Molecular oncology — perspectives in lung cancer

Huber, Rudolf M.; Stratakis, D F

doi:10.1016/j.lungcan.2004.07.973

Cited by 27 publications

(19 citation statements)

References 25 publications

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“…28 This mutation causes resistance to EGFR-TKI because of aberrant Ras/ERK pro-growth signaling that occurs independently of EGFR phosphorylation. 29,30 A recent study also demonstrated that cells expressing oncogenic allele of K-RAS activates Nrf2 via MAPK pathways in mouse embryonic fibroblasts. 31 However, we considered that constitutive activation of Nrf2 in A549 cells may be mainly due to dysfunction of Keap1, although Ras/ERK signaling partially contributes to the proliferation of these cells, as Nrf2 was still activated after treatment with U0126.…”

Section: Discussionmentioning

confidence: 98%

Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers

et al. 2012

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We previously demonstrated that the transcription factor NF-E2-related factor2 (Nrf2), expressed abundantly in non-small-cell lung cancer (NSCLC) cells, plays a pivotal role in the proliferation and chemoresistance of NSCLC. Here we show that Nrf2-mediated NSCLC cell proliferation is dually regulated by epidermal growth factor receptor (EGFR) signaling and an Nrf2 repressor protein Keap1 (Kelch-like ECH-associated protein-1). NSCLC cells expressing wild-type EGFR and Keap1 genes show enhanced proliferation on stimulation with EGFR ligand under non-stress conditions. Exposure to cigarette smoke extract (CSE) enhanced cell proliferation by modification of the Nrf2/Keap1 interaction. Although EGFR-tyrosine kinase inhibitor (TKI) inhibited the proliferation of these cells, exposure to CSE attenuated its efficacy. In NSCLC cells with Keap1 gene mutations, Nrf2 was constitutively activated owing to dysfunction of Keap1 and cells proliferated independently of EGFR signaling. Furthermore, EGFR-TKI was unable to inhibit their proliferation. In NSCLC cells with EGFR gene mutations, Nrf2 was constitutively activated by EGFR signaling. In these cells, proliferation was largely dependent on the EGFR signaling pathway. Although these cells were highly sensitive to EGFR-TKI, exposure to CSE or knockdown of Keap1 mRNA reduced sensitivity to EGFR-TKI. We found a case of NSCLC showing resistance to EGFR-TKI despite having EGFR-TKI-sensitive EGFR gene mutation because of dysfunctional mutation in Keap1 gene. Results indicate that oxidative stress reduces the anticancer effects of EGFR-TKI in wild-type Keap1 NSCLC cells. Analysis of Keap1 dysfunction may become a novel molecular marker to predict resistance to EGFR-TKI in NSCLC cells having EGFR-TKI-sensitive EGFR mutations. Finally, as the downstream molecule of both EGFR and Keap1 signaling, Nrf2 is an important molecular target for the treatment of NSCLC, where cells have mutations in EGFR, KRAS or Keap1 genes.

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Section: Discussionmentioning

confidence: 98%

Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers

et al. 2012

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“…The way forward for improved management and prognosis for individuals at high risk probably lies with early detection of disease. New molecular approaches provide potential hope for early diagnosis and screening of high-risk individuals, determination of prognosis and identification of innovative treatments (10). At the same time, modern imaging technologies afford hope of effective early detection (11).…”

Section: Introductionmentioning

confidence: 99%

Defining high-risk individuals in a population-based molecular-epidemiological study of lung cancer

Cassidy

Myles²,

Liloglou³

et al. 2006

Int J Oncol

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Abstract. Within the framework of the Liverpool Lung Project (LLP), population-based case-control and prospective cohort studies are in progress to identify molecular and epidemiological risk factors and define populations and individuals most at risk of developing lung cancer. This report describes a strategy for selection of a high-risk population and further provides support for the inclusion of occupational and genetic risk factors in future models. Data from the case-control study (256 incident cases and 314 population controls) were analysed to define a high-risk population. Detailed lifestyle and occupational information were collected during structured interviews. Models were constructed using conditional logistic regression and included terms for age, tobacco consumption and previous respiratory disease. Smoking duration was chosen as the most important predictor of lung cancer risk [>50 years (OR 15.65, 95% CI 6.10-40.15)]. However, such a model would preclude younger individuals. Several combinations of previous respiratory disease were also considered, of which a history of bronchitis, emphysema or pneumonia (BEP) was the most significant (OR 1.86, 95% CI 1.28-2.69). A high-risk subset (based on combinations of smoking duration and BEP) was identified, which have a 4.5-fold greater risk of developing lung cancer (OR 4.5, 95% CI 2. 33-8.68). Future refinement of the risk model to include individuals occupationally exposed to asbestos and with the p21 genotypes is discussed. There is real potential for environmental and genetic factors to improve on risk prediction and targeting of susceptible individuals beyond the traditional models based only on smoking and age. The development of a molecular-epidemiological model will inform the development of effective surveillance, early detection and chemoprevention strategies.

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“…k-ras mutation, which leads to aberrant Ras/MAP-K pro-growth signalling, has been well studied in cancer (Cunningham and Weinberg, 1985;Nelson et al, 1999;Huber and Stratakis, 2004). However, additional signalling pathways are acknowledged to play important roles in malignant disease, with the bone morphogenetic protein (BMP) signalling pathway emerging as important in multiple cancers (Nagatake et al, 1996;Tamada et al, 2001;Baldus et al, 2004;Dai et al, 2004;Kim et al, 2004).…”

mentioning

confidence: 99%

Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer

et al. 2005

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Bone morphogenetic proteins (BMPs) are an integral component of the TGFb superfamily, responsible for regulation of cell proliferation, differentiation, migration and programmed cell death in a variety of cell types. The BMPs transduce their signals directly through the SMAD family of proteins but they also have been reported to interact with the MAPK and Erk pathways. Inactivation of the BMP pathway genes has been implicated as important in several cancers. Recent work has shown that BMP3b is epigenetically inactivated in cancer and suggests that BMP6 can be epigenetically inactivated. We investigated whether BMP6 is epigenetically inactivated in cell lines and whether BMP3b and BMP6 are epigenetically inactivated in non-small-cell lung cancer (NSCLC). We also studied the relationship between BMP methylation and k-ras mutation. Here, we demonstrate that the BMP3b and BMP6 genes are common targets of epigenetic inactivation in NSCLC, and that they are significantly more likely to be concurrently inactivated (P ¼ 0.009). Furthermore, this coinactivation of BMP3b and BMP6 is significantly associated with mutation of k-ras codon 12 in lung cancer (P ¼ 0.003); those with a k-ras mutation were six times more likely to have concurrent methylation of these BMP loci. Hence, these data suggest that concurrent inactivation of the BMP and activation of the Ras signalling pathways are important in lung carcinogenesis.

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Molecular oncology — perspectives in lung cancer

Cited by 27 publications

References 25 publications

Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers

Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers

Defining high-risk individuals in a population-based molecular-epidemiological study of lung cancer

Interaction between the bone morphogenetic proteins and Ras/MAP-kinase signalling pathways in lung cancer

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