P21-activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration

Objective: Abundant evidence has illustrated that long non-coding RNA (lncRNA) plays a vital role in the regulation of tumor development and progression. Ectopic expression of a novel lncRNA, termed lnc-AGER-1, has been discovered in cancers, and this lncRNA was reported to exert an anti-tumor effect. However, its biological mechanism remains unelucidated in colorectal cancer. Methods: A total of 159 paired colorectal cancer specimens and adjacent tissues was applied to detect the expression of lnc-AGER-1 by the quantitative Real-time PCR (qRT-PCR), and a series of functional assays was executed to uncover the role of this lncRNA on colorectal cancer. Results: We found that the expression of lnc-AGER-1 in the tumor tissues was significantly down-regulated, while compared with adjacent normal tissues (0.0115 ± 0.0718 vs. 0.0347 ± 0.157; P < 0.0001). Also, lnc-AGER-1 was observably associated with clinical T status (r = −0.184, P = 0.024). Patients with advanced T status exerted a significantly lower level of lnc-AGER-1 than those with early T status (20.0% vs. 40.7%, P = 0.021). Over-expression of lnc-AGER-1 inhibited cell proliferation and migration efficiency, and induced cell cycle arrest at the G0/G1 phase, and promoted cell apoptosis. Further research proved that lnc-AGER-1 altered the expression of its neighbor gene, AGER, through acting as a competing endogenous RNA for miR-182 in colorectal cancer. Conclusion: lnc-AGER-1 has a suppressive role in colorectal cancer development via modulating AGER, which may serve as a target for colorectal cancer diagnosis and treatment.

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The Role of Lipid Rafts in Cancer Cell Adhesion and Migration

International Journal of Cell Biology ◽

10.1155/2012/763283 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 51

Author(s):

Toshiyuki Murai

Keyword(s):

Cell Adhesion ◽

Lipid Rafts ◽

Cancer Cell ◽

Cancer Progression ◽

Migration And Invasion ◽

Dynamic Features ◽

Cellular Functions ◽

Cancer Cell Adhesion ◽

Cell Adhesion And Migration ◽

And Migration

Lipid rafts are cholesterol-enriched microdomains of the cell membrane and possess a highly dynamic nature. They have been involved in various cellular functions including the regulation of cell adhesion and membrane signaling through proteins within lipid rafts. The dynamic features of the cancer cell surface may modulate the malignant phenotype of cancer, including adhesion disorders and aggressive phenotypes of migration and invasion. Recently, it was demonstrated that lipid rafts play critical roles in cancer cell adhesion and migration. This article summarizes the important roles of lipid rafts in cancer cell adhesion and migration, with a focus on the current state of knowledge. This article will improve the understanding of cancer progression and lead to the development of novel targets for cancer therapy.

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PAK4 methylation by the methyltransferase SETD6 attenuates cell adhesion

Scientific Reports ◽

10.1038/s41598-020-74081-1 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Zlata Vershinin ◽

Michal Feldman ◽

Dan Levy

Keyword(s):

Cell Adhesion ◽

Mammalian Cells ◽

Focal Adhesions ◽

Vital Role ◽

Migration And Invasion ◽

Wild Type ◽

Set Domain ◽

Cell Adhesion And Migration ◽

P21 Activated Kinase ◽

And Migration

Abstract P21-activated kinase 4 (PAK4), a member of serine/threonine kinases family is over-expressed in numerous cancer tumors and is associated with oncogenic cell proliferation, migration and invasion. Our recent work demonstrated that the SET-domain containing protein 6 (SETD6) interacts with and methylates PAK4 at chromatin in mammalian cells, leading to activation of the Wnt/β-catenin signaling pathway. In our current work, we identified lysine 473 (K473) on PAK4 as the primary methylation site by SETD6. Methylation of PAK4 at K473 activates β-catenin transcriptional activity and inhibits cell adhesion. Specific methylation of PAK4 at K473 also attenuates paxillin localization to focal adhesions leading to overall reduction in adhesion-related features, such as filopodia and actin structures. The altered adhesion of the PAK4 wild-type cells is accompanied with a decrease in the migrative and invasive characteristics of the cells. Taken together, our results suggest that methylation of PAK4 at K473 plays a vital role in the regulation of cell adhesion and migration.

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MiR-629-5p promotes colorectal cancer progression through targetting CXXC finger protein 4

Bioscience Reports ◽

10.1042/bsr20180613 ◽

2018 ◽

Vol 38 (4) ◽

Cited By ~ 4

Author(s):

Jinlai Lu ◽

Shuirong Lu ◽

Jingze Li ◽

Qi Yu ◽

Lang Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Cell Apoptosis ◽

Tumor Promoter ◽

Finger Protein ◽

Cell Proliferation And Migration ◽

Colorectal Cancer Progression ◽

And Migration ◽

Proliferation And Migration

MiR-629-5p has been shown to function as a tumor promoter in some types of cancer. However, the role of miR-629-5p in colorectal cancer remains unclear. Here, the significant up-regulation of miR-629-5p in colorectal cancer tissues and cell lines was observed. Overexpression of miR-629-5p showed a positive effect on cell proliferation and migration. The enhanced miR-629-5p level also suppressed cell apoptosis and resulted in a low Bax level and a high Bcl-2 level. Further down-regulating miR-629-5p demonstrated opposite effects. CXXC finger protein 4 (CXXC4) was predicted as a direct target of miR-629-5p. Dual-luciferase reporter and Western blotting assays exhibited miR-629-5p directly bound to the 3′UTR of CXXC4 and then down-regulated its expression at post-transcriptional level. CXXC4 knockdown rescued the decreased cell proliferation and migration and the enhanced cell apoptosis induced by inhibiting miR-629-5p expression. Notably, overexpression of miR-629-5p also conferred 5-fluorouracil sensitivity, which was partly abrogated by coexpression of CXXC4. Overall, the results presented here suggest that miR-629-5p functions as a tumor promoter by improving proliferation and migration and repressing apoptosis and 5-FU sensitivity in colorectal cancer progression by directly down-regulating CXXC4.

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Meprinα Transactivates the Epidermal Growth Factor Receptor (EGFR) via Ligand Shedding, thereby Enhancing Colorectal Cancer Cell Proliferation and Migration

Journal of Biological Chemistry ◽

10.1074/jbc.m112.368910 ◽

2012 ◽

Vol 287 (42) ◽

pp. 35201-35211 ◽

Cited By ~ 21

Author(s):

Petra Minder ◽

Elke Bayha ◽

Christoph Becker-Pauly ◽

Erwin E. Sterchi

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cancer Progression ◽

Cell Proliferation And Migration ◽

Epidermal Growth ◽

Colorectal Cancer Progression ◽

And Migration ◽

Proliferation And Migration

Meprinα, an astacin-type metalloprotease is overexpressed in colorectal cancer cells and is secreted in a non-polarized fashion, leading to the accumulation of meprinα in the tumor stroma. The transition from normal colonocytes to colorectal cancer correlates with increased meprinα activity at primary tumor sites. A role for meprinα in invasion and metastatic dissemination is supported by its pro-angiogenic and pro-migratory activity. In the present study, we provide evidence for a meprinα-mediated transactivation of the EGFR signaling pathway and suggest that this mechanism is involved in colorectal cancer progression. Using alkaline phosphatase-tagged EGFR ligands and an ELISA assay, we demonstrate that meprinα is capable of shedding epidermal growth factor (EGF) and transforming growth factor-α (TGFα) from the plasma membrane. Shedding was abrogated using actinonin, an inhibitor for meprinα. The physiological effects of meprinα-mediated shedding of EGF and TGFα were investigated with human colorectal adenocarcinoma cells (Caco-2). Proteolytically active meprinα leads to an increase in EGFR and ERK1/2 phosphorylation and subsequently enhances cell proliferation and migration. In conclusion, the implication of meprinα in the EGFR/MAPK signaling pathway indicates a role of meprinα in colorectal cancer progression.

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ENO3 promotes colorectal cancer progression by enhancing cell glycolysis

10.21203/rs.3.rs-1243620/v1 ◽

2022 ◽

Author(s):

Jingyu Chen ◽

Zizhen Zhang ◽

Jiaojiao Ni ◽

Jiawei Sun ◽

Fangyu Ju ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Enrichment Analysis ◽

Glycolytic Enzyme ◽

Colorectal Cancer Progression ◽

And Migration

Abstract Background Colorectal cancer (CRC) is among the leading cause of cancer-related morbidity and mortality worldwide. Aerobic glycolysis, as a metabolic hallmark of cancer, plays an important role in CRC progression. Enolase 3 (ENO3) is a glycolytic enzyme that catalyzes 2-phosphoglycerate into phosphoenolpyruvate, while its role in CRC is still unknown. Methods Bioinformatics analysis was performed to examine the expression changes and roles of ENO3 in CRC patients from public databases. Then, ENO3 expression was validated in CRC tissues using Quantitative real-time PCR (qRT-PCR), immunohistochemical (IHC) analysis, and western blot. Overexpression and silencing models were constructed using plasmid and lentivirus transfection. Cell viability, proliferation, and migration in vitro were applied to evaluate the protumoral effects of ENO3 on CRC. RNA sequencing and GO enrichment analysis of differentially expressed genes (DEGs) were performed to explore the underlying molecular mechanisms of ENO3 in CRC progression. The ATP and lactate production level were detected to assess cell glycolysis.

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Beyond adhesion: emerging roles for integrins in control of the tumor microenvironment

F1000Research ◽

10.12688/f1000research.11877.1 ◽

2017 ◽

Vol 6 ◽

pp. 1612 ◽

Cited By ~ 26

Author(s):

Whitney Longmate ◽

C Michael DiPersio

Keyword(s):

Cell Adhesion ◽

Tumor Microenvironment ◽

Cancer Progression ◽

Intercellular Communication ◽

Cell Types ◽

Critical Position ◽

Surface Receptors ◽

Cell Adhesion And Migration ◽

And Migration ◽

Cancer Clinic

While integrins were originally discovered as cell adhesion receptors, recent studies have reinforced the concept that integrins have central roles in cancer that extend far beyond controlling cell adhesion and migration. Indeed, as transmembrane cell surface receptors that occupy a critical position at the interface of cellular and extracellular interactions and are capable of both “inside-out” and “outside-in” signaling, integrins are uniquely poised to regulate the cell’s ability to promote, sense, and react to changes in the tumor microenvironment. Moreover, integrins are present on all cell types in the tumor microenvironment, and they have important roles in regulating intercellular communication. Decades of promising pre-clinical studies have implicated certain integrins as attractive therapeutic targets in the cancer clinic. Nevertheless, results of the few clinical trials that target integrins in cancer have thus far been disappointing. Importantly, these clinical failures likely reflect the emerging complexity of individual and combinatorial integrin function within both tumor cells and other cell types of the tumor microenvironment, together with a need to explore integrin-targeting agents not just as monotherapies but also as adjuvants to more conventional radiotherapies or chemotherapies. In this review, we will examine recent advances toward understanding how integrins regulate cancer progression, including their roles in intercellular communication and modulation of the tumor microenvironment. Additionally, we will discuss factors that underlie the limited efficacy of current efforts to target integrins in the cancer clinic as well as potential strategies to overcome these challenges.

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