Abstract
This study investigated the proteome modulated by oncogenic KRAS in immortalized airway epithelial cells. Chloride intracellular channel protein 4 (CLIC4), S100 proteins (S100A2 and S100A11), tropomyosin 2, cathepsin L1, integrinsα3, eukaryotic elongation factor 1, vimentin, and others were discriminated. We here focused on CLIC4 to investigate its potential involvement in carcinogenesis in the lung because previous studies suggested that some chloride channels and chloride channel regulators could function as tumor suppressors. CILC4 protein levels were reduced in some lung cancer cell lines. The restoration of CLIC4 in lung cancer cell lines in which CLIC4 expression was reduced attenuated their growth activity. The immunohistochemical expression of the CLIC4 protein was weaker in primary lung cancer cells than in non-tumorous airway epithelial cells and was occasionally undetectable in some tumors. CLIC4 protein levels were significantly lower in a subtype of mucinous ADC than in others, and were also significantly lower in KRAS-mutated ADC than in EGFR-mutated ADC. These results suggest that the alteration in CLIC4 could be involved in restrictedly the development of a specific fraction of lung adenocarcinomas. The potential benefit of the proteome modulated by oncogenic KRAS to lung cancer research has been demonstrated.
Highlights
Lung cancer is one of the most common causes of cancerrelated death in the developed world [1,2]
We focused on Chloride intracellular channel protein 4 (CLIC4), a member of the chloride intracellular channel protein family [6,7,8], because previous studies suggested that some chloride channels and chloride channel regulators could function as tumor suppressors [5]
A comprehensive evaluation of the signal intensities of these spots revealed that oncogenic KRAS-transduced cells had different expression profiles to those of empty vector- and wild-type KRAS-transduced cells, as KRAS/V12-transduced cells were classified into a distant branch on a dendrogram described by hierarchical clustering analysis of the Ward’s method (Fig. 1B)
Summary
Lung cancer is one of the most common causes of cancerrelated death in the developed world [1,2]. Some lung tumors are sensitive to conventional chemotherapeutic agents or certain molecular targeting agents, many are not [3,4]. Further understanding of the molecular basis of carcinogenesis in the lung is needed in order to develop novel therapeutic strategies. Our previous studies identified important molecules involved in carcinogenesis in the lung through a comprehensive search for the downstream targets of oncogenic KRAS [3,5]. KRAS is known to transmit potential signals that cause opposing biological effects. A disruption in the balance between these effects may occasionally result in a neoplastic transformation and promote the progression of carcinogenesis
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