection was noted. An initial correlation between chronic hepatitis B virus infection and MCV prevalence could not be confirmed among MCV seroconverters or in studies of a second hepatitis B virus-hyperendemic cohort from Qidong, China. In adults, MCV is typically an asymptomatic, common, and commensal viral infection that initiates rare cancers after virus (rather than host cell) mutations.


Qu L.,Nantong University | Kuai X.,Nantong University | Liu T.,Fudan University | Chen T.,Qidong Liver Cancer Institute | And 2 more authors.
PLoS ONE | Year: 2013

Background/Aim: To investigate the roles of biomedical factors, hepatitis B virus (HBV) DNA levels, genotypes, and specific viral mutation patterns on the progression of hepatocellular carcinoma (HCC) patients below 40 years of age in Qidong, China. Methods: We conducted a case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence was determined in 49 HCC and 90 chronic hepatitis (CH) patients below 40 years of age. Mutation exchanges during follow-up in 32 cases were compared with 65 controls with paired serum samples. In addition, a consecutive series of samples from 14 HCC cases were employed to compare the sequences before and after the occurrence of HCC. Results: After adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positive, HBV DNA levels ≥4.00 log10 copies/mL, pre-S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations were associated with risk of young age HCC. Moreover, the presence of an increasing number of HCC-related mutations (pre-S deletion, T1762/A1764, and T1766 and/or A1768 mutations) was associated with an increased risk of young age HCC. Paired samples analysis indicated that the increased HCC risk for at-risk sequence mutations were attributable to the persistence of these mutations, but not a single time point mutation. The longitudinal observation demonstrated a gradual combination of pre-S deletion, T1762/A1764 double mutations, and T1766 and/or A1768 mutations during the development of HCC. Conclusion: High HBV DNA levels and pre-S deletion were independent risk factors of young age HCC. Combination of pre-S deletion and core promoter mutations increased the risk and persistence of at-risk sequence mutations is critical for HCC development. © 2013 Qu et al.


Qu L.-S.,Nantong University | Liu J.-X.,Nantong University | Liu T.-T.,Fudan University | Shen X.-Z.,Fudan University | And 3 more authors.
PLoS ONE | Year: 2014

Background/Aim: To investigate the roles of mutations in pre-S and S regions of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China. Methods: We conducted an age matched case-control study within a cohort of 2387 male HBV carriers who were recruited from August, 1996. The HBV DNA sequence in pre-S/S regions was successfully determined in 96 HCC cases and 97 control subjects. In addition, a consecutive series of samples from 11 HCC cases were employed to evaluate the pre-S deletion patterns before and after the occurrence of HCC. Results: After adjustment for age, history of cigarette smoking and alcohol consumption, HBeAg positivity, pre-S deletions, pre-S2 start codon mutations, and T53C mutation were significantly associated with HCC, showing adjusted odds ratios (ORs) from 1.914 to 3.199. HCC patients also had a lower frequency of T31C mutation in pre-S2 gene, compared with control subjects (0.524; 95% CI 0.280-0.982). HBV pre-S deletions were clustered mainly in the 5′ end of pre-S2 region. Multivariate analysis showed that pre-S deletions and pre-S2 start codon mutations were independent risk factors for HCC. The OR (95% CI) were 2.434 (1.063-5.573) and 3.065 (1.099-8.547), respectively. The longitudinal observation indicated that the pre-S deletion mutations were not acquired at the beginning of HBV infection, but that the mutations occurred during the long course of liver disease. Conclusion: Pre-S deletions and pre-S2 start codon mutations were independently associated with the development of HCC. The results also provided direct evidence that pre-S deletion mutations were not acquired from the beginning of infection but arose de novo during the progression of liver disease. © 2014 Qu et al.


Chen J.G.,Qidong Liver Cancer Institute
Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi | Year: 2010

To study the relationship between hepatitis B virus (HBV) and primary liver cancer (PLC), and to assess the outcome of PLC in the carriers of HBsAg. General population over age of 15 from a community in Qidong was screened for HBsAg, anti-HBs, and alanine transaminase (ALT) in 1976, and followed-up thenceforth. From January 1, 1977 through December 31, 2007, 12 351 people were enrolled in the cohort, and their occurrence, outcome of PLC and other cancers, together with all the withdrawals due to death were linked to and checked with database from Qidong Cancer Registry and Qidong Vital Registry programs. The total observed person-years (PYs) were 355 305.0. One hundred and seventy-three PLC cases were identified among the HBsAg carriers, with an incidence of 361.55 per 100 000 PYs, while PLC cases were only 95 for the non-carriers, with an incidence of 30.90 per 100 000 PYs. The overall relative risk (RR) was 11.70 (95%CI: 9.06 - 15.19), with RR 12.30 for men and 10.46 for women. HBsAg carriers had high incidence at each age group, compared with the non-carriers for both men and women. Data from cross-over analysis showed that the incidence rates of PLC for the sub-cohorts of female non-carriers, male non-carriers, female carriers, and male carriers were 1.00, 3.07, 10.46, and 37.76, respectively. The cumulative rates of PLC in the 4 groups were 0.86%, 2.73%, 10.22%, and 34.19%, respectively. Results from non-conditional logistic regression model showed that the gender (male), age, HBsAg(+), and ALT(+) were risk factors for the development of PLC while anti-HBs(+) demonstrated a protective effect. No relationship was found among carriers and non-carriers for cancer sites such as lung, stomach, esophagus, intestine, pancreas, breast, cervix, bladder, and lymphoma, brain tumor, or leukemia. Causation and its strength, together with specificity and persistency of the association were confirmed from this HBsAg-related cohort study in the general population in Qidong. Intervention measures on HBV should be highlighted for the control of PLC among the HBV infected individuals.


Chen J.G.,Qidong Liver Cancer Institute
Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] | Year: 2010

To analyze the patterns and changes of liver cancer mortality in China. Data of national retrospective sampling survey for the years of 2004 - 2005 from 158 counties/cities/districts was used for the settings, covering a 2-year's population of 142 660 482 person years, in which 47 899 806 in urban areas, and 94 760 676 in rural areas. Furthermore, the areas of Eastern, Central, and Western were divided into the subsets, with populations of 52 556 694, 49 781 225 and 40 322 563 person years, respectively. The crude rate (CR) and the age-standardized rate by Chinese population of 1982 (CASR) and by world's population of 1985 (WASR) were calculated. The historical comparisons with the national survey data of 1973 - 1975 (First time) and with the sampling survey of 1990 - 1992 (Second time) were made, and the global comparisons with some selected countries were performed. A total of 37 645 death cases with liver cancer were recorded from the 158 samples in the year 2004 - 2005, with the CR of 26.26 per 100 000 (males: 27 398 cases, 37.55 per 100 000, and females: 10 067 cases, 14.45 per 100 000), which ranked the second after lung cancer, accounted for 19.33% of all sites of cancers (37 465/193 841). 93.04% of the sampling districts (147/158) showed the CRs amongst 10.00 to 39.00 per 100 000. The CASR was 17.86 per 100 000 (males: 26.44, females: 9.20), and the WASR was 23.48 per 100 000 (males: 34.61, females: 12.34). In the urban areas, the CR of liver cancer was 24.94 per 100 000 (11 945 cases, CASR: 15.34), and 26.93 per 100 000 (25 520 cases, CASR: 19.32) in the rural areas. The sex ratio of the male to female mortality rate was 2.60:1 (2.68:1 in urban areas, and 2.56:1 in rural areas). The death cases in the Eastern, Central, and Western areas were 14 909, 13 349 and 9 207, with CRs of 28.37, 26.82, and 22.83 per 100 000, respectively. The CR was increased by 89.77% compared with the data from the First time (1973 - 1975: 10.75 per 100 000), and increased by 28.73% compared with the data of the Second time (1990 - 1992: 20.37 per 100 000). In addition, the CR from 12.42 (the First) increased to 19.50 per 100 000 (the Second) in the urban areas, and from 10.12 (the First) increased to 20.67 per 100 000 (the Second) in the rural areas. Global comparison showed that the CR for the liver cancer in China ranked the sixth for men, and fifth for women; and it ranked the ninth, and seventh according to the WASR amongst the top-rate countries. Liver cancer is the second leading site of cancer death-cause in China. The CR has been rising, while the trend for the standardized rate is not so apparent. Control of the liver cancer should be still the priority of all anti-cancer activities in China.


Chen J.G.,Qidong Liver Cancer Institute
IARC scientific publications | Year: 2011

The Qidong cancer registry was established in 1972, and registration of cases is done by active and passive methods. The registry contributed data on 33 cancer sites or types registered during 1992-2000 for this survival study. Data on 22 cancers registered during 1972-2000 were utilized to elicit the survival trend by period and cohort approaches. Follow-up was done by a mixture of active and passive methods, with median follow-up ranging from 2-25 months. The proportion of cases with histologically verified cancer diagnosis ranged from 9-100%, and 87-100% of total registered cases were included for survival analysis. The top-ranking cancers on 5-year age-standardized relative survival (%) were thyroid (78%), breast (58%), corpus uteri (54%), larynx (51%) and urinary bladder (42%). The corresponding survival rates for common cancers were liver (6%), lung (7%) and stomach (18%). The 5-year relative survival by age group fluctuated and showed no distinct pattern or trend. The comparison of 5-year relative survival trend by cohort and period approaches revealed that period survival closely predicted the survival experience of cancer cases diagnosed in that period for most cancers.


Chen J.G.,Qidong Liver Cancer Institute
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology | Year: 2012

To survey the levels of Golgi glycoprotein (GP73), a hepatocellular carcinoma (HCC) marker, in residents of Qidong and determine the correlation of detected GP73 concentration ranges with outcome at two-year follow-up. A total of 12,378 individuals (age range: 35-69 years old) from Qidong were enrolled in the study. All participants were tested for hepatitis B virus (HBV) by detecting hepatitis B surface antigen (HBsAg) in serum. One-tenth of the participants were assigned to a stratified-random sample group (those with identification numbers ending with "0") to represent a "subgroup of the natural population" (HBsAgPop, n = 1227). All HBsAg carriers were stratified as a "subgroup of positivity" (HBsAgPve, n = 1025). One-tenth of all HBsAg-negative individuals were assigned to a stratified-random sample group to represent a "subgroup of negativity" (HBsAgNve, n = 1132). Enzyme-linked immunoassay was used to measure the serum GP73 and alpha-fetoprotein (AFP) levels; the distribution, medians (50th percentile), and 95th percentiles of GP73 were determined for the three subgroups. A two-year follow-up was carried out to observe the differential incidence of HCC between the HBsAgPve and HBsAgNve subgroups. A positively skewed distribution of the GP73 values was observed for all three subgroups. The medians for HBsAgPve, HBsAgNve, and HBsAgPop were 67 mug/L, 54 mug/L, and 55 mug/L; the 95th percentiles were 174 mug/L, 108 mug/L, and 114 mug/L, respectively. The AFP positivity rates were 7.23% (37/512) for carriers whose GP73 values were above the median level and 0.78% (4/513) for carriers with GP73 values below the median level, with a highly significant difference between the two (P less than 0.01). A the two-year follow-up, 23 (4.49%) of the 512 carriers with GP73 more than or equal to 67 mug/L had developed HCC, while only one patient (0.19%) of the 513 carriers with GP73 less than 67 mug/L developed HCC, which yielded a relative risk value of 23.6. In the non-carriers, no HCC cases had occurred, regardless of serum GP73 level. Serum GP73 has a higher potential as a diagnostic/prognostic marker of HCC in individuals with HBsAg positivity. In follow-up of HBsAg carriers, GP73 may help in the early detection of liver cancer.

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