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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.
Highlights
Lung cancer is one of the most commonly diagnosed malignancies worldwide and the leading cause of cancer-related death.[1,2] Lung cancers comprise four histological types as following: adenocarcinoma, squamous cell carcinoma, large cell carcinoma and small cell carcinoma
According to the current paradigm, lung adenocarcinoma develops primarily by step-wise progression accompanied by sequential morphologic changes, from atypical adenomatous hyperplasia (AAH) to bronchioloalveolar carcinoma (BAC), and to multiple types of invasive tumors, including mucinous and non-mucinous adenocarcinomas.[5]
Numerous studies have reported that K-rat sarcoma (RAS) mutation, the genetic alteration most frequently detected in lung cancer, is an early event responsible for the development of lung adenoma.[10,11,12,13,14]
Summary
Lung cancer is one of the most commonly diagnosed malignancies worldwide and the leading cause of cancer-related death.[1,2] Lung cancers comprise four histological types as following: adenocarcinoma, squamous cell carcinoma, large cell carcinoma and small cell carcinoma. Numerous studies have reported that K-RAS mutation, the genetic alteration most frequently detected in lung cancer, is an early event responsible for the development of lung adenoma.[10,11,12,13,14] the p14ARF–p53 pathway effectively defends the cell against aberrant oncogene activation.[15,16,17] it is important to determine whether one or more hidden tumor suppressors are inactivated in lung adenomas, or instead the p14ARF–p53 pathway provides an incomplete defense against oncogenic K-RAS-induced tumorigenesis If such hidden tumor suppressors exist, this issue could be resolved by identifying them. These observations provide an important clue about how adenoma develops and how K-RAS-activated adenoma cells evade cellular defense mechanisms
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