Abstract
We recently demonstrated that lysosomal protein transmembrane 4 beta (LAPTM4B) is elevated in non-small cell lung cancers (NSCLCs) and in the surrounding premalignant airway field of cancerization. In the present study, we sought to begin to understand the relevance of LAPTM4B expression and signaling to NSCLC pathogenesis. In situ hybridization analysis of LAPTM4B transcript in tissue microarrays comprised of 368 NSCLCs demonstrated that LAPTM4B expression was significantly increased in smoker compared to non-smoker lung adenocarcinoma tumors (P < 0.001) and was significantly associated with poor overall survival (P < 0.05) in adenocarcinoma patients. Knockdown of LAPTM4B expression inhibited cell growth, induced cellular apoptosis and decreased cellular autophagy in serum starved lung cancer cells. Expression profiling coupled with pathways analysis revealed decreased activation of the nuclear factor erythroid 2-like 2 (NRF2) stress response pathway following LAPTM4B knockdown. Further analysis demonstrated that LAPTM4B augmented the expression and nuclear translocation of the NRF2 transcription factor following serum deprivation as well as increased the expression of NRF2 target genes such as heme oxygenase 1/HMOX1). Our study points to the relevance of LAPTM4B expression to NSCLC pathogenesis as well as to the probable role of LAPTM4B/NRF2 signaling in promoting lung cancer cell survival.
Highlights
Genetic changes that are characteristic of lung tumors are present in adjacent visually normal-appearing airway epithelium[6,7,8,9,10,11,12,13,14]
We recently found that lysosomal protein transmembrane 4 beta (LAPTM4B) is an airway field cancerization marker that is largely elevated in Non-small cell lung cancer (NSCLC) and the surrounding airway epithelial field[11] indicating that LAPTM4B may play important roles in NSCLC pathogenesis
Our recent efforts to understand early events in NSCLC pathogenesis, through interrogating the transcriptome of the field cancerization in the airway and lung, demonstrated that LAPTM4B is largely up-regulated in the airway “field” closest to NSCLCs compared to more distant epithelial fields[11]
Summary
Genetic changes that are characteristic of lung tumors are present in adjacent visually normal-appearing airway epithelium[6,7,8,9,10,11,12,13,14] These airway field cancerization effects provide powerful means to understand early molecular aberrations in lung cancer development[6,7]. Our recent study demonstrated that lysosomal protein transmembrane 4 beta (LAPTM4B) is largely elevated in airways closest to tumors and in NSCLCs compared to normal lung tissues as well as promotes anchorage-independent growth of lung cancer cells[11]. LAPTM4B was shown in breast tumor cells to mediate formation of autolysosomes from fusion of lysosomes with autophagosomes, an essential step in activation of autophagy[22], in response to metabolic and genotoxic stress[23]. We report that high LAPTM4B expression is indicative of poor survival in LUAD and that LAPTM4B protects cells from starvation-induced stress, promotes cellular autophagy and activates NRF2-mediated cell stress response and pathway suggesting that LAPTM4B may be a viable target for NSCLC therapy
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