Yu Gan

Enriched Environment Inhibits Mouse Pancreatic Cancer Growth and Down-regulates the Expression of Mitochondria-related Genes in Cancer Cells

Psycho-social stress has been suggested to influence the development of cancer, but it remains poorly defined with regard to pancreatic cancer, a lethal malignancy with few effective treatment modalities. In this study, we sought to investigate the impacts of enriched environment (EE) housing, a rodent model of “eustress”, on the growth of mouse pancreatic cancer, and to explore the potential underlying mechanisms through gene expression profiling. The EE mice showed significantly reduced tumor weights in both subcutaneous (53%) and orthotopic (41%) models, while each single component of EE (inanimate stimulation, social stimulation or physical exercise) was not profound enough to achieve comparative anti-tumor effects as EE. The integrative transcriptomic and proteomic analysis revealed that in response to EE, a total of 129 genes in the tumors showed differential expression at both the mRNA and protein levels. The differentially expressed genes were mostly localized to the mitochondria and enriched in the citrate cycle and oxidative phosphorylation pathways. Interestingly, nearly all of the mitochondria-related genes were down-regulated by EE. Our data have provided experimental evidence in favor of the application of positive stress or of benign environmental stimulation in pancreatic cancer therapy.

Novel natural mutations in the Hepatitis B Virus reverse transcriptase domain associated with hepatocellular carcinoma

Background/Aim Hepatitis B Virus (HBV) mutations play a role in the development of hepatocellular carcinoma (HCC). However, the association between HBV polymerase gene mutations and HCC has not been reported. In this study, we conducted a multi-stage study to identify HCC-related mutations in the reverse transcriptase (RT) domain of the HBV polymerase gene. Methods A total of 231 HCCs and 237 non-HCC controls from Qidong, China, were included in this study. The entire sequence of HBV RT was first compared between 29 HCC and 35 non-HCC cases, and candidate mutations were then evaluated in two independent validation sets. Results There were 15 candidate mutations identified from the discovery set, with A799G and T1055A being consistently associated with HCC across all studies. A pooled analysis of samples revealed that A799G, A987G, and T1055A were independent risk factors for HCC, with adjusted odds ratios of 5.53 [95% confidence interval (CI), 1.69–18.10], 4.20 (95%CI, 1.15–15.35), and 3.78 (95%CI, 1.45–9.86), respectively. A longitudinal study showed that these mutations were detectable 4–5 years prior to HCC diagnosis. Conclusions Our study provides evidence the first that HBV RT contains naturally occurring mutations that can be used as predictive markers for HCC.

Enriched Housing Environment Enhances NK Cell Antitumor Immunity via Sympathetic Nerves-dependent Regulation of NKG2D and CCR5 in Mice

Mice housed in an enriched environment display a tumor-resistant phenotype due to eustress stimulation. However, the mechanisms underlying enriched environment-induced protection against cancers remain largely unexplained. In this study, we observed a significant antitumor effect induced by enriched environment in murine pancreatic cancer and lung cancer models. This effect remained intact in T/B lymphocyte-deficient Rag1-/- mice, but was nearly eliminated in natural killer (NK) cell-deficient Beige mice or in antibody-mediated NK-cell-depleted mice, suggesting a predominant role of NK cells in enriched environment-induced tumor inhibition. Exposure to enriched environment enhanced NK-cell activity against tumors and promoted tumoral infiltration of NK cells. Enriched environment increased the expression levels of CCR5 and NKG2D (KLRK1) in NK cells; blocking their function effectively blunted the enriched environment-induced enhancement of tumoral infiltration and cytotoxic activity of NK cells. Moreover, blockade of β-adrenergic signaling or chemical sympathectomy abolished the effects of enriched environment on NK cells and attenuated the antitumor effect of enriched environment. Taken together, our results provide new insight into the mechanism by which eustress exerts a beneficial effect against cancer. Cancer Res; 77(7); 1611-22. ©2017 AACR.

Qidong hepatitis B virus infection cohort: a 25-year prospective study in high risk area of primary liver cancer

Qidong hepatitis B virus (HBV) infection cohort (QBC) is a prospective community-based study designed to investigate causative factors of primary liver cancer (PLC) in Qidong, China, where both PLC and HBV infection are highly endemic. Residents aged 20-65 years, living in seven townships of Qidong, were surveyed using hepatitis B surface antigen (HBsAg) serum test and invited to participate in QBC from June 1991 to December 1991. A total of 852 and 786 participants were enrolled in HBsAg-positive and HBsAg-negative sub-cohorts in May 1992, respectively. All participants were actively followed up in person, received HBsAg, alanine aminotransferase (ALT), alpha-fetoprotein (AFP) tests and upper abdominal ultrasonic examination, and donated blood and urine samples once or twice a year. The total response rate was 99.6%, and the number of incident PLC was 201 till the end of February 2017. The ratio of incidence rates was 12.32 (95% confidence interval[CI]=7.16-21.21, P < 0.0001) in HBsAg-positive arm compared with HBsAg-negative arm. The relative risk of PLC was 13.25 (95% CI=6.67-26.33, P < 0.0001) and 28.05 (95% CI=13.87-56.73, P < 0.0001) in the HBsAg+/HBeAg- group and the HBsAg+/HBeAg+ group, respectively, as compared to the HBsAg-/HBeAg- group. A series of novel PLC-related mutations including A2159G, A2189C and G2203W at the C gene, A799G, A987G and T1055A at the P gene of HBV genome were identified by using samples from the cohort. The mutation in hepatitis B virus (HBV) basal core promoter region of HBV genome has an accumulative effect on the occurrence of PLC. In addition, the tripartite relationship of aflatoxin exposure, P53 mutation and PLC was also investigated. Dynamic prediction model for PLC risk by using its long-term follow-up information and serial blood samples for QBC was developed. This model is expected to improve the efficiency of PLC screening in HBV infection individuals.

Hepatitis B virus and risk of non-Hodgkin lymphoma: An updated meta-analysis of 58 studies

Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non‐Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different subgroups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta‐analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database, and 58 studies with a total of 53 714 NHL cases and 1 778 591 controls were finally included. Pooled estimates indicated a significantly increased NHL risk in HBV‐infected individuals (summary odds ratio [sOR]: 2.50; 95% confidence interval [CI]: 2.20‐2.83) regardless of the study design (case–control studies: sOR: 2.47; 95% CI: 2.16‐2.82; cohort studies: sOR: 2.64; 95% CI: 1.78‐3.91). Considerable heterogeneity was observed across studies that was primarily attributed to the NHL subtypes (meta‐regression: P < .05). Overall, B‐cell NHL (sOR: 2.46; 95% CI: 1.97‐3.07) presented a stronger association with HBV infection than T‐cell NHL (sOR: 1.67; 95% CI: 1.34‐2.10). Within the B‐cell NHL subtypes, HBV infection was significantly associated with diffuse large B‐cell lymphoma (DLBCL, sOR: 2.06; 95% CI: 1.48‐2.88) and follicular lymphoma (FL, sOR: 1.54; 95% CI: 1.11‐2.12), but not with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and Burkitt lymphoma. The results of this meta‐analysis support a positive link between HBV infection and NHL development. Further investigations for the mechanisms underlying HBV‐induced NHL are warranted.

TNFSF9 exerts an inhibitory effect on hepatocellular carcinoma

Tumor necrosis factor superfamily member 9 (TNFSF9), also known as 4‐1BBL and CD137L, has been implicated in cancer immunotherapy due to its function as a T‐cell co‐stimulator. We aimed to investigate the role of TNFSF9 in the cancer pathogenesis in hepatocellular carcinoma (HCC).