ILK Expression in Colorectal Cancer Is Associated with EMT, Cancer Stem Cell Markers and Chemoresistance

Tsoumas, Dimitrios; Nikou, Sofia; Giannopoulou, Efstathia; Tsaniras, Spyridon Champeris; Sirinian, Chaido; Maroulis, Ioannis; Taraviras, Stavros; Zolota, Vassiliki; Kalofonos, Haralabos; Bravou, Vasiliki

doi:10.21873/cgp.20071

Cited by 55 publications

(43 citation statements)

References 59 publications

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“…The contribution of ILK to cancer-induced MMT has never been described before, although its involvement was reported as being critical for EMT in colorectal cancer [16], adenomyosis [17], and glomerulonephritis [18]. The most unexpected result is, however, that MMT elicited in the PMCs by both groups of cancers did not require Snail1.…”

Section: Discussionmentioning

confidence: 94%

A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

Pakuła

Uruski

Niklas

et al. 2019

Cancers

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The study was designed to establish whether high aggressiveness of high-grade serous ovarian cancer cells (HGSOCs), which display rapid growth, advanced stage at diagnosis and the highest mortality among all epithelial ovarian cancer histotypes, may be linked with a specific pattern of mesothelial-mesenchymal transition (MMT) elicited by these cells in normal peritoneal mesothelial cells (PMCs). Experiments were performed on primary PMCs, stable and primary ovarian cancer cells, tumors from patients with ovarian cancer, and laboratory animals. Results of in vitro and in vivo tests showed that MMT triggered by HGSOCs (primary cells and OVCAR-3 line) is far more pronounced than the process evoked by cells representing less aggressive ovarian cancer histotypes (A2780, SKOV-3). Mechanistically, HGSOCs induce MMT via Smad 2/3, ILK, TGF-β1, HGF, and IGF-1, whereas A2780 and SKOV-3 cells via exclusively Smad 2/3 and HGF. The conditioned medium from PMCs undergoing MMT promoted the progression of cancer cells and the effects exerted by the cells triggered to undergo MMT by the HGSOCs were significantly stronger than those related to the activity of their less aggressive counterparts. Our findings indicate that MMT in PMCs provoked by HGSOCs is stronger, proceeds via different mechanisms and has more procancerous characteristics than MMT provoked by less aggressive cancer histotypes, which may at least partly explain high aggressiveness of HGSOCs.

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Section: Discussionmentioning

confidence: 94%

A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

Pakuła

Uruski

Niklas

et al. 2019

Cancers

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“…ILK is a focal adhesion-associated serine/threonine kinase that interacts with several integrins in a complex with Parvin and PINCH and acts as a multifunctional effector of growth factor signaling and cell–ECM interactions 80 , 81 . In CRC, ILK induces β-catenin–LEF1 interaction and transactivation, the loss of E-cadherin via induction of EMT-TFs, and the induction of stem cell markers 82 – 88 . In breast CSCs, interleukin-6 (IL-6), a key growth factor, induces the expression of the TF E2F1 via a STAT3/cyclin D1/CDK2 loop and subsequently triggers the activation of NF-κB and NOTCH signaling, which enhance ILK expression 89 .…”

Section: Signaling Via Cell Adhesion Molecules In Cancer Stem Cellsmentioning

confidence: 99%

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

2018

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Changes in cell adhesion and motility are considered key elements in determining the development of invasive and metastatic tumors. Co-opting the epithelial-to-mesenchymal transition (EMT) process, which is known to occur during embryonic development, and the associated changes in cell adhesion properties in cancer cells are considered major routes for tumor progression. More recent in vivo studies in tumor tissues and circulating tumor cell clusters suggest a stepwise EMT process rather than an “all-or-none” transition during tumor progression. In this commentary, we addressed the molecular mechanisms underlying the changes in cell adhesion and motility and adhesion-mediated signaling and their relationships to the partial EMT states and the acquisition of stemness traits by cancer cells.

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“…Colorectal cancer (CRC) is the third leading cause of cancer death worldwide; the 5-year relative survival rate is only 53% to 65% in spite of many efforts to improve diagnosis and chemotherapy ( Torre et al, 2015 ). Currently, tumor metastasis and resistance to chemotherapeutic treatment are considered as two critical factors that contribute to the death of CRC patients ( Tsoumas et al, 2018 ). Approximately 25% of newly diagnosed CRC patients develop metastases and 50% of all CRC patients die from metastatic disease ( Obrand and Gordon, 1997 ).…”

Section: Introductionmentioning

confidence: 99%

DSTYK Promotes Metastasis and Chemoresistance via EMT in Colorectal Cancer

et al. 2020

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Objective Tumor metastasis and resistance to chemotherapy are two critical factors that contribute to the high death rate of colorectal cancer (CRC) patients. Metastasis is facilitated by the epithelial-mesenchymal transition (EMT) of tumor cells, which has emerged not only as a fundamental process during metastasis, but is also a key process leading to chemoresistance of cancer cells. However, the underlying mechanisms of EMT in CRC cell remain unknown. Here, we aim to assess the role of dual serine/threonine and tyrosine protein kinase (DSTYK) in CRC metastasis and chemoresistance. Methods To study the role of DSTYK in TGF-β-induced EMT, we employed techniques including Crispr/Cas9 knockout (KO) to generate DSTYK KO cell lines, RT-PCR to detect the mRNA expression, immunofluorescence analyses, and western blots to detect protein levels of DSTYK in the following 4 cell lines: control LS411N-TβRII and LS411N-TβRII/DSTYK KO, control LS513 and LS513/DSTYK KO cells, treated with/without TGF-β. The effects of DSTYK on apoptosis were investigated by MTT assays, flow cytometry assays, and TUNEL assays. The expression of DSTYK in CRC patients and its correlation with EMT markers were determined by bioinformatics analysis. For in vivo analysis, both xenograft and orthotopic tumor mouse models were employed to investigate the function of DSTYK in chemoresistance and metastasis of tumors. Results In this study, we demonstrate that the novel kinase DSTYK promotes both TGF-β-induced EMT and the subsequent chemoresistance in CRC cells. DSTYK KO significantly attenuates TGF-β–induced EMT and chemoresistance in CRC cells. According to the Gene Expression Omnibus (GEO) database, the expression of DSTYK is not only positively correlated to the expression of TGF-β, but proportional to the death rate of CRC patients as well. Evidently, the expression of DSTYK in the metastatic colorectal cancer samples from patients was significantly higher than that of primary colorectal cancer samples. Further, we demonstrate in mouse models that chemotherapeutic drug treatment suppresses the growth of DSTYK KO tumors more effectively than control tumors. Conclusion Our findings identify DSTYK as a novel protein kinase in regulating TGF-β–mediated EMT and chemoresistance in CRC cells, which defines DSTYK as a potential therapeutic target for CRC therapy.

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ILK Expression in Colorectal Cancer Is Associated with EMT, Cancer Stem Cell Markers and Chemoresistance

Abstract: ILK overexpression in human CRC associates with EMT and CSC traits, contributing to tumor progression and chemoresistance.

Cited by 55 publications

References 59 publications

A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

DSTYK Promotes Metastasis and Chemoresistance via EMT in Colorectal Cancer

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