K-
            <i>RAS</i>
            Mutation in the Screening, Prognosis and Treatment of Cancer

Parsons, Barbara L.; Meng, Fanxue

doi:10.2217/bmm.09.95

Cited by 33 publications

(28 citation statements)

References 100 publications

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“…That up to 54% of the total reported CRC cases and cell lines lack mutations in the RAS protein (45)(46)(47)(48) implies there are other mechanisms leading to increased cell proliferation in colorectal cancer. Because RAS can be activated by either an activating mutation in the RAS gene or by mutations in genes that signal through RAS, and because our experiments were performed in the RAS GTPase wild-type colon cancer cell line HT-29, the miR-31 regulation of wild-type RAS protein could be an important factor leading to the aberrant activation of RAS signaling in colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-31 Activates the RAS Pathway and Functions as an Oncogenic MicroRNA in Human Colorectal Cancer by Repressing RAS p21 GTPase Activating Protein 1 (RASA1)

Sun¹,

Yu²,

et al. 2013

Journal of Biological Chemistry

162

151

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Background: MicroRNAs are important for colorectal cancer signal transduction. Results: miR-31 stimulates colorectal cancer cell proliferation and tumorigenesis by directly targeting RASA1. Conclusion: miR-31 activates the RAS pathway and functions as an oncogenic microRNA in human colorectal cancer. Significance: Learning how miRNAs participate in tumor signaling is crucial for understanding tumor signal transduction and cancer therapy.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-31 Activates the RAS Pathway and Functions as an Oncogenic MicroRNA in Human Colorectal Cancer by Repressing RAS p21 GTPase Activating Protein 1 (RASA1)

Sun¹,

Yu²,

et al. 2013

Journal of Biological Chemistry

162

151

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“…However, mutant K-Ras has not proved to be a useful biomarker due to the consistent observation that Ras mutations occur frequently in normal individuals, especially as they age. For example, studies in pancreatic samples also indicate the prevalence of K-Ras mutations in normal individuals (2)(3)(4). K-Ras mutations were also reported to be present in 20% of stool samples from normal healthy adults (3).…”

Section: Introductionmentioning

confidence: 99%

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

et al. 2012

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Genetic mutations that give rise to active mutant forms of Ras are oncogenic and found in several types of tumor. However, such mutations are not clear biomarkers for disease, since they are frequently detected in healthy individuals. Instead, it has become clear that elevated levels of Ras activity are critical for Ras-induced tumorigenesis. However, the mechanisms underlying the production of pathological levels of Ras activity are unclear. Here, we show that in the presence of oncogenic Ras, inflammatory stimuli initiate a positive feedback loop involving NF-κB that further amplifies Ras activity to pathological levels. Stimulation of Ras signaling by typical inflammatory stimuli was transient and had no long-term sequelae in wild-type mice. In contrast, these stimuli generated prolonged Ras signaling and led to chronic inflammation and precancerous pancreatic lesions (PanINs) in mice expressing physiological levels of oncogenic K-Ras. These effects of inflammatory stimuli were disrupted by deletion of inhibitor of NF-κB kinase 2 (IKK2) or inhibition of Cox-2. Likewise, expression of active IKK2 or Cox-2 or treatment with LPS generated chronic inflammation and PanINs only in mice expressing oncogenic K-Ras. The data support the hypothesis that in the presence of oncogenic Ras, inflammatory stimuli trigger an NF-κB-mediated positive feedback mechanism involving Cox-2 that amplifies Ras activity to pathological levels. Because a large proportion of the adult human population possesses Ras mutations in tissues including colon, pancreas, and lung, disruption of this positive feedback loop may be an important strategy for cancer prevention.

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“…Our model system is inspired by the anatomy of the human mammary gland, wherein tens of milk-producing mammary acini are organized into terminal duct lobular units (TDLUs) by a shared ECM. We chose Ras-transformed mammary acini as our model because most breast cancers originate in mammary acini (25), and Ras is the most frequent oncogene in human cancer (26). Our specific goal was to learn how potential mechanical cues generated by groups of genetically primed or structurally compromised acini determine the probability, timing, and extent of subsequent disorganization toward an invasive phenotype.…”

mentioning

confidence: 99%

Rapid disorganization of mechanically interacting systems of mammary acini

Shi

Ghosh

Engelke

et al. 2013

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

138

177

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Cells and multicellular structures can mechanically align and concentrate fibers in their ECM environment and can sense and respond to mechanical cues by differentiating, branching, or disorganizing. Here we show that mammary acini with compromised structural integrity can interconnect by forming long collagen lines. These collagen lines then coordinate and accelerate transition to an invasive phenotype. Interacting acini begin to disorganize within 12.5 ± 4.7 h in a spatially coordinated manner, whereas acini that do not interact mechanically with other acini disorganize more slowly (in 21.8 ± 4.1 h) and to a lesser extent (P < 0.0001). When the directed mechanical connections between acini were cut with a laser, the acini reverted to a slowly disorganizing phenotype. When acini were fully mechanically isolated from other acini and also from the bulk gel by box-cuts with a side length <900 μm, transition to an invasive phenotype was blocked in 20 of 20 experiments, regardless of waiting time. Thus, pairs or groups of mammary acini can interact mechanically over long distances through the collagen matrix, and these directed mechanical interactions facilitate transition to an invasive phenotype.mechanobiology | cancer E pithelial cells are physically coupled to their neighbors and are also in contact with the ECM. The ECM confers mechanical integrity to tissues and provides chemical, anatomical, and mechanical signals to cells, influencing differentiation, development, and pathogenesis (1-11). The extent to which mechanical cues are generated and received by individual cells has been studied both experimentally and theoretically (12)(13)(14). Progress has also been made in understanding the signaling pathways that cells use to sense external mechanics. Cell-ECM interactions are mediated in part by transmembrane proteins typified by the integrins, which link the cell's internal actin cytoskeleton with extracellular collagen fibers (15). Cells use multiple approaches for integrating mechanical cues with biochemical cues provided by soluble factors; for example, there is extensive multilayered cross-talk between integrin and TGF-β signaling (16,17). It is now also clear that key developmental regulators, such as Notch, can be directly activated by mechanical force (18,19).Less is known about the interactions of organized multicellular structures with the ECM and how those interactions affect tissue architecture, composition, and stability, as well as the molecular pathways by which these effects are mediated. In certain situations, contractile multicellular structures are able to mechanically reorganize biopolymer networks over long distances and in a highly directional manner, generating what are variously referred to as fibers, tracts, cables, straps, or lines. Regions of highly directional collagen alignment and concentration have been seen in systems ranging from single cells and tumor explants to human clinical samples (6,8,10,(20)(21)(22). Vader et al. demonstrated that the formation of long collagen lines is ...

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K- RAS Mutation in the Screening, Prognosis and Treatment of Cancer

Cited by 33 publications

References 100 publications

MicroRNA-31 Activates the RAS Pathway and Functions as an Oncogenic MicroRNA in Human Colorectal Cancer by Repressing RAS p21 GTPase Activating Protein 1 (RASA1)

MicroRNA-31 Activates the RAS Pathway and Functions as an Oncogenic MicroRNA in Human Colorectal Cancer by Repressing RAS p21 GTPase Activating Protein 1 (RASA1)

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

Rapid disorganization of mechanically interacting systems of mammary acini

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