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:10.1101/743443

Cited by 3 publications

(3 citation statements)

References 42 publications

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“…32 In addition, loss of KLF4 accelerates the development of CRC. 33 Furthermore, Figure 8. continued tissues of EV-treated mice with oe-LINC01915 or combined with sh-CH25H.…”

Section: ■ Discussionmentioning

confidence: 98%

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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“…32 In addition, loss of KLF4 accelerates the development of CRC. 33 Furthermore, Figure 8. continued tissues of EV-treated mice with oe-LINC01915 or combined with sh-CH25H.…”

Section: ■ Discussionmentioning

confidence: 98%

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: Discussionmentioning

confidence: 68%

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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“…in CRC patient tumor sections. However, the expression of KLF4 is positively correlated with the epithelial marker E-cadherin [ 6 ].…”

Section: Colorectal Cancermentioning

confidence: 99%

Recent Discoveries on the Involvement of Krüppel-Like Factor 4 in the Most Common Cancer Types

Taracha-Wisniewska

Kotarba

Dworkin

et al. 2020

IJMS

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Krüppel-like factor 4 (KLF4) is a transcription factor highly conserved in evolution. It is particularly well known for its role in inducing pluripotent stem cells. In addition, KLF4 plays many roles in cancer. The results of most studies suggest that KLF4 is a tumor suppressor. However, the functioning of KLF4 is regulated at many levels. These include regulation of transcription, alternative splicing, miRNA, post-translational modifications, subcellular localization, protein stability and interactions with other molecules. Simple experiments aimed at assaying transcript levels or protein levels fail to address this complexity and thus may deliver misleading results. Tumor subtypes are also important; for example, in prostate cancer KLF4 is highly expressed in indolent tumors where it impedes tumor progression, while it is absent from aggressive prostate tumors. KLF4 is important in regulating response to many known drugs, and it also plays a role in tumor microenvironment. More and more information is available about upstream regulators, downstream targets and signaling pathways associated with the involvement of KLF4 in cancer. Furthermore, KLF4 performs critical function in the overall regulation of tissue homeostasis, cellular integrity, and progression towards malignancy. Here we summarize and analyze the latest findings concerning this fascinating transcription factor.

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

Cited by 3 publications

References 42 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

Recent Discoveries on the Involvement of Krüppel-Like Factor 4 in the Most Common Cancer Types

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