Highly Prevalent Genetic Alterations in Receptor Tyrosine Kinases and Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase Pathways in Anaplastic and Follicular Thyroid Cancers

Li, Zhi; Hou, Peng; Ji, Meiju; Guan, Haixia; Studeman, Kimberly; Jensen, Kirk; Vasko, Vasily; El‐Naggar, Adel K.; Xing, Minzhi

doi:10.1210/jc.2008-0273

Cited by 347 publications

(334 citation statements)

References 31 publications

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“…Interestingly, these two pathways are often activated in combination specifically in anaplastic thyroid carcinomas (Liu et al, 2008;Miller et al, 2009). This is also consistent with the previous observation of only a mild miR-21 overexpression in papillary thyroid cancers carrying activating mutations of Braf, which in turn specifically activate the MAPK pathway, while being unable to activate the PI3K pathway (He et al, 2005).…”

Section: Discussionsupporting

confidence: 91%

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

et al. 2010

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miR-21 is a microRNA (miRNA) frequently overexpressed in human cancers. Here we show that miR-21 is upregulated both in vitro and in vivo by oncogenic Ras, thus linking this miRNA to one of the most frequently activated oncogenes in human cancers. Ras regulation of miR-21 occurs with a delayed kinetic and requires at least two Ras downstream pathways. A screen of human thyroid cancers and non-small-cell lung cancers for the expression of miR-21 reveals that it is overexpressed mainly in anaplastic thyroid carcinomas, the most aggressive form of thyroid cancer, whereas in lung its overexpression appears to be inversely correlated with tumor progression. We also show that a LNA directed against miR-21 slows down tumor growth in mice. Consistently, a search for mRNAs downregulated by miR-21 shows an enrichment for mRNAs encoding cell cycle checkpoints regulators, suggesting an important role for miR-21 in oncogenic Ras-induced cell proliferation.

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Section: Discussionsupporting

confidence: 91%

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

et al. 2010

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“…To date, activating mutations of p110α have been found in a significant fraction of commonly occurring human cancers, whereas no somatic mutations have been identified in the other class IA isoforms p110β and p110δ (11,12). On the other hand, there are several cancer types that have been reported to have elevated levels and/or genomic amplifications of these other isoforms, indicating that they too may contribute to cancer (13,14). In addition, activation of receptor tyrosine kinases such as VEGF receptor, EGF receptor, PDGF receptor, or human epidermal growth factor receptor 2 (HER2) leading to the activation of the PI3K pathway usually requires p110α for signaling and tumorigenesis (15)(16)(17).…”

mentioning

confidence: 99%

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

Schmit

Utermark

Zhang

et al. 2014

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

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There has been increasing interest in the use of isoform-selective inhibitors of phosphatidylinositide-3-kinase (PI3K) in cancer therapy. Using conditional deletion of the p110 catalytic isoforms of PI3K to predict sensitivity of cancer types to such inhibitors, we and others have demonstrated that tumors deficient of the phosphatase and tensin homolog (PTEN) are often dependent on the p110β isoform of PI3K. Because human cancers usually arise due to multiple genetic events, determining whether other genetic alterations might alter the p110 isoform requirements of PTEN-null tumors becomes a critical question. To investigate further the roles of p110 isoforms in PTEN-deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110α, and loss of PTEN. In this model, ablation of p110β had no effect on tumor growth, whereas p110α ablation blocked tumor formation. Because ablation of PTEN alone is often p110β dependent, we wondered if the same held true in the ovary. Because PTEN loss alone in the ovary did not result in tumor formation, we tested PI3K isoform dependence in ovarian surface epithelium (OSE) cells deficient in both PTEN and p53. These cells were indeed p110β dependent, whereas OSEs expressing activated Kras with or without PTEN loss were p110α dependent. Furthermore, isoform-selective inhibitors showed a similar pattern of the isoform dependence in established Kras G12D /PTEN-deficient tumors. Taken together, our data suggest that, whereas in some tissues PTEN-null tumors appear to inherently depend on p110β, the p110 isoform reliance of PTEN-deficient tumors may be altered by concurrent mutations that activate p110α.ovarian cancer | PI3K inhibitors | genetically engineered mouse model

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“…PI3K/Akt signal pathway is a critical event in a wide variety of cellular processes, including proliferation, migration, and survival (Huang & Kontos 2002;Liu et al 2008). In a very interesting study, AKT was one of the proteins recruited to the membrane by PIP3 where it was activated by other PIP3-activated protein, PDK1 (Mora et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Over-expression of PTEN on proliferation and apoptosis in canine mammary tumors cells

Tong

Zhang

Sun

et al. 2016

Animal Cells and Systems

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Phosphatase and tensin homolog (PTEN) is an important tumor-suppressor gene which constitutes an important PI3K/Akt pathway by regulating the signaling of multiple biological processes, including apoptosis, metabolism, cell proliferation, and cell growth has been gaining increasing attention. However, the role of PTEN in regulating apoptosis of canine mammary tumors cells still needs further investigation. In this experiment, the effect of PTEN on proliferation and apoptosis in canine mammary tumors (CMT) cells was analyzed. As a result, gene and protein expression levels of apoptosis-related genes were detected. Eukaryotic expression vector pcDNA3.1+-PTEN were successfully constructed and stably transferred into canine CMT cells after geneticin (G418) selection. After pcDNA3.1+-PTEN transfection, compared with control group, the cells proliferation was inhibited and the cell apoptosis was increased in CMT cells. The expression of p-Akt was decreased and the apoptosis-related genes, such as caspase-3, caspase-9, and Bax, were increased. These data serve to demonstrate the function of PTEN on apoptosis and gene regulatory in PI3K/Akt pathway in CMT cells. Collectively, our data link the tumorsuppressor activities of PTEN to the machinery controlling cell cycle through the modulation of signaling molecules whose signal target is the functional inactivation of the apoptosis gene product. ARTICLE HISTORY

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Highly Prevalent Genetic Alterations in Receptor Tyrosine Kinases and Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase Pathways in Anaplastic and Follicular Thyroid Cancers

Abstract: Genetic alterations in the RTKs and PI3K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former.

Cited by 347 publications

References 31 publications

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

Over-expression of PTEN on proliferation and apoptosis in canine mammary tumors cells

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