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Review
. 2016 Feb 18;35(7):827-32.
doi: 10.1038/onc.2015.153. Epub 2015 May 11.

How do K-RAS-activated cells evade cellular defense mechanisms?

Y-S Lee  1 , S-C Bae  1
Affiliations
Review

How do K-RAS-activated cells evade cellular defense mechanisms?

Y-S Lee et al. Oncogene. .

Abstract

Lung adenocarcinomas, like other cancers, develop through the accumulation of epigenetic and genetic alterations. Numerous studies have shown that K-RAS mutation is among the most important early events in carcinogenesis of the lung. However, it is also well established that growth-stimulating signals feed back into growth-suppressing pathways, and any imbalance in these signaling networks will cause the cell to exit the cell cycle, thereby preventing uncontrolled cell growth. How, then, do K-RAS-activated cells evade cellular defense mechanisms? To answer this question, it is necessary to identify the molecular event(s) responsible for the development of early dysplastic lesions that are unable to defend against aberrant oncogene activation. Lineage-determining transcriptional regulators govern differentiation status during normal lung development, as well as in lung adenocarcinoma. Among the genes involved in K-RAS-induced lung tumorigenesis, RUNX3 is unique: inactivation of Runx3 in mouse lung induces lung adenoma and abrogates the ARF-p53 pathway. This observation raises the possibility of intimate cross-talk between the differentiation program and oncogene surveillance. In this review, we summarized evidences suggesting that K-RAS-activated cells do not evade cellular defense mechanisms per se; instead, cells with K-RAS mutations are selected only if they occur in cells in which defense mechanism is abrogated.

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Figures

Figure 1
Figure 1
Current paradigm of lung adenocarcinoma. The majority of lung adenocarcinomas develop through a multi-step tumorigenesis pathway. Tumors develop from atypical adenomatous hyperplasia (AAH) to bronchioalveolar carcinoma (BAC), and ultimately progress to multiple types of invasive tumors. Mouse lung adenoma is equivalent to human AAH and BAC. RUNX3 is inactivated in most early AAH (human) and early adenoma (mouse). K-Ras activation is detected in relatively late AAH or adenoma.,
Figure 2
Figure 2
Lung epithelial cells. (a) Bronchioalveolar stem cells (BASCs) give rise to bronchiolar epithelial cells (BSC or Clara cells) and alveolar epithelial cells (ASC or AT2 cells), which are involved in tissue renewal. BASCs express both BSC-specific markers (CC10) and ASC-specific markers (SP-C). BSCs generate BSCs, Clara cells, goblet cells and ciliated cells, whereas AT2 cells generate AT2 and AT1 cells. (b) BASCs, BSCs and AT2 cells are the known cells of origins of lung adenomas/adenocarcinomas.
Figure 3
Figure 3
p53 tumor-suppressor pathways. (a) Two major pathways trigger p53 activation. (1) DNA damage stress is sensed by the ATM/ATR kinases, which activate the CHK1/CHK2 kinases, which in turn stabilize p53. Aberrant oncogene activation is sensed by the RUNX3–BRD2 complex, which induces expression of ARF, which in turn inactivates HDM2 and thereby stabilizes p53. (b) Mechanism for sensing constitutive RAS activation. Normal RAS activity is downregulated to the basal level soon after mitogenic stimulation (top panel, green line). Although RAS is activated, the RUNX3–BRD2 complex is formed (middle panel, green line) and ARF expression is induced (bottom panel, green line). In normal cells, RUNX3–BRD2 complex formation and ARF expression occurs for only a short time (1–3 h after mitogenic stimulation) and disappears when RAS activity is downregulated. However, heterozygous mutation of RAS results in maintenance of 50% of the maximum level of RAS activity. This persistent RAS activity maintains the RUNX3–BRD2 complex and ARF expression until the G1/S check point.
Figure 4
Figure 4
A model for the step-wise progression of lung adenocarcinoma. Adenoma development may require abrogation of both the differentiation program and oncogene surveillance. These two events could occur independently: for example, the differentiation program could be abrogated by silencing of Nkx2-1, and oncogene surveillance mechanism could be disabled by p53 deletion. Alternatively, the two events could occur simultaneously by inactivation Runx3, allowing adenoma cells to progress to adenocarcinoma upon oncogenic Ras mutation.
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References

    1. 1Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999; 49: 8–31. - PubMed
    1. 2Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013; 63: 11–30. - PubMed
    1. 3Minna JD, Roth JA, Gazdar AF. Focus on lung cancer. Cancer Cell 2002; 1: 49–52. - PubMed
    1. 4Travis WD. Pathology of lung cancer. Clin Chest Med 2002; 23: 65–81. - PubMed
    1. 5Wistuba II, Gazdar AF. Lung cancer preneoplasia. Annu Rev Pathol 2006; 1: 331–348. - PubMed

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