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

Agbo, Kimberley C.; Huang, Jessie Z.; Ghaleb, Amr M.; Williams, Jennie L.; Shroyer, Kenneth R.; Bialkowska, Agnieszka B.; Yang, Vincent W.

doi:10.20517/2394-4722.2019.35

Cited by 12 publications

(9 citation statements)

References 47 publications

(64 reference statements)

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“…Besides, KLF4 is a tumor suppressor which could suppress the tumor cell proliferation, migration, and metastasis . In addition, loss of KLF4 accelerates the development of CRC . Furthermore, the present study verified that miR-92a-3p targeted KLF4 to augment cell proliferation-associated genes such as MMP-9 and VEGF in CRC by reducing CH25H expression.…”

Section: Discussionsupporting

confidence: 76%

LINC01915 Facilitates the Conversion of Normal Fibroblasts into Cancer-Associated Fibroblasts Induced by Colorectal Cancer-Derived Extracellular Vesicles through the miR-92a-3p/KLF4/CH25H Axis

Zhou

Wang

Liu

et al. 2021

ACS Biomater. Sci. Eng.

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Increasing long non-coding RNAs are reported to regulate the cell growth, apoptosis, and metastasis of cancerassociated fibroblasts (CAFs).This study aimed to explore how LINC01915 influences the conversion of normal fibroblasts (NFs) into CAFs in colorectal cancer (CRC). LINC01915 expression was initially measured in clinical tissue samples and in NFs and CAFs. Identification of the interaction between LINC01915, miR-92a-3p, KLF4, and CH25H was done. The effects of LINC01915, miR-92a-3p, and KLF4 on the angiogenesis, extracellular vesicle (EV) uptake by NFs, and activation of stromal cells were assessed using gain-or loss-of-function approaches. Xenograft mouse models were established to validate these in vitro findings in vivo. EVs were shown to stimulate NF proliferation, migration, and angiogenesis, as well as facilitate NF conversion into CAFs. CRC tissues and CAFs showed downregulated expression of LINC01915, which was associated with poor prognosis of patients. Moreover, employed LINC01915 inhibited tumor angiogenesis, CAF activation, and the uptake of tumor-derived EVs by NFs. Mechanistically, LINC01915 could competitively bind to miR-92a-3p and caused upregulation of the miR-92a-3p target KLF4 which, in turn, promoted the transcription of CH25H, leading to the suppressed uptake of EVs by NFs. The in vivo and in vitro experimental results showed that LINC01915 inhibited the uptake of CRC-derived EVs by NFs through the miR-92a-3p/KLF4/CH25H axis, thus arresting the angiogenesis and the conversion of NFs into CAFs and in turn prevent tumor growth. These data together supported the inhibiting role of LINC01915 in the conversion of NFs into CAFs triggered by the CRC-derived EVs and the ensuing tumor growth, which may be related to its regulation on the miR-92a-3p/KLF4/CH25H axis.

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Section: Discussionsupporting

confidence: 76%

LINC01915 Facilitates the Conversion of Normal Fibroblasts into Cancer-Associated Fibroblasts Induced by Colorectal Cancer-Derived Extracellular Vesicles through the miR-92a-3p/KLF4/CH25H Axis

Zhou

Wang

Liu

et al. 2021

ACS Biomater. Sci. Eng.

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“…In fact, in wt-CFTR CFBE cells, KLF4 KO promotes a "leakier" epithelium (by decreasing TEER), phenotypes often associated with a more mesenchymal state. Such an impact has been described previously [45]. Surprisingly, in F508del-CFTR cells, which are already more mesenchymal [7,8], KLF4 KO leads to the opposite effect, with cells acquiring higher levels of TEER (although not reaching wt-CFTR levels).…”

Section: Discussionsupporting

confidence: 72%

Impact of KLF4 on Cell Proliferation and Epithelial Differentiation in the Context of Cystic Fibrosis

Sousa

Pankonien

Simões

et al. 2020

IJMS

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Cystic fibrosis (CF) cells display a more cancer-like phenotype vs. non-CF cells. KLF4 overexpression has been described in CF and this transcriptional factor acts as a negative regulator of wt-CFTR. KLF4 is described as exerting its effects in a cell-context-dependent fashion, but it is generally considered a major regulator of proliferation, differentiation, and wound healing, all the processes that are also altered in CF. Therefore, it is relevant to characterize the differential role of KLF4 in these processes in CF vs. non-CF cells. To this end, we used wt- and F508del-CFTR CFBE cells and their respective KLF4 knockout (KO) counterparts to evaluate processes like cell proliferation, polarization, and wound healing, as well as to compare the expression of several epithelial differentiation markers. Our data indicate no major impact of KLF4 KO in proliferation and a differential impact of KLF4 KO in transepithelial electrical resistance (TEER) acquisition and wound healing in wt- vs. F508del-CFTR cells. In parallel, we also observed a differential impact on the levels of some differentiation markers and epithelial-mesencymal transition (EMT)-associated transcription factors. In conclusion, KLF4 impacts TEER acquisition, wound healing, and the expression of differentiation markers in a way that is partially dependent on the CFTR-status of the cell.

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“…Additionally, KLF4 may regulate the expression of the Snail Family Transcription Repressor 1 (SNAI1). Interestingly, SNAI2 gene expression is dramatically increased in NEC and a similar negative correlation with KLF4 expression has been observed in the epithelialmesenchymal transition in colorectal cancer 25 .…”

Section: Putative Nec-specific Regulatory Network Dysfunctionsupporting

confidence: 68%

NEC-Associated DNA Methylation Signatures in Colon are Evident in Stool Samples of Affected Individuals

Good¹,

Chu

Shaw

et al. 2020

Preprint

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Neonatal necrotizing enterocolitis (NEC) is a devastating and unpredictable gastrointestinal disease with a high mortality rate in premature infants. Currently, no predictive or diagnostic biomarkers exist for NEC. Clinical intervention is reactive to the overt manifestations of disease resulting in high levels of morbidity and mortality. To better understand the molecular mechanisms that underpin NEC, we have undertaken a high resolution genome wide epigenomic analysis using solution phase hybridization and next generation DNA sequencing of bisulfite converted DNA. Our data reveal a broad and significant genomic hypermethylation in surgical NEC tissues compared to non-NEC controls. These changes were found to be far more pronounced in regions outside CpG islands and gene regulatory elements, which suggests that NEC-specific hypermethylation is not a non-specific global phenomenon. We identified a number of important biological pathways that are dysregulated in NEC and observed a clear association between NEC methylation changes and gene expression. Significantly, we found that the same patterns of global methylation identified in surgical NEC tissue are also detectable in stool samples from affected infants. To our knowledge, this is the first evidence of a methylomic signature that is both associated with NEC and detectable non-invasively. These findings point towards a new opportunity for the development of novel screening, diagnostic and phenotyping methods for NEC that could be deployed in the NICU for improved detection of this devastating disease.

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

Cited by 12 publications

References 47 publications

LINC01915 Facilitates the Conversion of Normal Fibroblasts into Cancer-Associated Fibroblasts Induced by Colorectal Cancer-Derived Extracellular Vesicles through the miR-92a-3p/KLF4/CH25H Axis

LINC01915 Facilitates the Conversion of Normal Fibroblasts into Cancer-Associated Fibroblasts Induced by Colorectal Cancer-Derived Extracellular Vesicles through the miR-92a-3p/KLF4/CH25H Axis

Impact of KLF4 on Cell Proliferation and Epithelial Differentiation in the Context of Cystic Fibrosis

NEC-Associated DNA Methylation Signatures in Colon are Evident in Stool Samples of Affected Individuals

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