Krüppel-like factors in cancer progression: three fingers on the steering wheel

Limame, Ridha; Beeck, Ken Op de; Lardon, Filip; Wever, Olivier De; Pauwels, Patrick

doi:10.18632/oncotarget.1456

Cited by 58 publications

(47 citation statements)

References 147 publications

(200 reference statements)

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“…Most KLFs are upregulated in the early stages of cancer and are known to inhibit cancer cell invasiveness. However, the expression of EMT-suppressing KLFs is predominantly downregulated when the cells undergo systemic dissemination, which usually occurs in the advanced stages [60]. These findings support our clinicopathological analysis of the inverse correlation between miR-141 and KLF12 is related to cancer metastasis.…”

Section: Discussionsupporting

confidence: 78%

MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis

et al. 2017

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BackgroundCancer metastasis is determined by the formation of the metastatic niche and the ability of cancer cells to adapt to microenvironmental stresses. Anoikis resistance is a fundamental feature of metastatic cancer cell survival during metastatic cancer progression. However, the mechanisms underlying anoikis resistance in ovarian cancer are still unclear.MethodsExpressions of miRNA-141 and its downstream targets were evaluated by qPCR, Western blotting, Immunohistochemical (IHC) and in situ hybridization (ISH) assays. The luciferase assays were used to prove KLF12 as the downstream target of miR-141. The cDNA microarray and apoptotic protein arrays were used to identify the targets of miR-141 and KLF12. The competition of KLF12 and Sp1 on survivin promoter was examined by ChIP assay. IHC analysis on ovarian cancer tissue array was used to evaluate the expressions of KLF12 and miR-141 and to show the clinical relevance. The functional studies were performed by in vitro and in vivo tumorigenic assays.ResultsEnforced expression of miR-141 promotes, while knockdown of miR-141 expression inhibits, cell proliferation, anchorage-independent capacity, anoikis resistance, tumor growth and peritoneal metastases of ovarian cancer cells. Bioinformatics and functional analysis identified that Kruppel-related zinc finger protein AP-2rep (KLF12) is directly targeted by miR-141. Consistent with this finding, knockdown of KLF12 phenocopied the effects of miR-141 overexpression in ovarian cancer cells. In contrast, restoration of KLF12 in miR-141-expressing cells significantly attenuated anoikis resistance in ovarian cancer cells via interfering with Sp1-mediated survivin transcription, which inhibits the intrinsic apoptotic pathway and is crucial for ovarian cancer cell survival, anoikis resistance and peritoneal metastases. Immunohistochemical (IHC) and in situ hybridization (ISH) assays confirmed that miRNA-141 expression is inversely correlated with KLF12 expression and significantly associated with advanced ovarian cancers accompanied with distal metastases, underscoring the clinical relevance of our findings.ConclusionsOur data identify a novel signaling axis of miR-141/KLF12/Sp1/survivin in enhancing anoikis resistance and likely serves as a potential therapeutic target for metastatic ovarian cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0582-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 78%

MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis

et al. 2017

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“…We refer the reader to recent excellent reviews on this family (Tetrault et al ., 2013; Knoedler & Denver, 2014; Limame et al , 2014), which now also includes multiple biologically active KLF splice isoforms (Camacho-Venegas et al ., 2013) and the related gene KLF18 that is present in the sequenced genomes of most placental mammals (Pei & Grishin, 2013). KLF proteins are characterized by a conserved DNA-binding domain with three tandem C 2 H 2 -type zinc finger motifs at the carboxy-terminus and which recognizes the GT/GC box or CACCC element sites in promoter/5′ regulatory and enhancer regions (Fig.…”

Section: Kruppel-like Factorsmentioning

confidence: 99%

The Krüppel-like factors in female reproductive system pathologies

Simmen¹,

Heard²,

Simmen³

et al. 2015

Journal of Molecular Endocrinology

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Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling leading to aberrant cell proliferation, survival and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets and involve a range of paracrine and autocrine regulatory circuits. Members of the Krüppel-like family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Here we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms and discuss their potential as targets for therapeutic intervention.

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“…Krüppel-like factors (KLFs), members of the zinc finger family of transcription factors, have been found to be involved in the regulation of many biological processes, such as cell growth and differentiation [63, 64]. Accumulated evidence has suggested that KLFs play a critical role in tumorigenesis [65-67].…”

Section: Introductionmentioning

confidence: 99%

Aberrant regulation of FBW7 in cancer

Wang

Ye²,

Liu³

et al. 2014

Oncotarget

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FBW7 (F-box and WD repeat domain-containing 7) or Fbxw7 is a tumor suppressor, which promotes the ubiquitination and subsequent degradation of numerous oncoproteins including Mcl-1, Cyclin E, Notch, c- Jun, and c-Myc. In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-δ, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p. Given that the Fbw7 tumor suppressor is frequently inactivated or deleted in various human cancers, targeting FBW7 regulators is a promising anti-cancer therapeutic strategy.

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Krüppel-like factors in cancer progression: three fingers on the steering wheel

Cited by 58 publications

References 147 publications

MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis

MicroRNA-141 enhances anoikis resistance in metastatic progression of ovarian cancer through targeting KLF12/Sp1/survivin axis

The Krüppel-like factors in female reproductive system pathologies

Aberrant regulation of FBW7 in cancer

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