RESUMO
CD133 is a cellular surface protein that has been reported to be a cancer stem cell marker, and thus it is considered to be a potential target for cancer treatment. However, the mechanism regulating CD133 expression is not yet understood. In this study, we analyzed the activity of five putative promoters (P1-P5) of CD133 in human embryonic kidney (HEK) 293 cells and colon cancer cell line WiDr, and found that the activity of promoters, particularly of P5, is elevated by overexpression of hypoxia-inducible factors (HIF-1α and HIF-2α). Deletion and mutation analysis identified one of the two E-twenty six (ETS) binding sites (EBSs) in the P5 region as being essential for its promoter activity induced by HIF-1α and HIF-2α. In addition, a chromatin imunoprecipitation assay demonstrated that HIF-1α and HIF-2α bind to the proximal P5 promoter at the EBSs. The immunoprecipitation assay showed that HIF-1α physically interacts with Elk1; however, HIF-2α did not bind to Elk1 or ETS1. Furthermore, knockdown of both HIF-1α and HIF-2α resulted in a reduction of CD133 expression in WiDr. Taken together, our results revealed that HIF-1α and HIF-2α activate CD133 promoter through ETS proteins.
Assuntos
Antígenos CD/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Glicoproteínas/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Peptídeos/genética , Proteína Proto-Oncogênica c-ets-1/fisiologia , Ativação Transcricional , Proteínas Elk-1 do Domínio ets/fisiologia , Antígeno AC133 , Antígenos CD/metabolismo , Sítios de Ligação , Hipóxia Celular , Linhagem Celular Tumoral , Expressão Gênica , Técnicas de Silenciamento de Genes , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Peptídeos/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Regulação para CimaRESUMO
BACKGROUND AND AIM: According to a few recent reports on the long-term clinical outcome of gastric marginal zone B-cell mucosa associated lymphoid tissue lymphoma (MALT lymphoma); localized gastric MALT lymphoma generally has a favorable prognosis. However, the risk of metachronous gastric cancer has not been evaluated. In this study, we analyzed long-term outcomes of localized gastric MALT lymphoma including the incidence of metachronous gastric cancer. METHODS: Between April 1996 and May 2008, 60 patients (31 men and 29 women; mean age 58.1 years) with localized gastric MALT lymphoma (stage I and II(1) according to Lugano classification) were analyzed retrospectively. RESULTS: Forty-eight patients (82.6%) achieved complete remission by eradication therapy. Radiation therapy was conducted on eight patients as second-line treatment, and all of them achieved remission. The median follow-up period was 76 months (range, 12-157 months). One patient had local relapse after remission for 5 years and three patients developed early gastric cancer without recurrence of lymphoma (5%). All of the three gastric cancers appeared in the same areas where MALT lymphoma had been eradicated. CONCLUSION: Eradication therapy and radiation therapy for localized gastric MALT lymphoma have a favorable long-term outcome, though regular follow-up endoscopy should be performed for detecting metachronous early gastric cancer.