Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Joannes, Audrey; Grelet, Simon; Duca, Laurent; Gilles, Christine; Kileztky, Claire; Dalstein, Véronique; Birembaut, Philippe; Polette, Myriam; Nawrocki‐Raby, Béatrice

doi:10.1158/1541-7786.mcr-13-0386-t

Cited by 42 publications

(40 citation statements)

References 43 publications

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“…A recent study demonstrated that Fhit silencing in bronchial cells induced over-expression of two primary EMT-associated targets, MMP-9 and vimentin [35]. In this study, Fhit silencing increased cell invasion dependent on Slug, a member of the Snail family of transcription factors known to be key mediators of EMT.…”

Section: Fhit As a Tumor Suppressor Genesupporting

confidence: 53%

“…Since the discovery of this first gene at a fragile locus, nearly one thousand reports concerning the FHIT gene or gene product have been published and many include evidence of the role of Fhit protein in tumor suppression and correlation of loss of Fhit expression with various clinical features of various types of cancer, such as poor prognosis, invasiveness, and poor outcome [6]. Very recently, several reports described a role for Fhit in preventing epithelial-mesenchymal transition (EMT), an important morphologic change that occurs in cancers as they become invasive [35]. But the most recent function to be assigned to Fhit, and perhaps its most significant cancer-associated function, is the discovery that Fhit is a genome ‘caretaker’, whose loss induces global genome instability [7].…”

Section: Introductionmentioning

confidence: 99%

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The FHIT gene product: tumor suppressor and genome “caretaker”

Waters

Saldivar

Hosseini

et al. 2014

Cell. Mol. Life Sci.

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The FHIT gene at FRA3B is one of the earliest and most frequently altered genes in the majority of human cancers. It was recently discovered that the FHIT gene is not the most fragile locus in epithelial cells, the cell of origin for most Fhit negative cancers, eroding support for past claims that deletions at this locus are simply passenger events that are carried along in expanding cancer clones, due to extreme vulnerability to DNA damage rather than to loss of FHIT function. Indeed, recent reports have reconfirmed FHIT as a tumor suppressor gene with roles in apoptosis and prevention of the epithelial-mesenchymal transition. Other recent works have identified a novel role for the FHIT gene product, Fhit, as a genome ‘caretaker.’ Loss of this caretaker function leads to nucleotide imbalance, spontaneous replication stress, and DNA breaks. Because Fhit loss-induced DNA damage is “checkpoint blind,” cells accumulate further DNA damage during subsequent cell cycles, accruing global genome instability that could facilitate oncogenic mutation acquisition and expedite clonal expansion. Loss of Fhit activity therefore induces a mutator phenotype. Evidence for FHIT as a mutator gene is discussed in light of these recent investigations of Fhit loss and subsequent genome instability.

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Section: Fhit As a Tumor Suppressor Genesupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

The FHIT gene product: tumor suppressor and genome “caretaker”

Waters

Saldivar

Hosseini

et al. 2014

Cell. Mol. Life Sci.

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“…In addition, the CFS large genes frequently disrupted by the viral integration were also found to be involved in oncogenic signaling pathways. For example, FHIT , which is located in FRA3B and is one of the most frequently disrupted large CFS genes, regulates EMT by targeting the EGFR/Src/ ERK/Slug signaling pathway and can also induce apoptosis via the death receptor signaling pathway [Deng et al, 2007;Joannes et al, 2014]. Decreased expression of LRP1B was also shown to promote cell migration via the RhoA/Cdc42 pathway and actin skeleton remodeling in renal cell cancer [Ni et al, 2013].…”

Section: Hpv and Cervical Cancermentioning

confidence: 99%

Human Papillomavirus and the Development of Different Cancers

Gao¹,

Smith²

2016

Cytogenet Genome Res

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Human papillomaviruses (HPV) are responsible for the development of almost all cervical cancers. HPV is also found in 85% of anal cancer and in 50% of penile, vulvar, and vaginal cancers, and they are increasingly found in a subset of head and neck cancers, i.e., oropharyngeal squamous cell carcinomas (OPSCC). The model for how HPV causes cancer is derived from several decades of study on cervical cancer, and it is just presumed that this model is not only completely valid for cervical cancer but for all other HPV-driven cancers as well. Next-generation sequencing (NGS) has now provided the necessary tools to characterize genomic alterations in cancer cells and can precisely determine the physical status of HPV in those cells as well. We discuss recent discoveries from different applications of NGS in both cervical cancer and OPSCCs, including whole-genome sequencing and mate-pair NGS. We also discuss what NGS studies have revealed about the different ways that HPV can be involved in cancer formation, specifically comparing cervical cancer and OPSCC.

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“…SLUG is a downstream target of Shh signaling and is closely associated with the EMT (36). The Shh signaling pathway has also been established to be a key contributor to the process of EMT (37).…”

Section: A B Cmentioning

confidence: 99%

Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

et al. 2016

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Abstract. Breast cancer is the most common malignant cancer among women. The Hedgehog (Hh) signaling pathway serves a key role in malignant cancer cell growth and migration. However, little is known with regard to the specific function of the Hh signaling pathway in human breast cancer. The current study investigated the specific role of Hh signaling in the human breast cancer cell line MDA-MB-231. Expression of components of Shh-Gli signaling, as well as the Gli-responsive genes B-cell lymphoma 2 (Bcl-2) and cyclin D1, were investigated in MDA-MB-231 cells using western blotting. The effects of Shh-Gli signaling on MDA-MB-231 proliferation were analyzed by MTT assay. The role of E-cadherin in the epithelial-mesenchymal transition process was determined by western blot while matrix metalloproteinase (MMP)-9/MMP-2 secretion was studied by enzyme-linked immunosorbent assay. The results indicated that Shh-Gli signaling was activated in MDA-MB-231 cells, significantly enhancing cell viability. Overexpression of Gli positively regulated the transcription of Bcl-2 and cyclin D1 thereby regulating MDA-MB-231 cell proliferation and survival. Treatment of MDA-MB-231 cells with human sonic hedgehog, n-terminus for 72 h significantly reduced E-cadherin protein levels and enhanced secretion of MMP-9 and MMP-2. These findings suggest that Shh-Gli signaling is significantly activated in human breast cancer cells, and is accompanied by enhanced cell viability, proliferation and migration capacities.

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Fhit Regulates EMT Targets through an EGFR/Src/ERK/Slug Signaling Axis in Human Bronchial Cells

Cited by 42 publications

References 43 publications

The FHIT gene product: tumor suppressor and genome “caretaker”

The FHIT gene product: tumor suppressor and genome “caretaker”

Human Papillomavirus and the Development of Different Cancers

Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

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