ABSTRACT
MicroRNAs play essential roles in gene expression regulation during carcinogenesis. Here, we investigated the role of miR-7 and the mechanism by which it is dysregulated in gastric cancer (GC). We used genome-wide screenings and identified RELA and FOS as novel targets of miR-7. Overexpression of miR-7 repressed RELA and FOS expression and prevented GC cell proliferation and tumorigenesis. These effects were clinically relevant, as low miR-7 expression was correlated with high RELA and FOS expression and poor survival in GC patients. Intriguingly, we found that miR-7 indirectly regulated RELA activation by targeting the IκB kinase IKKε. Furthermore, IKKε and RELA can repress miR-7 transcription, which forms a feedback circuit between miR-7 and nuclear factor κB (NF-κB) signaling. Additionally, we demonstrate that down-regulation of miR-7 may occur as a result of the aberrant activation of NF-κB signaling by Helicobacter pylori infection. These findings suggest that miR-7 may serve as an important regulator in GC development and progression.
Subject(s)
Carcinogenesis/metabolism , MicroRNAs/physiology , Stomach Neoplasms/metabolism , Transcription Factor RelA/metabolism , 3' Untranslated Regions , Animals , Base Sequence , Binding Sites , Carcinogenesis/genetics , Cell Line, Tumor , Cell Proliferation , Feedback, Physiological , Female , Gene Expression Regulation, Neoplastic , Humans , I-kappa B Kinase/metabolism , Male , Mice, Nude , Middle Aged , Neoplasm Transplantation , Proteome/genetics , Proteome/metabolism , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , RNA Interference , Signal Transduction , Stomach Neoplasms/genetics , Stomach Neoplasms/mortality , Transcription Factor RelA/genetics , TranscriptomeABSTRACT
AIM: To reduce the incidence and mortality of rectal cancer and address the hypothesis that colorectal cancer often arise from precursor lesion(s), either adenomas or non-adenomatous polyps, by conducting a population-based mass screening for colorectal cancer in Haining County, Zhejiang, PRC. METHODS: From 1977 to 1980, physicians screened the population of Haining County using 15 cm rigid endoscopy. Of over 240000 participants, 4076 of them were diagnosed with precursor lesions, either adenomas or non-adenomatous polyps, which were then removed surgically. All individuals with precursor lesions were followed up and reexamined by endoscopy every two to five years up to 1998. RESULTS: After the initial screening, 953 metachronous adenomas and 417 non-adenomatous polyps were detected and removed from the members of this cohort. Further, 27 cases of colorectal cancer were detected and treated. Log-rank tests showed that the survival time among those cancer patients who under went mass screening increased significantly compared to that of other colorectal cancer patients (P<0.0001). According to the population-based cancer registry in Haining County, age-adjusted incidence and mortality of rectal cancer decreased by 41% and 29% from 1977-1981 to 1992-1996, respectively. Observed cumulative 20-year rectal cancer incidence was 31% lower than the expected in the screened group; the mortality due to rectal cancer was 18% lower than the expected in the screened group. CONCLUSION: Mass screening for rectal cancer and precursor lesions with protocoscopy in the general population and periodical following-up with routine endoscopy for high-risk patients may decrease both the incidence and mortality of rectal cancer.
