Cofilin-1, LIMK1 and SSH1 are differentially expressed in locally advanced colorectal cancer and according to consensus molecular subtypes

Abstract

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.

LIMK1: A Promising Prognostic and Immune Infiltration Indicator in Colorectal Cancer

“…However, the role of LIMK1 in the immune tumor microenvironment has not been extensively discussed. Only some researchers have found that the expression of LIMK1 is enriched in immune (CMS1) subtypes of CRC [17]. In our study, we found that LIMK1 was associated with multiple tumor-in ltrating immune cells in CRC.…”

“…It was reported that LIMK1 was highly expressed in a variety of tumors and is related to patient prognosis. Although studies have shown that LIMK1 is up-regulated in CRC and causes poor prognosis [17]. And the related mechanism of LIMK1 regulating CRC progression has been studied [18].…”

The Expression of LIMK1 is Related to the Poor Prognosis and Immune Function of Hepatocellular Carcinoma

“…At present, the role of LIMK1 in HCC has not been fully reported. According to previous research results, miRNA-27-3p and miRNA-520-3p are the targets of LIMK1, and they can inhibit tumor development [14,27,28]. At the same time, studies of potential mechanisms have shown that LIMK1 has a certain in uence in tumor progression [23,29].…”

CRISPR/Cas9-mediated Bag-1 knockout increased mesenchymal characteristics of MCF-7 cells via Akt hyperactivation-mediated actin cytoskeleton remodeling

“…Reorganization of the cytoskeleton through Akt inhibition in Bag-1 KO cells is also confirmed by the alternation of phosphorylation of cofilin at Ser3. It is indicated that phosphorylation of cofilin at Ser3 inactivates its function by severing F-actin and promotes actin polymerization [31]. Akt inhibitor decreased the phospho-cofilin level at Ser3 in Bag-1 KO cells which led to the polymerization of F-actin (Fig 4B).…”