Krüppel‐like factor 4 promotes <i>c‐Met</i> amplification‐mediated gefitinib resistance in non‐small‐cell lung cancer

Feng, Wei; Xie, Qianyi; Liu, Suo; Ji, Ying; Li, Chunyun; Wang, Chunle; Jin, Longyu

doi:10.1111/cas.13601

Cited by 16 publications

(17 citation statements)

References 43 publications

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“…Overexpression of peptidylarginine deiminase IV (PAD4) has been demonstrated to decrease the activity of EMT by inhibiting the expression of ETS-domain containing protein (Elk1), which then suppresses the resistance of NSCLC cell lines to gefitinib ( 22 ). Feng et al ( 23 ) indicated that Krüppel-like factor 4 (KLF4) is an important contributing factor for gefitinib resistance in c-Met-overexpressed-NSCLC cells by repressing the expression of apoptosis-related proteins. In addition, microRNAs have been recently reported to be widely involved in acquired gefitinib resistance in NSCLC ( 24 , 25 ).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of CTEN is associated with gefitinib resistance in non‑small cell lung cancer

Zhang

Pan

et al. 2020

Oncol Lett

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COOH-terminus tensin-like molecule (CTEN) is a member of the tensin family, which is considered to be one of the novel proto-oncogenes involved in tumorigenesis and cancer progression. However, the mechanisms of CTEN in acquired resistance of non-small cell lung cancer (NSCLC) remain relatively unknown. The aim of the present study was to understand the roles of CTEN in acquired gefitinib resistance of NSCLC. The present study investigated the expression level of CTEN using reverse transcription-quantitative polymerase chain reaction and Western blot analysis. Cell Counting kit-8 and colony-formation assays were performed to evaluate the proliferative and colony-formative abilities of PC9 and PC9/GR cells in vitro . Mouse xenograft models were used to assess the growth of PC9/GR cells in vivo . A gefitinib-resistant NSCLC cell line (PC9/GR) was established, and the protein and mRNA expression levels of CTEN were observed to be higher in PC9/GR cells than in PC9 cells. Notably, the sensitivity of PC9/GR cells to gefitinib was observed to be decreased when CTEN was overexpressed, while PC9/GR cells with CTEN-downregulation showed markedly enhanced sensitivity to gefitinib. In vitro proliferation and colony formation assays revealed that increased CTEN markedly promoted the cell proliferative and colony-forming capacities of PC9 and PC9/GR cells, and CTEN-silencing inhibited the cell proliferative and colony-forming abilities of the PC9 and PC9/GR cells. Notably, deficient expression of CTEN notably retarded the growth of PC9/GR xenografts in vivo . In addition, the plasma mRNA expression of CTEN was notably elevated in patients with NSCLC with acquired gefitinib resistance. Overexpression of CTEN is associated with acquired gefitinib resistance in NSCLC. CTEN may be investigated as a potential therapeutic target for the treatment of patients with NSCLC with acquired gefitinib resistance.

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Section: Discussionmentioning

confidence: 99%

Overexpression of CTEN is associated with gefitinib resistance in non‑small cell lung cancer

Zhang

Pan

et al. 2020

Oncol Lett

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“…Krüppel‐like transcription factor (KLF4) is a zinger transcription factor and plays a criterial role in regulating cell proliferation, differentiation, apoptosis, and migration . KLF4 has been found to act as an oncogene or tumor suppressor gene in different cancers in a context‐dependent manner .…”

Section: Introductionmentioning

confidence: 99%

Helicobacter pylori CagA promotes the malignant transformation of gastric mucosal epithelial cells through the dysregulation of the miR‐155/KLF4 signaling pathway

Ren

Zhao

et al. 2019

Molecular Carcinogenesis

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The Helicobacter pylori (H. pylori) cytotoxin-associated gene A (CagA) and Krüppel-like transcription factor (KLF4) were both closely associated with the development and progression of gastric cancer (GC). However, the nature of the interactions between CagA and KLF4 in GC development has not been elucidated. Therefore, we focused on the CagA-mediated promotion of the malignant transformation of gastric epithelial cells. Herein, we first examined the expression of KLF4 in both human cancer and paracarcinoma tissues with or without H. pylori infection and found that KLF4 expression was significantly decreased in H. pylori-positive GC cells compared with the H. pylori-negative GC cells. Further functional studies revealed that the increased expression of CagA could suppress KLF4 expression and promote the malignant transformation of normal epithelial cells. Subsequently, we found that CagA could upregulate miR-155 and further restrict the expression of downstream KLF4. More importantly, the overexpression of miR-155 in GES-1 promoted epithelial-mesenchymal transition and eventually facilitated tumor growth in vivo. Overall, the identification of the CagA/miR-155/KLF4 signaling pathway provided a new insight into the development and treatment of GC. K E Y W O R D S CagA, gastric cancer, Helicobacter pylori, Krüppel-like factor 4, miR-155

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“…Nevertheless, KLF4 is important in regulating response to many known drugs [ 1 ]. These include cetuximab [ 23 ], cisplatin [ 19 , 43 , 72 , 84 , 102 ], gefitinib [ 79 ], glibenclamide [ 78 ], mesalazine [ 22 ] and Sijunzi decoction [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…This finding is very significant as it demonstrates that the expression of KLF4 can be increased by the oral administration of the small molecule drug glibenclamide, at least in this particular context. KLF4 promotes resistance to gefitinib, an EGFR inhibitor, in NSCLC cells with c-Met overexpression [ 79 ]. The underlying molecular mechanism involves the regulation of phosphorylation of c-Met and Akt, as KLF4 negatively regulates the expression of β-catenin and inhibits the binding between c-Met and β-catenin [ 79 ].…”

Section: Lung Cancermentioning

confidence: 99%

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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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Krüppel‐like factor 4 promotes c‐Met amplification‐mediated gefitinib resistance in non‐small‐cell lung cancer

Cited by 16 publications

References 43 publications

Overexpression of CTEN is associated with gefitinib resistance in non‑small cell lung cancer

Overexpression of CTEN is associated with gefitinib resistance in non‑small cell lung cancer

Helicobacter pylori CagA promotes the malignant transformation of gastric mucosal epithelial cells through the dysregulation of the miR‐155/KLF4 signaling pathway

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

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