Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteínas Tirosina Quinasas Receptoras/genética , Anciano , Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Células HEK293 , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
POU5F1B (POU domain class 5 transcription factor 1B), a processed pseudogene that is highly homologous to OCT4, was recently shown to be transcribed in cancer cells, but its clinical relevance and biological function have remained unclear. We now show that POU5F1B, which is located adjacent to MYC on human chromosome 8q24, is frequently amplified in gastric cancer (GC) cell lines. POU5F1B, but not OCT4, was also found to be expressed at a high level in GC cell lines and clinical specimens. In addition, the DNA copy number and mRNA abundance for POU5F1B showed a positive correlation in both cancer cell lines and GC specimens. Overexpression of POU5F1B in GC cells promoted colony formation in vitro as well as both tumorigenicity and tumor growth in vivo, and these effects were enhanced in the additional presence of MYC overexpression. Furthermore, knockdown of POU5F1B expression with a short hairpin RNA confirmed a role for the endogenous pseudogene in the promotion of cancer cell growth in vitro and tumor growth in vivo. POU5F1B overexpression induced upregulation of various growth factors in GC cells as well as exhibited mitogenic, angiogenic and antiapoptotic effects in GC xenografts. Finally, amplification of POU5F1B was detected in 17 (12%) of 145 cases of GC and was a significant predictor of poor prognosis in patients with stage IV disease. In conclusion, we found that the POU5F1B pseudogene is amplified and expressed at a high level in, as well as confers an aggressive phenotype on, GC, and that POU5F1B amplification is associated with a poor prognosis in GC patients.
Asunto(s)
Factor 3 de Transcripción de Unión a Octámeros/genética , Seudogenes , Neoplasias Gástricas/genética , Animales , Proliferación Celular/genética , Femenino , Amplificación de Genes , Dosificación de Gen , Células HEK293 , Xenoinjertos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Factor 3 de Transcripción de Unión a Octámeros/biosíntesis , Fenotipo , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Activin A is a multi-functional cytokine belonging to the transforming growth factor-ß (TGF-ß) superfamily; however, the effect of activin A on angiogenesis remains largely unclear. We found that inhibin ß A subunit (INHBA) mRNA is overexpressed in gastric cancer (GC) specimens and investigated the effect of activin A, a homodimer of INHBA, on angiogenesis in GC. METHODS: Anti-angiogenic effects of activin A via p21 induction were evaluated using human umbilical vein endothelial cells (HUVECs) in vitro and a stable INHBA-introduced GC cell line in vivo. RESULTS: Compared with TGF-ß, activin A potently inhibited the cellular proliferation and tube formation of HUVECs with induction of p21. A promoter assay and a chromatin immunoprecipitation assay revealed that activin A directly regulates p21 transcriptional activity through Smads. Stable p21-knockdown significantly enhanced the cellular proliferation of HUVECs. Notably, stable p21-knockdown exhibited a resistance to activin-mediated growth inhibition in HUVECs, indicating that p21 induction has a key role on activin A-mediated growth inhibition in vascular endothelial cells. Finally, a stable INHBA-introduced GC cell line exhibited a decrease in tumour growth and angiogenesis in vivo. CONCLUSION: Our findings highlight the suppressive role of activin A, unlike TGF-ß, on tumour growth and angiogenesis in GC.
