EGFR overexpression and chromosome 3p deletion are two frequent events in head and neck cancers. We previously mapped the smallest region of recurrent copy-number loss at 3p12.2-p14.1. LRIG1, a negative regulator of EGFR, was found at 3p14, and its copy-number loss correlated with poor clinical outcome. Inducible expression of LRIG1 in head and neck cancer TW01 cells, a line with low LRIG1 levels, suppressed cell proliferation in vitro and tumor growth in vivo. Gene expression profiling, quantitative RT-PCR, chromatin immunoprecipitation, and western blot analysis demonstrated that LRIG1 modulated extracellular matrix (ECM) remodeling and EGFR-MAPK-SPHK1 transduction pathway by suppressing expression of EGFR ligands/activators, MMPs and SPHK1. In addition, LRIG1 induction triggered cell morphology changes and integrin inactivation, which coupled with reduced SNAI2 expression. By contrast, knockdown of endogenous LRIG1 in TW06 cells, a line with normal LRIG1 levels, significantly enhanced cell proliferation, migration and invasiveness. Such tumor-promoting effects could be abolished by specific MAPK or SPHK1 inhibitors. Our data suggest LRIG1 as a tumor suppressor for head and neck cancers; LRIG1 downregulation in cancer cells enhances EGFR-MAPK-SPHK1 signaling and ECM remodeling activity, leading to malignant phenotypes of head and neck cancers.

Three triterpenic acids, oleanolic acid, ursolic acid and maslinic acid, at 2 or 4 μmol/L were used to study their antiangiogenic potential in human liver cancer Hep3B, Huh7 and HA22T cell lines. The effects of these compounds upon the level and/or expression of hypoxia-inducible factor (HIF)-1α, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin (IL)-8, urokinase plasminogen activator (uPA), reactive oxygen species (ROS), nitric oxide (NO) and cell invasion and migration were examined. Results showed that these triterpenic acids at 4 μmol/L significantly suppressed HIF-1α expression in three cell lines (P < 0.05); and these compounds at test doses failed to affect bFGF expression (P > 0.05). Three triterpenic acids dose-dependently decreased production and expression of VEGF and IL-8, retained glutathione level, lowered ROS and NO levels, and declined cell invasion and migration in test cell lines (P < 0.05). These compounds also dose-dependently reduced uPA production and expression in Hep3B and Huh7 cell lines (P < 0.05); but these agents only at 4 μmol/L significantly suppressed uPA production and expression in HA22T cells (P < 0.05). These findings suggest that these triterpenic acids are potent antiangiogenic agents to retard invasion and migration in liver cancer cells.

Traveling to endemic areas carries a risk of hepatitis E virus (HEV) infection, but no molecular analysis to document sources of infection is available. Eighteen (38%) of 47 patients with acute non-A, non-B, non-C hepatitis were positive for antibody to HEV (anti-HEV), and 9 (50%) of these were also positive for serum HEV RNA by polymerase chain reaction following reverse transcription. Only 1 (5%) of the 21 patients with acute hepatitis A was positive for HEV RNA. Travel to endemic areas (mostly to China; odds ratio, 22.2; 95% confidence interval, 4.7-105.8) and deeper jaundice (odds ratio, 5.2; 95% confidence interval, 1.01-27.2) were the only factors associated with HEV infection in multivariate analysis. The two HEV isolates from two patients who had traveled to China and the HEV isolate from a patient whose travel history was obscure formed a monophyletic group with the isolates from Guangzhou. The HEV isolates from our patients show a homology of 72% to 78% in nucleotide sequence with the Burma, Beijing, India, Pakistan, and Xiangjiang strains; a homology of 81% to 91% with the Guangzhou strains; and a homology of 76% with the Mexico strain. The close relationship between the Taiwan isolates and the Guangzhou strains was further supported by the short Kimura's two-parameter distances among them. In summary, HEV infection does occur in this area. Epidemiological and molecular analyses strongly indicate that most cases of HEV infection originated from travel to HEV-endemic areas. (HEPATOLOGY 1998;27:1415-1420.)Hepatitis E virus (HEV) is transmitted through a fecal-oral route. 1-14 HEV induces acute hepatitis and is responsible for a significant portion of the fulminant hepatitis in epidemic and sporadic cases, especially in women in the third trimester of pregnancy.

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