cDNA Microarray Gene Expression Profiling of Hedgehog Signaling Pathway Inhibition in Human Colon Cancer Cells

Shi, Ting; Mazumdar, Tapati; DeVecchio, Jennifer; Duan, Zhong Hui; Agyeman, Akwasi; Aziz, Mehar; Houghton, Janet A.

doi:10.1371/journal.pone.0013054

Cited by 62 publications

(64 citation statements)

References 54 publications

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“…Decreased survivin expression upon inhibition of hedgehog signaling has been described in at least one study in colon cancer cells in culture (46). The fact that we could antagonize the SMO inhibitor effect by GLI1 overexpression and that this phenomenon was also observed after GLI1 silencing indicates that this effect is specific.…”

Section: Discussionsupporting

confidence: 65%

Role of Hedgehog Signaling in Malignant Pleural Mesothelioma

Shi

Moura

Opitz

et al. 2012

Clinical Cancer Research

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Purpose: The aim of this study was to assess the activity of hedgehog signaling pathway in malignant pleural mesothelioma (MPM).Experimental Design: The expression of hedgehog signaling components was assessed by quantitative PCR and in situ hybridization in 45 clinical samples. Primary MPM cultures were developed in serum-free condition in 3% oxygen and were used to investigate the effects of smoothened (SMO) inhibitors or GLI1 silencing on cell growth and hedgehog signaling. In vivo effects of SMO antagonists were determined in an MPM xenograft growing in nude mice.Results: A significant increase in GLI1, sonic hedgehog, and human hedgehog interacting protein gene expression was observed in MPM tumors compared with nontumoral pleural tissue. SMO antagonists inhibited GLI1 expression and cell growth in sensitive primary cultures. This effect was mimicked by GLI1 silencing. Reduced survivin and YAP protein levels were also observed. Survivin protein levels were rescued by overexpression of GLI1 or constitutively active YAP1. Treatment of tumor-bearing mice with the SMO inhibitor HhAntag led to a significant inhibition of tumor growth in vivo accompanied by decreased Ki-67 and nuclear YAP immunostaining and a significant difference in selected gene expression profile in tumors.Conclusions: An aberrant hedgehog signaling is present in MPM, and inhibition of hedgehog signaling decreases tumor growth indicating potential new therapeutic approach.

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Section: Discussionsupporting

confidence: 65%

Role of Hedgehog Signaling in Malignant Pleural Mesothelioma

Shi

Moura

Opitz

et al. 2012

Clinical Cancer Research

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“…Our data strongly suggest that eIF4E3 is a cap-dependent tumor suppressor. In support of this, recent studies relate the loss of eIF4E3 to the malignant phenotype in oral cancers (33), and we observe a reduction of eIF4E3 in M4/M5 AML patients relative to healthy volunteers, whereas eIF4E1 is 3-to 10-fold more elevated here than in healthy volunteers (13). In cells, it is possible that binding key partner proteins increases the affinity of eIF4E3 for the cap, and also perhaps for other elements in the 5′-UTR, enabling it to more efficiently compete and thereby suppress eIF4E1 activity.…”

Section: Discussionmentioning

confidence: 75%

eIF4E3 acts as a tumor suppressor by utilizing an atypical mode of methyl-7-guanosine cap recognition

Osborne

Volpon

Kornblatt

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

104

143

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Recognition of the methyl-7-guanosine (m 7 G) cap structure on mRNA is an essential feature of mRNA metabolism and thus gene expression. Eukaryotic translation initiation factor 4E (eIF4E) promotes translation, mRNA export, proliferation, and oncogenic transformation dependent on this cap-binding activity. eIF4E-cap recognition is mediated via complementary charge interactions of the positively charged m 7 G cap between the negative π-electron clouds from two aromatic residues. Here, we demonstrate that a variant subfamily, eIF4E3, specifically binds the m 7 G cap in the absence of an aromatic sandwich, using instead a different spatial arrangement of residues to provide the necessary electrostatic and van der Waals contacts. Contacts are much more extensive between eIF4E3-cap than other family members. Structural analyses of other cap-binding proteins indicate this recognition mode is atypical. We demonstrate that eIF4E3 relies on this cap-binding activity to act as a tumor suppressor, competing with the growthpromoting functions of eIF4E. In fact, reduced eIF4E3 in high eIF4E cancers suggests that eIF4E3 underlies a clinically relevant inhibitory mechanism that is lost in some malignancies. Taken together, there is more structural plasticity in cap recognition than previously thought, and this is physiologically relevant.M etabolism of mRNA is a complex and highly regulated process dependent on the association of the methyl-7-guanosine (m 7 G) cap structure on the 5′ end of transcripts with appropriate proteins (1-3). In mammalian cells, the two major cap-binding proteins are the nuclear cap-binding complex (CBC) (4) and eukaryotic translation initiation factor 4E (eIF4E) (3). Specific cap recognition is key for the fate of transcripts and impacts processes such as mRNA processing and bulk mRNA export via the CBC or the nuclear export of specific transcripts as well as bulk translation by eIF4E (5). NMR and crystallographic studies reveal that m 7 G cap is specifically recognized by both the CBC and eIF4E via intercalation of the m 7 G cap moiety with the side chains of two aromatic residues, i.e., an aromatic sandwich (4, 6-9). This is an electrostatically driven process relying on the partial positive charge of the m 7 G cap and the negative π-electron clouds of the aromatic residues. The aromatic residues are completely conserved in these cap-binding proteins. This recognition motif is used almost exclusively by proteins that specifically bind the m 7 G cap including eIF4E, CBC, and vaccinia virus protein VP39 (4, 10).Dysregulation of cap-binding proteins can have striking physiological consequences. For instance through its cap-binding activity and subsequent effects on gene expression, eIF4E plays an important role in proliferation and survival (1, 3). Indeed, eIF4E is overexpressed in about 30% of human cancers and its overexpression is oncogenic in cell culture and animal models (2, 11). Mutation of the cap-binding site of eIF4E impairs its activities in translation, mRNA export, and oncogenic transform...

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“…It has been reported that GANT61 induced a G0/G1 arrest, with upregulation of p21 in human colon cancer cells (66). Importantly, in bleomycin- Figure 7.…”

Section: Discussionmentioning

confidence: 92%