The common use of wok cooking in China might be an important but controllable risk factor in the etiology of lung cancer. In the United States, where cooking oils are usually refined for purity, additional studies should be conducted to further quantify the potential risks of such methods of cooking.

Nitric oxide (NO . ), an important signaling molecule and a component of inflammatory response, is involved in tumorigenesis. However, the quantity of NO. and the cellular microenvironment influences the role of NO . in tumor development. We used a genetic strategy to test the hypothesis that an inflammatory microenvironment with an enhanced level of NO . accelerates spontaneous tumor development. C. parvuminduced inflammation and increased NO . synthase-2 (NOS2) expression coincided with accelerated spontaneous tumor development, mostly lymphomas, in p53À/ÀNOS2+/+ C57BL6 mice when compared with the controls (P = 0.001). However, p53À/ÀNOS2À/À mice did not show any difference in tumor latency between C. parvum-treated and control groups. In C. parvum-treated p53À/ÀNOS2+/+ mice, tumor development was preceded by a higher expression of NOS2 and phosphorylated Akt-Ser 473

Accumulating evidence suggests a role for inflammation in the development and progression of cancer. Our group recently identified a cytokine gene signature in lung tissue associated with lung cancer prognosis. Therefore, we hypothesized that concentrations of circulating cytokines in serum may be associated with lung cancer survival. Ten serum cytokines, namely, interleukin (IL)-1B, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, granulocyte macrophage colony-stimulating factor, interferon (IFN)-;, and tumor necrosis factor-A, were assessed in 353 non -small cell lung cancer cases from a case-control study of lung cancer in the greater Baltimore, Maryland area. Cytokines were measured using an ultrasensitive electrochemiluminescence immunoassay. IL-6 serum concentrations (z4.0 pg/mL) were associated with significantly poorer survival in both African Americans [hazard ratio (HR), 2.71; 95% confidence interval (CI), 1.26-5.80] and Caucasians (HR, 1.71; 95% CI, 1.22-2.40). IL-10 (HR, 2.62; 95% CI, 1.33-5.15) and IL-12 (HR, 1.98; 95% CI, 1.14-3.44) were associated with lung cancer survival only in African Americans. Some evidence for an association of tumor necrosis factor-A levels with survival in Caucasians was observed, although these results were not significant. These hypothesis-generating findings indicate that selected serum cytokine concentrations are associated with lung cancer survival, and indicate that further research is warranted to better understand the mechanistic underpinnings of these associations. (Cancer Epidemiol Biomarkers Prev 2009;18(1):215 -22)

Inflammation influences the development of cancer. The nitric oxide synthase (NOS2) is induced by inflammatory cytokines, e.g., tumor necrosis factor ␣ and interleukin 1␤, and produces nitric oxide (NO ⅐ ), a critical mediator of the inflammatory response. Because p53 governs NO ⅐ production by transcriptionally transrepressing NOS2, we used a genetic strategy to determine whether NO ⅐ and p53 cooperatively regulate tumorigenesis. Lymphomas developed more rapidly in p53؊/؊NOS2؊/؊ or p53؊/؊NOS2؉/؊ mice than in p53؊/؊NOS2؉/؉ mice that were crossbred into a >95% C57BL6 background and maintained in a pathogenfree condition. Likewise, sarcomas and lymphomas developed faster in p53؉/؊NOS2؊/؊ or p53؉/؊NOS2؉/؊ than in p53؉/؊NOS2؉/؉ mice. When compared with the double knockout mice, p53؊/؊NOS2؉/؉ mice showed a higher apoptotic index and a decreased proliferation index with an increased expression of death receptor ligands, CD95-L and tumor necrosis factor-related apoptosis-inducing ligand, and the cell cycle checkpoint protein, p21 waf1 , in the spleen and thymus before tumor development. Furthermore, mice deficient in both p53 and NOS2 produced a high level of anti-inflammatory interleukin 10 when compared with p53-deficient mice. These studies provide genetic and mechanistic evidence that NO ⅐ can suppress tumorigenesis.

The p53 tumor suppressor gene is commonly mutated in human hepatocellular carcinoma (HCC). The most frequent mutation in HCC in populations exposed to a high dietary intake of aflatoxin B1 (AFB1) is an AGGarg-->AGTser missense mutation in codon 249 of the p53 gene. We analyzed HCCs from Monterrey, Mexico, for the codon 249ser hotspot mutation. We also analyzed the serum AFB1-albumin adduct levels of the donors and family members to measure the current AFB1 exposure in this population. Moreover, the presence of hepatitis B and/or C viral infection (HBV or HCV) was analyzed serologically in the patients. Tumor cells were microdissected from tissue sections and exon 7 p53 sequences were amplified by polymerase chain reaction from genomic DNA and sequenced directly. The serological tests for anti-p53 antibodies, HBV or HCV were done by ELISA. Immunohistochemical analysis of p53 protein was done using a polyclonal rabbit antiserum (CM-1). Eight of 21 cases were positive by p53 immunohistochemistry. Of the 16 cases sequenced for exon 7 of p53 three codon 249 AGGarg-->AGTser mutations were found. Serum antibodies recognizing p53 protein were found in one of 18 patients. Positive serology for HBV and/or HCV was found in 12 of 20 cases. The serum AFB1-albumin adduct levels in this population ranged from 0.54 to 4.64 pmol aflatoxin/mg albumin. These results indicate that dietary AFB1 and hepatitis viruses are etiological agents in the molecular pathogenesis of HCC in this geographic region of Mexico.

Serum anti-p53 antibodies can predate clinical diagnosis of certain tumors, such as ASL, and may be useful in identifying individuals at high cancer risk, such as workers with occupational exposure to vinyl chloride.

Coke oven workers are exposed to high levels of carcinogenic polyeyclic aromatic hydrocarbons, including benzo [a]

ING2 (inhibitor of growth family, member 2) is a member of the plant homeodomain (PHD)-containing ING family of putative tumor suppressors. As part of mSin3A-HDAC corepressor complexes, ING2 binds to tri-methylated lysine 4 of histone H3 (H3K4me3) to regulate chromatin modification and gene expression. ING2 also functionally interacts with the tumor suppressor protein p53 to regulate cellular senescence, apoptosis and DNA damage response in vitro, and is thus expected to modulate carcinogenesis and aging. Here we investigate the developmental and physiological functions of Ing2 through targeted germline disruption. Consistent with its abundant expression in mouse and human testes, male mice deficient for Ing2 showed abnormal spermatogenesis and were infertile. Numbers of mature sperm and sperm motility were significantly reduced in Ing2 −/− mice (∼2% of wild type, P<0.0001 and ∼10% of wild type, P<0.0001, respectively). Their testes showed degeneration of seminiferous tubules, meiotic arrest before pachytene stage with incomplete meiotic recombination, induction of p53, and enhanced apoptosis. This phenotype was only partially abrogated by concomitant loss of p53 in the germline. The arrested spermatocytes in Ing2 −/− testes were characterized by lack of specific HDAC1 accumulation and deregulated chromatin acetylation. The role of Ing2 in germ cell maturation may extend to human ING2 as well. Using publicly available gene expression datasets, low expression of ING2 was found in teratozoospermic sperm (>3-fold reduction) and in testes from patients with defective spermatogenesis (>7-fold reduction in Sertoli-cell only Syndrome). This study establishes ING2 as a novel regulator of spermatogenesis functioning through both p53- and chromatin-mediated mechanisms, suggests that an HDAC1/ING2/H3K4me3-regulated, stage-specific coordination of chromatin modifications is essential to normal spermatogenesis, and provides an animal model to study idiopathic and iatrogenic infertility in men. In addition, a bona fide tumor suppressive role of Ing2 is demonstrated by increased incidence of soft-tissue sarcomas in Ing2− /− mice.