RESUMEN
Generation of splice variants in the RON receptor tyrosine kinase facilitates the invasive phenotype of colorectal cancers. Here, we report a new splice variant of RON in the human colorectal cancer cell line HCT116. This variant is encoded by a transcript differing from the full-length RON mRNA by an in-frame deletion of 106 amino acids in the extracellular domain of RON ß-chain. The deleted transcript originates by an alternative deletion of exon 2 and exon 3. The molecular weight of this variant is 160 kDa. Thus, we named this variant RONΔ160(E2E3). This variant is a single-chain protein and expressed in the intracellular compartment. We found that RONΔ160(E2E3) had no tyrosine phosphorylation ability, but it has constitutively activated Akt activity in transfected HEK293 epithelial cells. The expression of this variant in HEK293 cells resulted in an increased migratory activity in vitro mediated through the PI-3K/Akt pathway. Our data describes a new splice variant of RON and suggests a novel role for the RON receptor in the progression of metastasis in colorectal cancer.
Asunto(s)
Adenocarcinoma/enzimología , Adenocarcinoma/genética , Movimiento Celular/genética , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/genética , Variación Genética , Proteínas Tirosina Quinasas Receptoras/genética , Tirosina/metabolismo , Empalme Alternativo/genética , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Fosforilación/genética , Proteínas Tirosina Quinasas Receptoras/metabolismoRESUMEN
Colorectal cancer is one of the most common causes of cancer-related deaths throughout the world. Recently, we reported that proteasome subunit PSMA7 located on 20q13 amplicon was overexpressed and associated with liver metastasis of colorectal cancer. The results indicate that PSMA7 may play an important role in the colorectal cancer progression and provide a unique target site for the development of therapeutic drugs. However, it is unknown how aberrant PSMA7 activation critically regulates the metastatic behavior of colorectal cancer cells. To investigate the role of PSMA7 in the progression of colorectal cancer, we employed the RNA interference technology to knock down the PSMA7 gene in human colon cancer cell line RKO and analyzed its effect and explored the involved mechanisms. Depletion of PSMA7 by shRNA in RKO cells inhibited their anchorage-independent growth and cell invasion and migration. Moreover, PSMA7 depletion was able to strongly suppress the in vivo tumorigenic ability of RKO cells. These effects may be induced by inhibiting CD44 expression directly or indirectly. Genetic or pharmacological inhibition of PSMA7 may therefore be a beneficial strategy in the treatment of colorectal cancer patients.