RESUMO
Tumor metastasis is the dominant cause of death in colorectal cancer (CRC) patients, and it often involves dysregulation of various cytoskeletal proteins. Plastin 1 (PLS1) is an actin-bundling protein that has been implicated in the structure of intestinal epithelial microvilli; however, its role in CRC metastasis has not yet been determined. In this study, we demonstrated that PLS1 is highly expressed in 33.3% (45/135) of CRC patients and is correlated with lymph node metastasis and poor survival. In in vitro and in vivo experiments, PLS1 induced the migration and invasion of CRC cells and the metastases to the liver and lung in mice. Moreover, the expressions of key factors for CRC metastases, matrix metalloproteinase (MMP) 9 and 2, were enhanced by PLS1, which was dependent on phosphorylating ERK1/2 activated by IQGAP1/Rac1 signaling. The connection between these signals and PLS1 was further confirmed in CRC tissues of patients and the metastatic nodules from a mouse model. These findings suggest that PLS1 promotes CRC metastasis through the IQGAP1/Rac1/ERK pathway. Targeting PLS1 may provide a potential approach to inhibit the metastasis of CRC cells.
Assuntos
Neoplasias Colorretais/patologia , Glicoproteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Feminino , Humanos , Mucosa Intestinal/patologia , Mucosa Intestinal/cirurgia , Sistema de Sinalização das MAP Quinases , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Reto/patologia , Reto/cirurgia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismoRESUMO
Actin-related protein 2/3 complex subunit 4 (ARPC4) acts as an actin nucleator in actin cytoskeleton branching and contributes to cell migration. ARPC4 has previously been demonstrated to be abnormally expressed in various colorectal carcinoma cell lines, particularly SW620 cells. The present study explored the biological action and the possible mechanisms underlying the function of ARPC4 in the progression of carcinoma. The proliferation and migration of SW620 cells transfected with ARPC4-specific short interfering (si)RNAs were assessed using western blot, cell counting, flow cytometry and transwell assays. SW620 cells exhibited the highest ARPC4 expression of the cell lines investigated, and siRNA538 was the most effective of the siRNAs considered. The results of the present study demonstrated that ARPC4-silencing exhibited a significant effect on the capacity of cells for migration, but did not affect their proliferative ability. ARPC4-silencing inhibited human SW620 cell migration, but not proliferation, in vitro, suggesting that ARPC4 may be a putative therapeutic target for colorectal carcinoma.
RESUMO
Hypoxia-inducible factor-1 (HIF-1α) exerts an important role in protecting against cardiac tissue damage, for example, following ischemia-reperfusion (I/R), although the time frame during which it acts has yet to be fully elucidated. In the present study, a culture model of myocardial cells from Sprague-Dawley rats was used to examine the expression levels of HIF-1α and various downstream effectors at different times following I/R. The levels of HIF-1α were manipulated by overexpressing HIF-1α prior to I/R. HIF-1α levels peaked at 6 h following I/R, subsequently decreasing to low levels. The levels of downstream effectors peaked at 48 h, and decreased almost to pre-I/R levels by 72 h. These results suggest that HIF-1α and its downstream targets offer only short-term protection following I/R. These results may have implications for the treatment of I/R-associated injury in a variety of clinical contexts.