Circulating MACC1 Transcripts in Colorectal Cancer Patient Plasma Predict Metastasis and Prognosis

Stein, Ulrike; Burock, Susen; Herrmann, Pia; Wendler, Ina; Niederstrasser, Markus; Wernecke, Klaus‐Dieter; Schlag, Peter M.

doi:10.1371/journal.pone.0049249

Cited by 70 publications

(69 citation statements)

References 40 publications

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“…Most investigations of the role of MACC1 in cancer progression focused on the mechanism whereby MACC1 promotes metastasis in a variety of cancers [16,17,18,19,20,21,22]. The present study attempted for the first time to explore its role in mediating cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

MACC1 Suppresses Cell Apoptosis in Hepatocellular Carcinoma by Targeting the HGF/c-MET/AKT Pathway

Yao

Dou

et al. 2015

Cell Physiol Biochem

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Background & Aims: To investigate the expression and prognostic value of MACC1 in patients with HCC and identify the mechanism by which MACC1 inhibits HCC cell apoptosis. Methods: MACC1 and p-AKT expression was studied using immunohistochemistry of both HCC tissues and adjacent liver tissues. qRT-PCR and western immunoblotting were used to examine the expression of target genes at the mRNA and protein levels, respectively. The MTT assay was used to assess cell viability, and cell apoptosis was determined by DAPI staining, Annexin V/PI staining and Caspase 3/7 assay. Nude mice were used to perform in vivo experiments. Results: The overexpression of MACC1 was found in HCC tissues and was correlated with poor postsurgical prognosis. There was a positive relationship between MACC1 and p-AKT expression in HCC tissues. In vitro experiments showed that MACC1 repressed HCC cell apoptosis and promoted cell growth. Knockdown of c-MET abolished the anti-apoptotic function of MACC1. Next, MACC1 was verified to activate PI3K/AKT signaling by sensitizing HGF/c-MET signaling in HCC. MACC1 overexpression enhanced the HGF-driven phosphorylation of BAD, Caspase 9 and FKHRL1 and inhibited their pro-apoptotic functions in HCC cells. Finally, MACC1 was shown to inhibit cell apoptosis and promote HCC growth in vivo. Conclusions: This investigation revealed that MACC1 overexpression predicted worse prognosis after liver resection, which was attributed to the repression of HCC cell apoptosis via a molecular mechanism in which MACC1 accelerated the activation of the HGF/c-MET/PI3K/AKT pathway and phosphorylated BAD, Caspase 9 and FKHRL1, ultimately preventing their nuclear translocation and their pro-apoptotic function.

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Section: Discussionmentioning

confidence: 99%

MACC1 Suppresses Cell Apoptosis in Hepatocellular Carcinoma by Targeting the HGF/c-MET/AKT Pathway

Yao

Dou

et al. 2015

Cell Physiol Biochem

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“…MACC1 regulates cell proliferation by modulating the transcription of MEF, the receptor of hepatocyte growth factor HGF [296]. Similarly to this study, strong upregulation of the HOTAIRM1 lncRNA was also observed.…”

Section: Nervous System Development and Function Tissue Morphology supporting

confidence: 85%

Induced pluripotent stem cells from patients with ataxia-telangiectasia

Nayler¹

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A-T (Ataxia-Telangiectasia) is a multi-systemic, rare genetic disorder hallmarked by predisposition to cancer, immune deficiency and most notably progressive neurodegeneration [1]. A-T results from mutation of the ATM gene (11q22.3). ATM is a protein kinase belonging to the phosphatidylinositol 3-kinase-like family [2]. ATM exerts control over genomic integrity by recognizing and responding to DNA damage, through phosphorylation of substrates involved in cell cycle control and DNA damage repair [1]. The ATM protein is involved with numerous cellular processes and as such, A-T represents a paradigm for neurodegenerative disorders, as well as cancer.Experimental models of ATM function have been restricted to systems of limited context to understanding ATM biology and its potential role in development and tissue formation.Animal models have failed to faithfully recapitulate the full spectrum of A-T symptoms including the neurodegenerative aspect, which remains poorly understood. To date, studies on A-T have failed to answer the fundamental question of why certain cell types are seemingly more affected than others. As access to pluripotent stem cells becomes mainstream, it becomes possible, to a degree, to recreate and study in vitro processes giving rise to various cell types, including neurons, using directed differentiation protocols.We hypothesized that ATM deficient cells may be difficult or impossible to reprogram without intervention or assistance, and that this difficulty may be at least in part due excessive levels of reprogramming-induced or existing DNA damage, to the poor growth characteristics of A-T cells or the inability to participate in certain pathways necessary for reprogramming. We show that it was indeed possible to generate iPSCs from A-T patients albeit at reduced efficiency. This thesis describes the first generation and characterization of bona fide iPS cells from patients with A-T. Additionally we use this model system to explore the role and functionality of ATM in an embryonic setting, showing that ATM signaling is vitally required for the maintenance of cell cycle control and DNA fidelity after DNA damage. We have defined the transcriptional landscape of pluripotent stem cells from patients with A-T and point to novel findings regarding oxidative phosphorylation pathways. Further to this, we have used this model system to explore the role of ATM in neurogenesis and neuronal activity. We provide evidence that fosters support for the theory that A-T involves aspects of mitochondrial dysfunction and explore whether calcium trafficking is defective in neurons generated from patient iPSCs. Importantly we have illustrated the proof of concept that genetic manipulation of neuronal cells is possible by delivery of full length ATM, which also restored a functional DNA damage response.Finally, we utilized a neuronal differentiation protocol to generate neural progenitors characteristic of the developing cerebellum, and describe the transcriptome of these cells in the absence of ATM. These ...

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“…MACC1, HGF/MET sinyal yolağının etkinleşmesi üzerinden tümör gelişimi ve yayılımının anahtar bir düzenleyicisi olarak görev alır (5,6). Hücre çoğalması, hareketlilik, nüfus edebilirlik ve yayılımı sağlamak için epitelyal-mezenkimal geçişte önemli bir rol oynar (5,7).…”

Section: Introductionunclassified

“…Hücre çoğalması, hareketlilik, nüfus edebilirlik ve yayılımı sağlamak için epitelyal-mezenkimal geçişte önemli bir rol oynar (5,7). MACC1 proteini bir transkripsiyon faktörü olarak işlev görür ve reseptör tirozin kinazların (Met) özendirici bölgelerine (promoter) bağlanır (5)(6)(7)(8). Met'in transkripsiyon etkinliğini uyarmak için esas olan, Met özendirici bölgesi üzerinde özel Sp1 bağlanma bölgelerinin 60 bç yakınına bağlanır ve HGF/c-Met uyarı yolağının etkinliğini uyarır ve hücre çoğalmasını, hareketliliğini ve yayılımı arttırır (9).…”

Section: Introductionunclassified

“…Klinik çalışmalar MACC1'in uzak yayılımcı gelişim için tanı koydurucu bir belirteç ve yüksek yayılım riskli kolorektal kanser belirlenmesine olanak olduğunu düşündürmektedir (10). Çünkü MACC1, birincil kolon kanserine göre yayılımcı kolon kanserinde aşırı ifade olur (5,6,(8)(9)(10). Benzer şekilde, normal dokulara göre birincil kolon kanserinde de aşırı ifade olur (9,11).…”

Section: Introductionunclassified

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Investigation of MACC1-AS1 gene mutations in colorectal cancer

Taib¹,

İğci²,

Borazan³

et al. 2014

Gaziantep Med J

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Colorectal cancer is the frequent cause of mortality in Western world. Metastasis associated with colon cancer 1 (MACC1) gene acts as a key regulator of HGF/Met pathway and is expressed highly in colorectal cancer. MACC1 serves as a prognostic indicator for invasion and metastasis of several cancers. Potential links between MACC1 AS1 RNA locus that located in the intron 6 of MACC1 gene and high expression of MACC1 are unknown. Herein, the secondary structure of MACC-AS1 noncoding RNA and the complementarities between MACC1 mRNA and MACC1-AS1 were analyzed by RNAFold and IntaRNA programs. Since MACC1-AS1 has a proper secondary structure to hybridize with MACC1 mRNA, a potential role of MACC1-AS1 in regulation of MACC1 expression could be thought. The study included 104 controls and 96 patients. Genomic DNA was isolated from blood samples and analyzed by PCR-SSCP and sequence analysis. Three fragments and six genotypes (1, 2, 3, 1&2, 1&3, 2&3) were observed in the exon 1 of MACC1-AS1. A and GT (rs200028381) insertions in genotype 1, G>A substitution and A insertion in genotype 2 were detected. However, no association was observed between these SNPs and colorectal cancer (P>0.05). This is the first investigation on MACC1-AS1 gene mutation in colorectal cancer using molecular techniques. Novel SNPs in exon 1 were identified. In order to understand the association between colorectal tumors and MACC1-AS1 RNA expression clearly; further analysis, like Western blotting and immunohistochemistry of MACC1 and RNA analysis for MACC1-AS1, are needed. Keywords: Colorectal cancer; DNA sequence analysis; MACC1-AS1; mutation screening Özet Kolorektal kanser, batı dünyasında sık gözlenen ölüm nedenlerindendir. Metastazla ilişkili kolon kanseri 1 (MACC1) geni, HGF/Met yolağının anahtar düzenleyicisidir. Kolorektal kanserde yüksek oranda ifade olmaktadır. MACC1 geninin altıncı intronunda MACC1-AS1 karşıt anlamlı RNA bölgesi bulunmaktadır. Bu çalışmada, kodlanmayan MACC1-AS1 RNA'sının ikincil yapısı RNAFold, MACC1 mRNA'sı ile arasındaki etkileşim IntaRNA adlı programlarla analiz edilmiş ve MACC1 gen ifadesinin kontrolünde rol almaya uygun yapısı nedeniyle kolorektal kanserde gözlenen MACC1'in yüksek ifadesi ile ilişkili olabileceği varsayılmıştır. Konu ile ilgili açık bir bilgi bulunmamaktadır. Bu çalışma MACC1'in kodlanmayan bölgesindeki (MACC1-AS1) olası genomik değişimler ve kolorektal kanser arasındaki bağlantıyı araştıran ilk çalışmadır. Çalışmaya 104 kontrol ve 96 hasta birey katılmıştır. Kan örneklerinden elde edilen genomik DNA polimeraz zincir reaksiyonu (PCR) yöntemiyle çoğaltılmış ve tek zincir konformasyon polimorfizmi (SSCP) ile analiz edilmiş ve dizin analizine tabi tutulmuştur. Kontrol ve hasta örneklerinde ekzon 1'de, üç farklı banddan (1, 2, 3) oluşan 6 genotip (1, 2, 3, 1&2, 1&3, 2&3) gözlenmiştir. Dizin analizi neticesinde genotip 1'in bir A eklenmesi ve ayrıca GT eklenmesi (rs200028381), genotip 2'nin ise G>A yer değişimi ve A eklenmesi barındırdığı görülmüş; ancak, genotip 3'te bir farklılık bulunamamışt...

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Circulating MACC1 Transcripts in Colorectal Cancer Patient Plasma Predict Metastasis and Prognosis

Cited by 70 publications

References 40 publications

MACC1 Suppresses Cell Apoptosis in Hepatocellular Carcinoma by Targeting the HGF/c-MET/AKT Pathway

MACC1 Suppresses Cell Apoptosis in Hepatocellular Carcinoma by Targeting the HGF/c-MET/AKT Pathway

Induced pluripotent stem cells from patients with ataxia-telangiectasia

Investigation of MACC1-AS1 gene mutations in colorectal cancer

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