KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis

Ghaleb, Amr M.; Elkarim, Enas A.; Bialkowska, Agnieszka B.; Yang, Vincent W.

doi:10.1158/1541-7786.mcr-15-0410

Cited by 27 publications

(22 citation statements)

References 50 publications

(91 reference statements)

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“…We also noted that the mutant and 295 wild-type gene sets exhibited enrichment of different classes of transcription factor (Figure 296 3C). The wild-type set is highly enriched in zinc-finger transcription factor binding sites ( shown to function as tumor suppressors in colorectal cancer [27][28][29] . KLF4 has been shown to 300 interact with Beta-catenin and inhibit Wnt signaling in the colon 30,31 .…”

Section: Comparison Of Functional Trends Between Mutant and Wild-typementioning

confidence: 99%

Multiproteomic and Transcriptomic Analysis of Oncogenic β-Catenin Molecular Networks

et al. 2018

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The dysregulation of Wnt signaling is a frequent occurrence in many different cancers. Oncogenic mutations of CTNNB1/β-catenin, the key nuclear effector of canonical Wnt signaling, lead to the accumulation and stabilization of β-catenin protein with diverse effects in cancer cells. Although the transcriptional response to Wnt/β-catenin signaling activation has been widely studied, an integrated understanding of the effects of oncogenic β-catenin on molecular networks is lacking. We used affinity-purification mass spectrometry (AP-MS), label-free liquid chromatography-tandem mass spectrometry, and RNA-Seq to compare protein-protein interactions, protein expression, and gene expression in colorectal cancer cells expressing mutant (oncogenic) or wild-type β-catenin. We generate an integrated molecular network and use it to identify novel protein modules that are associated with mutant or wild-type β-catenin. We identify a DNA methyltransferase I associated subnetwork that is enriched in cells with mutant β-catenin and a subnetwork enriched in wild-type cells associated with the CDKN2A tumor suppressor, linking these processes to the transformation of colorectal cancer cells through oncogenic β-catenin signaling. In summary, multiomics analysis of a defined colorectal cancer cell model provides a significantly more comprehensive identification of functional molecular networks associated with oncogenic β-catenin signaling.

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Section: Comparison Of Functional Trends Between Mutant and Wild-typementioning

confidence: 99%

Multiproteomic and Transcriptomic Analysis of Oncogenic β-Catenin Molecular Networks

et al. 2018

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“…It has been shown that loss of KLF4 expression is associated with the early stage of CRC development and that KLF4 is a prognostic indicator for CRC survival and recurrence [14,15] . Recently, we demonstrated that KLF4 also plays a protective role against tumor formation during inflammation-induced colorectal tumorigenesis [16][17][18] . The biochemical mechanisms triggering the acquisition of the invasive phenotype and the subsequent systemic spread of the cancer cell have been areas of intensive research.…”

Section: Introductionmentioning

confidence: 99%

Loss of the Krüppel-like factor 4 tumor suppressor is associated with epithelial-mesenchymal transition in colorectal cancer

Agbo¹,

Huang²,

Ghaleb³

et al. 2019

JCMT

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Aim: Colorectal cancer (CRC) is the third leading cancer-related cause of death due to its propensity to metastasize. Epithelial-mesenchymal transition (EMT) is a multistep process important for invasion and metastasis of CRC. Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor highly expressed in differentiated cells of the intestinal epithelium. KLF4 has been shown to play a tumor suppressor role during CRC tumorigenesis-its loss accelerates development and progression of cancer. The present study examined the relationship between KLF4 and markers of EMT in CRC. Methods: Immunofluorescence staining for KLF4 and EMT markers was performed on archived patient samples after colorectal cancer resection and on colonic tissues of mice with colitis-associated cancer. Results: We found that KLF4 expression is lost in tumor sections obtained from CRC patients and in those of mouse colon following azoxymethane and dextran sodium sulfate (AOM/DSS) treatment when compared to their respective normal appearing mucosa. Importantly, in CRC patient tumor sections, we observed a negative correlation between KLF4 levels and mesenchymal markers including TWIST, β-catenin, claudin-1, N-cadherin, and vimentin. Similarly, in tumor tissues from AOM/DSS-treated mice, KLF4 levels were negatively correlated with mesenchymal markers including SNAI2, β-catenin, and vimentin and positively correlated with the epithelial marker E-cadherin. Conclusion: These findings suggest that the loss of KLF4 expression is a potentially significant indicator of EMT in CRC.

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“…KLF4 plays an important role in tumor initiating, growth, and metastasis. Ghaleb AM et al found that KLF4 suppressed the development of colonic neoplasia (Ghaleb et al, 2016). Chuan Tian et al revealed that KLF4 overexpression inhibits the growth and metastasis of hepatocellular carcinoma cells (Tian et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway

Wang

et al. 2020

Front. Pharmacol.

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Krüppel-like factor 4 (KLF4) is a transcription factor and plays a vital role in cancer initiation and development. However, the role of Krüppel-like factor 4 in the metastasis of non-small cell lung cancer (NSCLC) is not clear. Here, we demonstrated that the expression of Krüppel-like factor 4 was significantly decreased in human non-small cell lung cancer tissues compared with that in normal tissues using Western blot. We performed immunohistochemical staining and observed the decreased expression of Krüppel-like factor 4 in human lung cancer tissues, and metastatic tumor tissues located in the trachea and main bronchus. We also found that the Ecadherin expression was decreased, while vimentin expression was increased in human NSCLC tissues and metastatic tumor tissues located in the trachea and main bronchus. Additionally, enforced expression of Krüppel-like factor 4 in mouse lungs significantly inhibited the metastasis of circulating Lewis lung carcinoma cells to the lungs by attenuating mesenchymal-epithelial transition (MET). Furthermore, cell scratch assays and Matrigel invasion assays revealed that overexpression of Krüppel-like factor 4 inhibited the migration and invasion of non-small cell lung cancer cell lines A549, H1299, H226, and H1650 cells. Moreover, overexpression of Krüppel-like factor 4 attenuated TGF-b1-induced epithelial-mesenchymal transition (EMT) in A549, and inhibited the phosphorylation of c-Jun-NH2-terminal kinase (JNK), an important pathway in metastasis in non-small cell lung cancer. Our in vivo and in vitro findings illustrate that Krüppel-like factor 4 inhibited metastasis and migration of non-small cell lung cancer, and indicate that Krüppel-like factor 4 could be a potential therapeutic target for the treatment of non-small cell lung cancer.

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KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis

Cited by 27 publications

References 50 publications

Multiproteomic and Transcriptomic Analysis of Oncogenic β-Catenin Molecular Networks

Multiproteomic and Transcriptomic Analysis of Oncogenic β-Catenin Molecular Networks

Loss of the Krüppel-like factor 4 tumor suppressor is associated with epithelial-mesenchymal transition in colorectal cancer

Overexpression of Krüppel-Like Factor 4 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Through c-Jun-NH2-Terminal Kinase/Epithelial-Mesenchymal Transition Signaling Pathway

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