Emerging Roles of Krüppel-Like Factor 4 in Cancer and Cancer Stem Cells

Ding, Bo; Liu, Ping; Li, Wen; Sun, Ping

doi:10.7314/apjcp.2015.16.9.3629

Cited by 22 publications

(16 citation statements)

References 56 publications

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“…KLF4, as a well-known member of the KLF family, is one of the four factors that can reprogram adult fibroblasts into induced pluripotent stem cells. The significance of KLF4 in CSC regulation has recently increased [137–139]. BMI1 and KLF4 expression levels were found to be elevated in ALDH-high cervical cancer cells that display high stem-like features compared to the ALDH-low cell population [67], indicating that BMI1 and KLF4 may be CCSC markers.…”

Section: Other Potential Markers For Ccscsmentioning

confidence: 99%

Cancer stem cells (CSCs), cervical CSCs and targeted therapies

2016

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Accumulating evidence has shown that cancer stem cells (CSCs) have a tumour-initiating capacity and play crucial roles in tumour metastasis, relapse and chemo/radio-resistance. As tumour propagation initiators, CSCs are considered to be promising targets for obtaining a better therapeutic outcome. Cervical carcinoma is the most common gynaecological malignancy and has a high cancer mortality rate among females. As a result, the investigation of cervical cancer stem cells (CCSCs) is of great value. However, the numbers of cancer cells and corresponding CSCs in malignancy are dynamically balanced, and CSCs may reside in the CSC niche, about which little is known to date. Therefore, due to their complicated molecular phenotypes and biological behaviours, it remains challenging to obtain “purified” CSCs and continuously culture CSCs for further in vitro studies without the cells losing their stem properties. At present, CSC-related markers and functional assays are used to purify, identify and therapeutically target CSCs both in vitro and in vivo. Nevertheless, CSC-related markers are not universal to all tumour types, although some markers may be valid in multiple tumour types. Additionally, functional identifications based on CSC-specific properties are usually limited in in vivo studies. Furthermore, an optimal method for identifying potential CCSCs in CCSC studies has not been previously published, and these techniques are currently of great importance. This article updates our knowledge on CSCs and CCSCs, reviews potential stem cell markers and functional assays for identifying CCSCs, and describes the potential of targeting CCSCs in the treatment of cervical carcinoma.

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Section: Other Potential Markers For Ccscsmentioning

confidence: 99%

Cancer stem cells (CSCs), cervical CSCs and targeted therapies

2016

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“…Research conducted over the past decade has highlighted the significance of KLF4 deregulation in cancer development and progression. 17 However, little is known about the impact of deregulated KLF4 on TGF-β signaling in the context of tumor development. We and others have recently characterized KLF4 as a potent tumor suppressor in HCC, demonstrating that loss of KLF4 promotes tumorigenesis and epithelial to mesenchymal transition (EMT) of HCC cells.…”

Section: Introductionmentioning

confidence: 99%

Loss of KLF4 and consequential downregulation of Smad7 exacerbate oncogenic TGF-β signaling in and promote progression of hepatocellular carcinoma

et al. 2017

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Hyperactivation of TGF-β signaling pathway is a common feature of hepatocellular carcinoma (HCC) progression. However, the driver factors leading to enhanced TGF-β activity are not well characterized. Here, we explore the mechanisms that loss of Krüppel-like factor 4 (KLF4) exacerbates oncogenic TGF-β signaling in human HCC. The expression of KLF4 and TGF-β signaling components in primary HCC and their clinicopathologic relevance and significance was evaluated by using tissue microarray and immunohistochemistry. Cellular and molecular impacts of altered KLF4 expression and TGF-β signaling were determined using immunofluorescence, Western blot, reverse-transcriptase polymerase chain reaction, chromatin immunoprecipitation, and promoter reporter assays. Loss of KLF4 expression in primary HCC closely correlated with decreased Smad7 expression, increased p-Smad2/3 expression, and independently predicts reduced overall and relapse-free survival after surgery. TGF-β signaling components were expressed in most HCC cells, and activation of TGF-β signaling promoted cell migration and invasion. Enforced KLF4 expression blocked TGF-β signal transduction and inhibited cell migration and invasion via activation of Smad7 transcription, whereas deletion of its C-terminal zinc-finger domain diminished this effect. KLF4 protein physically interacts with the Smad7 promoter. Promoter deletion and point mutation analyses revealed that a region between nucleotides −15 bp and −9 bp of the Smad7 promoter was required for the induction of Smad7 promoter activity by KLF4. Our data indicate that KLF4 suppresses oncogenic TGF-β signaling by activation of Smad7 transcription, and that loss of KLF4 expression in primary HCC may contribute to activation of oncogenic TGF-β signaling and subsequent tumor progression.

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“…Krüppel‐like factor 4 (KLF4), known as gut‐enriched Krüppel‐like factor, is a zinc finger‐containing transcription factor with essential functions, including cell proliferation, differentiation and stem cell reprogramming . KLF4 plays opposing roles in different human cancers by transcriptionally regulating its downstream target genes . Recently, KLF4 has been shown to be associated with chemotherapy resistance in a few tumors .…”

mentioning

confidence: 99%

“…(5,6) KLF4 plays opposing roles in different human cancers by transcriptionally regulating its downstream target genes. (7,8) Recently, KLF4 has been shown to be associated with chemotherapy resistance in a few tumors. (9)(10)(11) However, the involvement of KLF4 in chemotherapy resistance in osteosarcoma cells remains unknown.…”

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confidence: 99%

Krüppel‐like factor 4 promotes high‐mobility group box 1‐induced chemotherapy resistance in osteosarcoma cells

et al. 2016

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Osteosarcoma is the most common primary malignant bone tumor, and the frequent acquisition of chemoresistance is often an obstacle to achieving favorable outcomes during chemotherapy. Recently, Krüppel‐like factor 4 (KLF4) has been shown to be associated with chemotherapy resistance in a few tumors; however, the involvement of KLF4 in chemotherapy resistance in osteosarcoma cells remains unknown. In this study, quantitative real‐time PCR and western blot analysis revealed that KLF4 expression was significantly increased in response to cisplatin, methotrexate and doxorubicin treatment in osteosarcoma cells, and knockdown of KLF4 increased sensitivity to these anticancer drugs by decreasing cellular clonogenic ability and increasing apoptosis. Moreover, our data suggest that KLF4‐regulated drug resistance might, at least partially, positively regulate high‐mobility group box 1 (HMGB1), which was found to be a significant contributor to chemoresistance in osteosarcoma cells in our previous study. In summary, this study highlights the significance of KLF4/HMGB1 interaction in regulating chemotherapy resistance, and suggests that targeting KLF4/high‐mobility group box 1 may be a therapeutic strategy for osteosarcoma chemotherapy.

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Emerging Roles of Krüppel-Like Factor 4 in Cancer and Cancer Stem Cells

Cited by 22 publications

References 56 publications

Cancer stem cells (CSCs), cervical CSCs and targeted therapies

Cancer stem cells (CSCs), cervical CSCs and targeted therapies

Loss of KLF4 and consequential downregulation of Smad7 exacerbate oncogenic TGF-β signaling in and promote progression of hepatocellular carcinoma

Krüppel‐like factor 4 promotes high‐mobility group box 1‐induced chemotherapy resistance in osteosarcoma cells

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