A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity

Almasabi, Saleh; Ahmed, Afsar U.; Boyd, Richard; Williams, Bryan R.G.

doi:10.3389/fgene.2021.638558

Cited by 20 publications

(18 citation statements)

References 193 publications

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“…Integrin-linked kinase (ILK) plays a key role as a multifunctional effector of growth factor signaling and cell–matrix interaction [ 58 ]. Some studies have found that ILK is associated with the process of EMT and immune, which could be seen as an EMT-immune-related gene [ 59 , 60 ]. A study found that ILK is up-regulated in colorectal cancer and other tumors [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

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Identification and validation of EMT-immune-related prognostic biomarkers CDKN2A, CMTM8 and ILK in colon cancer

et al. 2022

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Colon cancer (CC) is a disease with high incidence and mortality rate. The interaction between epithelial-mesenchymal transition (EMT) and immune status has important clinical significance. We aim to identify EMT-immune-related prognostic biomarkers in colon cancer. The GEO2R and GEPIA 2.0 were utilized to calculate the differential expression genes between CC and normal mucosa. Immport, InnateDB and EMTome databases were used to define EMT-immune-related genes. We conducted batch prognostic analysis by TCGA data. The expression patterns were verified by multiple datasets and lab experiments. GEPIA 2.0 and TIMER 2.0 were utilized to analyze the correlation of the hub genes with EMT markers and immune infiltration. GeneMANIA, STRING, and Metascape were used for co-expression and pathway enrichment analysis. Finally, we established a signature by the method of multivariate Cox regression analysis. CDKN2A, CMTM8 and ILK were filtered out as prognostic genes. CDKN2A and CMTM8 were up-regulated, while ILK was down-regulated in CC. CDKN2A was positively correlated with infiltration of macrophages, Th2 cells, Treg cells, and negatively correlated with NK cells. CMTM8 was negatively correlated with CD8+ T cells, dendritic cells, and NK cells. ILK was positively correlated with CD8+ T cells and dendritic cells. Moreover, CDKN2A, CMTM8 and ILK were significantly correlated with EMT markers. The three genes could participate in the TGF-β pathway. The prognosis model established by the three hub genes was an independent prognosis factor, which can better predict the prognosis. CDKN2A, CMTM8 and ILK are promising prognostic biomarkers and may be potential therapeutic targets in colon cancer.

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Section: Discussionmentioning

confidence: 99%

“…Some studies have found that ILK is associated with the process of EMT and immune, which could be seen as an EMT-immune-related gene [ 59 , 60 ]. A study found that ILK is up-regulated in colorectal cancer and other tumors [ 60 ]. We found that ILK is down-regulated in colon cancer and leads to a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of EMT-immune-related prognostic biomarkers CDKN2A, CMTM8 and ILK in colon cancer

et al. 2022

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“…We have previously shown that myeloid-ILK deficiency reduced inflammation of experimental colitis by regulating neutrophil infiltration and cytokine production ( 32 ). While this suggested that ILK plays an important role in the inflammatory tumor microenvironment in colon cancer ( 36 ), mechanisms involved remain to be established.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we have previously shown that myeloid-ILK deficiency reduced intestinal inflammation in experimental colitis by regulating neutrophil infiltration and cytokine production ( 32 ). These studies suggest that while ILK is an essential molecule for promoting the inflammatory tumor microenvironment ( 36 ) and its different compartments, its importance in regulating the different TME components remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Integrin-Linked Kinase Expression Characterizes the Immunosuppressive Tumor Microenvironment in Colorectal Cancer and Regulates PD-L1 Expression and Immune Cell Cytotoxicity

et al. 2022

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Integrin-linked kinase (ILK) has been implicated as a molecular driver and mediator in both inflammation and tumorigenesis of the colon. However, a role for ILK in the tumor microenvironment (TME) and immune evasion has not been investigated. Here, we show a correlation of ILK expression with the immunosuppressive TME and cancer prognosis. We also uncover a role for ILK in the regulation of programmed death-ligand 1 (PD-L1) expression and immune cell cytotoxicity. Interrogation of web-based data-mining platforms, showed upregulation of ILK expression in tumors and adjacent-non tumor tissue of colorectal cancer (CRC) associated with poor survival and advanced stages. ILK expression was correlated with cancer-associated fibroblast (CAFs) and immunosuppressive cell infiltration including regulatory T cells (Treg) and M2 macrophages (M2) in addition to their gene markers. ILK expression was also significantly correlated with the expression of different cytokines and chemokines. ILK expression showed pronounced association with different important immune checkpoints including PD-L1. Deletion of the ILK gene in PD-L1 positive CRC cell lines using a doxycycline inducible-CRISPR/Cas9, resulted in suppression of both the basal and IFNγ-induced PD-L1 expression via downregulating NF-κB p65. This subsequently sensitized the CRC cells to NK92 immune cell cytotoxicity. These findings suggest that ILK can be used as a biomarker for prognosis and immune cell infiltration in colon cancer. Moreover, ILK could provide a therapeutic target to prevent immune evasion mediated by the expression of PD-L1.

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“…Integrin-linked kinase (ILK) is conceptually a serine-threonine protein kinase and can control many biological behaviors of cells, including growth, survival, differentiation and migration [8]. Many studies show that ILK overexpression is associated with the carcinogenesis and metastasis of diverse cancers, such as hepatocellular carcinoma, colorectal cancer and BC [9][10][11].…”

Section: Agingmentioning

confidence: 99%

Circular RNA circ_0000515 adsorbs miR-542-3p to accelerate bladder cancer progression via up-regulating ILK expression

Peng

Guan²,

Leng

et al. 2022

Aging

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Background: Bladder cancer (BC) is a common cause of cancer-relevant deaths globally. This study is designed to delve into expressions, biological functions and molecular mechanisms of circ_0000515 in BC. Methods: Quantitative real-time polymerase chain reaction was accomplished to examine circ_0000515, miR-542-3p and integrin-linked kinase (ILK) mRNA expressions in BC tissues and cell lines. In RT-4 and RT-112 cells with circ_0000515 depletion and UMUC3 and BIU-87 cells with this circ RNA overexpression, a cell counting kit-8 assay was adopted to monitor the viability. Besides, transwell assay was conducted to detect cell migration and aggressiveness, and luciferase reporter gene assay was applied to probe the interplay among circ_0000515, miR-542-3p and ILK mRNA. Additionally, Besides, the regulatory function of circ_0000515 on miR-542-3p expression was under the assay of quantitative real-time polymerase chain reaction, and western blot was fulfilled to determine the regulative function of circ_0000515/miR-542-3p axis on ILK protein expressions. A xenograft animal was modeled to examine lung metastasis in vivo . Results: Circ_0000515 and ILK expressions were significantly elevated in BC tissues and cell lines, while that of miR-542-3p was dramatically suppressed. Knocking down circ_0000515 could significantly repress the growth, migration and aggressiveness of BC cells while overexpression of circ_0000515 showed opposite effects. Moreover, circ_0000515 knockdown inhibited pulmonary metastasis in vivo . Circ_0000515 was validated to adsorb miR-542-3p, and ILK was testified as the downriver target of miR-542-3p. Circ_0000515 could ascend ILK expression through repressing that of miR-542-3p. Conclusions: Circ_0000515, as a tumor promoter, strengthens the viability, migration and aggressiveness of BC cells via modulating miR-542-3p/ILK axis.

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A Potential Role for Integrin-Linked Kinase in Colorectal Cancer Growth and Progression via Regulating Senescence and Immunity

Cited by 20 publications

References 193 publications

Identification and validation of EMT-immune-related prognostic biomarkers CDKN2A, CMTM8 and ILK in colon cancer

Identification and validation of EMT-immune-related prognostic biomarkers CDKN2A, CMTM8 and ILK in colon cancer

Integrin-Linked Kinase Expression Characterizes the Immunosuppressive Tumor Microenvironment in Colorectal Cancer and Regulates PD-L1 Expression and Immune Cell Cytotoxicity

Circular RNA circ_0000515 adsorbs miR-542-3p to accelerate bladder cancer progression via up-regulating ILK expression

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