Regulation of Lung Cancer Metastasis by Klf4-Numb-like Signaling

Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico.
Cancer Research (Impact Factor: 9.33). 02/2013; 73(8). DOI: 10.1158/0008-5472.CAN-12-4232
Source: PubMed


Metastatic traits appear to be acquired by transformed cells with progenitor-like cancer-initiating properties, but there remains little mechanistic insight into this linkage. In this report, we show that the polarity protein Numbl, which is expressed normally in neuronal progenitors, becomes overexpressed and mislocalized in cancer cells from a variety of human tumors. Numbl overexpression relies on loss of the tumor suppressor microRNA miR-296), which actively represses translation of Numbl in normal cells. In turn, deregulated expression of Numbl mediates random tumor cell migration and invasion, blocking anoikis and promoting metastatic dissemination. In clinical specimens of non-small cell lung cancer, we found that Numbl overexpression correlated with a reduction in overall patient survival. Mechanistically, Numbl-mediated tumorigenesis involved suppression of a "stemness" transcriptional program driven by the stem cell programming transcription factor Klf4, thereby preserving a pool of progenitor-like cells in lung cancer. Our results reveal that Numbl-Klf4 signaling is critical to maintain multiple nodes of metastatic progression, including persistence of cancer-initiating cells, rationalizing its therapeutic exploitation to improve the treatment of advanced lung cancer.

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Available from: Valentina Vaira, Sep 18, 2014
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    • "Thus, one miRNA may have different functions when interacting with different targets [46]. Among these miRNAs, miR-296-5p was recently found to be progressively lost during tumor progression and was correlated with metastatic disease in colorectal, breast, lung, parathyroid, liver, and bile duct cancers [47] [48] [49]. Furthermore, miR-296-5p was found to be located on chromosome 20q13.32, "
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    ABSTRACT: Upregulation of Pin1 was shown to advance the functioning of several oncogenic pathways. It was recently shown that Pin1 is potentially an excellent prognostic marker and can also serve as a novel therapeutic target for prostate cancer. However, the molecular mechanism of Pin1 overexpression in prostate cancer is still unclear. In the present study, we showed that mRNA expression levels of Pin1 were not correlated with Pin1 protein levels in prostate cell lines which indicated that Pin1 may be regulated at the post-transcriptional level. A key player in post-transcriptional regulation is represented by microRNAs (miRNAs) that negatively regulate expressions of protein-coding genes at the post-transcriptional level. A bioinformatics analysis revealed that miR-296-5p has a conserved binding site in the Pin1 3'-untranslated region (UTR). A luciferase reporter assay demonstrated that the seed region of miR-296-5p directly interacts with the 3'-UTR of Pin1 mRNA. Moreover, miR-296-5p expression was found to be inversely correlated with Pin1 expression in prostate cancer cell lines and prostate cancer tissues. Furthermore, restoration of miR-296-5p or the knockdown of Pin1 had the same effect in inhibition the ability of cell proliferation and anchorage-independent growth of prostate cancer cell lines. Our results support miR-296-5p playing a tumor-suppressive role by targeting Pin1 and implicate potential effects of miR-296-5p in the prognosis of and clinical application to prostate cancer therapy.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 06/2014; 1843(9). DOI:10.1016/j.bbamcr.2014.06.001 · 5.02 Impact Factor
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    • "Also recently, repression of KLF4 by the cell polarity protein Numb-like (Numbl/NUMBL) was reported from knockdown experiments in the A549 lung cancer cell line. Downregulation of miR-296 causes aberrant expression of its target NUMBL leading to reduced KLF4-expression and increased random cell migration, invasion and in vivo metastasis [100]. This mechanism may be more general since loss of miR-296 is described in several cancers [101]. "
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    ABSTRACT: Krüppel-like factors (KLFs) comprise a highly conserved family of zinc finger transcription factors, that are involved in a plethora of cellular processes, ranging from proliferation and apoptosis to differentiation, migration and pluripotency. During the last few years, evidence on their role and deregulation in different human cancers has been emerging. This review will discuss current knowledge on Krüppel-like transcription in the epithelial-mesenchymal transition (EMT), invasion and metastasis, with a focus on epithelial cancer biology and the extensive interface with pluripotency. Furthermore, as KLFs are able to mediate different outcomes, important influences of the cellular and microenvironmental context will be highlighted. Finally, we attempt to integrate diverse findings on KLF functions in EMT and stem cell biology to fit in the current model of cellular plasticity as a tool for successful metastatic dissemination.
    Oncotarget 11/2013; 5(1). DOI:10.18632/oncotarget.1456 · 6.36 Impact Factor
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    • "As loss of NumbL did not influence Notch signaling at this stage, it will be of interest for future studies to identify the pathways and factors regulated by NumbL. This is important not only due to the requirement of NumbL during X. laevis neurogenesis, but also the emerging role of NumbL in tumorgenesis [63]. "
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    ABSTRACT: Members of the vertebrate Numb family of cell fate determinants serve multiple functions throughout early embryogenesis, including an essential role in the development of the nervous system. The Numb proteins interact with various partner proteins and correspondingly participate in multiple cellular activities, including inhibition of the Notch pathway. Here, we describe the expression characteristics of Numb and Numblike (NumbL) during Xenopus development and characterize the function of NumbL during primary neurogenesis. NumbL, in contrast to Numb, is expressed in the territories of primary neurogenesis and is positively regulated by the Neurogenin family of proneural transcription factors. Knockdown of NumbL afforded a complete loss of primary neurons and did not lead to an increase in Notch signaling in the open neural plate. Furthermore, we provide evidence that interaction of NumbL with the AP-2 complex is required for NumbL function during primary neurogenesis. We demonstrate an essential role of NumbL during Xenopus primary neurogenesis and provide evidence for a Notch-independent function of NumbL in this context.
    BMC Developmental Biology 10/2013; 13(1):36. DOI:10.1186/1471-213X-13-36 · 2.67 Impact Factor
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