Proteome Analysis for Downstream Targets of Oncogenic KRAS - the Potential Participation of CLIC4 in Carcinogenesis in the Lung

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.

Head and neck squamous cancer progression is marked by CLIC4 attenuation in tumor epithelium and reciprocal stromal upregulation of miR-142-3p, a novel post-transcriptional regulator of CLIC4

“…CLIC4 has been implicated in angiogenesis [3][4][5], pulmonary arterial hypertension [6,7], epithelial differentiation [8], myofibroblast differentiation [9][10][11], response to oxidative stress [12][13][14][15], cellular adhesion and integrin trafficking [16][17][18], immunity [19][20][21][22], and cancer [23][24][25][26][27][28][29][30][31]. Despite the elucidation of many CLIC4 functions, little is known regarding the regulation of CLIC4 expression.…”

The potential significance of alpha‐enolase (ENO1) in lung adenocarcinomas – A utility of the immunohistochemical expression in pathologic diagnosis

“…We previously identified important molecules involved in lung carcinogenesis through a comprehensive search for downstream targets of KRAS , the most common oncogene . The downstream targets of the KRAS oncogene were found to be essential not only in KRAS ‐mediated carcinogenesis, but also in EGFR ‐ and other unknown potential oncogene‐mediated lung carcinogenesis . Thus, different driver oncogenes have been suggested to activate a common signaling pathway to promote carcinogenesis .…”

“…[3][4][5] The downstream targets of the KRAS oncogene were found to be essential not only in KRAS-mediated carcinogenesis, but also in EGFR-and other unknown potential oncogene-mediated lung carcinogenesis. [3][4][5] Thus, different driver oncogenes have been suggested to activate a common signaling pathway to promote carcinogenesis. [6][7][8] Studies on the downstream targets of the KRAS oncogene are considered to be a useful strategy for elucidating the common important molecular bases of lung cancers.…”

Alterations in cathepsin L expression in lung cancers

“…We previously identified important molecules involved in lung carcinogenesis through a comprehensive search for downstream targets of KRAS , the most common oncogene . Some of the downstream targets of the KRAS oncogene were found to be essential not only in KRAS ‐mediated carcinogenesis, but also in EGFR ‐ as well as other unknown potential oncogene‐mediated lung carcinogenesis . Thus, investigations into the downstream targets of the KRAS oncogene are considered to be a useful strategy for elucidating the common important molecular bases of lung cancer.…”

“…Thus, investigations into the downstream targets of the KRAS oncogene are considered to be a useful strategy for elucidating the common important molecular bases of lung cancer. Among the downstream targets identified in our recent study, we herein focused on cathepsin L.…”