RESUMO
BACKGROUND: Colorectal cancer (CRC) is among the deadliest cancers, wherein early dissemination of tumor cells, and consequently, metastasis formation, are the main causes of mortality and poor prognosis. Cofilin-1 (CFL-1) and its modulators, LIMK1/SSH1, play key roles in mediating the invasiveness by driving actin cytoskeleton reorganization in various cancer types. However, their clinical significance and prognostic value in CRC has not been fully explored. Here, we evaluated the clinical contribution of these actin regulators according to TNM and consensus molecular subtypes (CMSs) classification. METHODS: CFL-1, LIMK1 and SSH1 mRNA/protein levels were assessed by real-time PCR and immunohistochemical analyses using normal adjacent and tumor tissues obtained from a clinical cohort of CRC patients. The expression levels of these proteins were associated with clinicopathological features by using the chi square test. In addition, using RNA-Seq data of CRC patients from The Cancer Genome Atlas (TCGA) database, we determine how these actin regulators are expressed and distributed according to TNM and CMSs classification. Based on gene expression profiling, Kaplan-Meier survival analysis was used to evaluated overall survival. RESULTS: Bioinformatic analysis revealed that LIMK1 expression was upregulated in all tumor stages. Patients with high levels of LIMK1 demonstrated significantly lower overall survival rates and exhibited greater lymph node metastatic potential in a clinical cohort. In contrast, CFL-1 and SSH1 have expression downregulated in all tumor stages. However, immunohistochemical analyses showed that patients with high protein levels of CFL-1 and SSH1 exhibited greater lymph node metastatic potential and greater depth of local invasion. In addition, using the CMSs classification to evaluate different biological phenotypes of CRC, we observed that LIMK1 and SSH1 genes are upregulated in immune (CMS1) and mesenchymal (CMS4) subtypes. However, patients with high levels of LIMK1 also demonstrated significantly lower overall survival rates in canonical (CMS2), and metabolic (CMS3) subtypes. CONCLUSIONS: We demonstrated that CFL-1 and its modulators, LIMK1/SSH1, are differentially expressed and associated with lymph node metastasis in CRC. Finally, this expression profile may be useful to predict patients with aggressive signatures, particularly, the immune and mesenchymal subtypes of CRC.
RESUMO
Colorectal cancer represents the fourth highest mortality rate among cancer types worldwide. An understanding of the molecular mechanisms that regulate their progression can prevents or reduces mortality due to this disease. Epithelial cells present an apical junctional complex connected to the actin cytoskeleton, which maintains the dynamic properties of this complex, tissue architecture and cell homeostasis. Several studies have indicated that apical junctional complex alterations and actin cytoskeleton disorganization play a critical role in epithelial cancer progression. However, few studies have examined the existence of an interrelation between these 2 components, particularly in colorectal cancer. This review discusses the recent progress toward elucidating the role of alterations of apical junctional complex constituents and of modifications of actin cytoskeleton organization and discusses how these events are interlinked to modulate cellular responses related to colorectal cancer progression toward successful metastasis.
RESUMO
câncer colorretal constitui uma das principais causas de câncer no Brasil e no mundo. O microambiente inflamatório desempenha um importante papel na iniciação, promoção e progressão deste tipo de câncer. O TNF-α é um componente deste microambiente e conhecido por ativar via NF-κB. Neste contexto, o partenolídeo, uma lactona sesquiterpênica, com importante função anti-inflamatória por inibir a via NF-κB,apresenta-se como uma promissora molécula anticâncer por prevenir progressão no ciclo celular, migração, invasão e sobrevivência de células tumorais. No entanto, seus efeitos no câncer colorretal necessitam ser melhor definidos. O objetivo do presenteestudo foi analisar a ação do partenolídeo na reversão de características pró-tumoraisem células derivadas de câncer colorretal, Caco-2, HT-29 e HCT-116. Nossos resultados mostram que a atividade de NF-κB está diferencialmente ativa entre asdiferentes linhagens de células de câncer colorretal e que a resposta citotóxica ao tratamento com partenolídeo está relacionada com essa ativação. O partenolídeo foi capaz de prevenir a ativação da via NF-κB induzida por TNF-α através da redução da fosforilação do IκBα nas linhagens Caco-2 e HT-29, porém parece ter outro alvo inibitório nas células HCT-116, pois estas não apresentaram redução na translocação nuclear de NF-κB...
Colorectal cancer is one the main cancer types in Brazil and world. Inflammatorymicroenvironmet plays an important role in the initiation, promotion and progression of this cancer. TNF-a is an important constituent of this microenvironment, which is known as activator of NF-κB pathway. In this context, the parthenolide, a esquiterpene lactone that have anti-inflammatory function through NF-κB inhibition, presents promising anticancer properties for preventing cell cycle progression, migration,invasion and cell survival. However, the effects on colorectal cancer need to be best understood. This study aims to analyze the parthenolide action reversing pro-tumor characteristics of Caco-2, HT-29 and HCT-116 colorectal cancer cells. Our results shown the NF-κB pathway is differentially active among cell types of colorectal cancerand citotoxic response to parthenolide treatment has relationship with this level of activation. Parthenolide was able to prevent the TNF-α induced-activation NF-κB pathway through to decrease IκBα phosphorilation in Caco-2 and HT-29, but seem have another inhibitory target in HCT-116 cells, because it did not observed reduction of NF-κB nuclear in these cells...