Krüppel-like factor 5 as potential molecular marker in cervical cancer and the KLF family profile expression

Marrero‐Rodríguez, Daniel; Taniguchi‐Ponciano, Keiko; Jiménez-Vega, Florinda; Romero-Morelos, Pablo; Mendoza, Mónica; Mantilla, Alejandra; Rodríguez-Esquivel, Miriam; Hernández, Daniel; Hernández, Ángeles; Gómez-Gutiérrez, Guillermo; Muñoz-Hernandez, Nancy; Cruz, Hugo Arreola-De la; Vargas-Requena, Claudia; Díaz-Hernández, Cecilia; Serna-Reyna, Luis; Meraz-Ríos, Marco Antonio; Bandala, Cindy; Ortiz-Leon, Jorge; Salcedo, Mauricio

doi:10.1007/s13277-014-2380-4

Cited by 31 publications

(34 citation statements)

References 44 publications

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“…KLFs and SPs belong to the triple‐zinc finger family of transcription factors, a class of regulatory proteins with special secondary structures stabilized by a zinc ion . Activation of KLF/SP has been shown to contribute to tumorigenesis . We show that knocking down eEF2K reduces the protein levels of KLF5 and SP1 and hence leads to a reduction in the levels of bound KLF5/SP1 to the VEGF promoter, hence inhibiting the transcription of VEGF .…”

Section: Discussionmentioning

confidence: 85%

“…33 Activation of KLF/SP has been shown to contribute to tumorigenesis. 34,35 We show that knocking down eEF2K reduces the protein levels of KLF5 and SP1 and hence leads to a reduction in the levels of bound KLF5/SP1 to the VEGF promoter, hence inhibiting the transcription of VEGF. KLF5 has been reported to aid the proliferation and migration of cancer stem cells in HCC.…”

Section: Discussionmentioning

confidence: 85%

“…[36][37][38] SP1 is involved in tumor growth and invasion of HCC. 39,40 KLF5 and SP1 are also potential tumor prognosis markers in other types of cancers (i.e., breast cancers) where eEF2K is highly expressed, 35,41,42 hence the regulation of KLF5 and SP1 by eEF2K may not only be limited to HCC.…”

Section: Discussionmentioning

confidence: 99%

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Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3

Zhou

et al. 2019

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is an aggressive malignancy with increasing mortality in China. Angiogenesis is crucial for tumor formation, development and metastasis in HCC. Previous studies indicated that high expression levels of elongation factor 2 kinase (eEF2K), a protein kinase that negatively regulates the elongation stage of translation, were associated with poor prognosis of HCC. Here, we show that pharmacological inhibition or knockdown of eEF2K in highly metastatic liver cancer cells inhibits their colony forming and migratory capacities, as well as reducing their invasiveness. Importantly, knocking down eEF2K by lentiviral directed shRNA prevented tumor growth and angiogenesis of HCC in mice. Silencing of eEF2K in endothelial cells (HUVECs) led to a reduction in vascularization, evidenced by a decrease in capillary‐like structures in the matrigel. Notably, knocking down eEF2K reduced the expression of angiogenesis‐related growth factors in liver cancer cells and the expression of growth factor receptors on HUVECs, and thus restricted signaling crosstalk that promotes angiogenesis between HCC cells and endothelial cells. We also showed that silencing of eEF2K effectively reduced protein levels of SP1/KLF5 transcription factors and hence decreased the levels of bound SP1/KLF5 to the VEGF promoter, resulted in a decrease in VEGF mRNA expression. Knocking down eEF2K also led to a striking decrease in the phosphorylation of PI3K/Akt and STAT3, indicating inactivation of these tumorigenic pathways. Taken together, our data suggest that eEF2K contributes to angiogenesis and tumor progression in HCC via SP1/KLF5‐mediated VEGF expression, as well as the subsequent stimulation of PI3K/Akt and STAT3 signaling.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 85%

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Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3

Zhou

et al. 2019

Intl Journal of Cancer

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“…Besides that, KLF5 expression can be regulated by miRNAs or posttranslation modification . In tumorigenesis, KLF5 has dual functions, being tumor suppressing gene and tumor promoting gene . Meanwhile, recent study revealed that KLF5 acetylation is crucial for the transition from tumor suppressor to tumor promoter .…”

Section: Introductionmentioning

confidence: 99%

miR‐214‐5p targets KLF5 and suppresses proliferation of human hepatocellular carcinoma cells

Pang

Wang

et al. 2018

J of Cellular Biochemistry

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MicroRNAs (miRNAs) are small endogenous conserved RNAs regulating genes expression through base pairing with the 3'-untranslated region (3'-UTR) of target messenger RNAs. MiR-214-5p is a newly identified miRNA with its biological role largely unknown. In this study, we explored miR-214-5p expression status in 78 paired tumor and nontumor tissues obtained from patients with hepatocellular carcinoma (HCC) by RT-qPCR. The effects of miR-214-5p expression on HCC cell proliferation, cell cycle progression, and cell migration were measured by CCK-8 assay, flow cytometry, and wound-healing assay. A dual-luciferase activity assay was performed to identify whether KLF5 was a target of miR-214-5p. Kaplan-Meier curve and log-rank test were used to investigate the effects of miR-214-5p and KLF5 on overall survival and disease-free survival of patients with HCC. We found miR-214-5p expression was sharply reduced in HCC tissues and cell lines compared with the normal tissues and cell lines. Functional assay revealed that miR-214-5p overexpression could downregulate cell proliferation, cell migration, and arrested cell cycle at G0/G1 phase. Further, we validated Krüppel-like factor 5 (KLF5) as a direct target of miR-214-5p, and was upregulated in HCC and inversely correlated with the expression of miR-214-5p. Moreover, we found the low expression of miR-214-5p and high expression of KLF5 were correlated with tumor size, tumor stage, and poorer 5-year overall survival and disease-free survival of patients with HCC. In conclusion, our results suggested miR-214-5p functions as a tumor suppressor through targeting KLF5 in HCC. Also, miR-214-5p and KLF5 were identified as potential prognostic markers and might be therapeutic targets in HCC.

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“…Therefore, study of Eppk1 expression might shed lights on initiation and development of cervical cancer. In addition, Marrero-rodriguez et al found that KLF5 showed a gradual up-regulation trend in normal tissues, low-grade intraepithelial lesions, intraepithelial squamous lesions and CC samples, indicating that the up-regulation of KLF5 expression plays a certain role in the occurrence and development of cervical cancer [18]. We also demonstrated that the co-expression pattern between KLF5 and Eppk1 as well as Eppk1 is a target of KLF5 in CC cells, suggesting that inhibition of KLF5 expression by pharmacologic treatment (such as ML264) may be bene cial for treatment of CC.…”

Section: Discussionmentioning

confidence: 99%

KLF5-mediated EPPK1 Expression Promotes Cell Proliferation in Cervical Cancer via the P38 Signaling Pathway

Pan

Liu

Chang

et al. 2020

Preprint

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Abstract Background: Epiplakin1 (Eppk1) is part of the EGF signal and is involved in cytoskeleton reorganization and cell proliferation. However, the role of Eppk1 in cervical cancer remains unknown. Methods: The expression of Eppk1 and KLF5 as well as their correlation were assessed by RNA-seq, qRT-PCR, TCGA database and immunofluorescence staining. In CC cell lines, adenovirus-mediated overexpression or knockdown of KLF5 and Eppk1 as well as corresponding assessment of cell proliferation and signaling were determined by western blot and CCK8 experiments. Assays of lucifase reporter gene and CHIP were used to investigate mechanism between KLF5 and Eppk1. Results: Eppk1 expression was markedly in CC tissues and cell lines companied by KLF5 upregulation. The results of immunofluorescence staining further showed that the increased expression of Eppk1 and KLF5 correlated with progression of cervical tumorigenesis. Overexpression of KLF5 significantly increased Eppk1 expression at transcription and translation levels. Conversely, the knockdown of KLF5 by siRNA against KLF5 decreased Eppk1 expression. Mechanical studies showed that KLF5 activated Eppk1 transcription by direct binding to the Eppk1 promoter. Gain- and loss-of-function experiments showed that KLF5 promoted cell proliferation in Hela by upregulating Eppk1 expression. Moreover, KLF5-mediated the activation of EGFR and p38 signaling significantly decreased after Eppk1 knockdown companied with reduction of proliferating activity, suggesting that Eppk1 lies upstream of p38 signaling affecting cell proliferation in CC. Finally, the expression of Eppk1 positively correlated with tumor size. Conclusions: Eppk1 may be an effective therapeutic target on affecting EGFR-associated p38 signaling pathway and cell proliferation in cervical cancer.

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Krüppel-like factor 5 as potential molecular marker in cervical cancer and the KLF family profile expression

Cited by 31 publications

References 44 publications

Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3

Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3

miR‐214‐5p targets KLF5 and suppresses proliferation of human hepatocellular carcinoma cells

KLF5-mediated EPPK1 Expression Promotes Cell Proliferation in Cervical Cancer via the P38 Signaling Pathway

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