Abstract
Lung cancer remains the most dangerous type of cancer despite recent progress in therapeutic modalities. Development of prognostic markers and therapeutic targets is necessary to enhance lung cancer patient survival. Sestrin family genes (Sestrin1, Sestrin2, and Sestrin3) are involved in protecting cells from stress. In particular, Sestrin2, which mainly protects cells from oxidative stress and acts as a leucine sensor protein in mammalian target of rapamycin (mTOR) signaling, is thought to affect various cancers in different ways. To investigate the role of Sestrin2 expression in lung cancer cells, we knocked down Sestrin2 in A549, a non-small cell lung cancer cell line; this resulted in reduced cell proliferation, migration, sphere formation, and drug resistance, suggesting that Sestrin2 is closely related to lung cancer progression. We analyzed Sestrin2 expression in human tissue using various bioinformatic databases and confirmed higher expression of Sestrin2 in lung cancer cells than in normal lung cells using Oncomine and the Human Protein Atlas. Moreover, analyses using Prognoscan and KMplotter showed that Sestrin2 expression is negatively correlated with the survival of lung cancer patients in multiple datasets. Co-expressed gene analysis revealed Sestrin2-regulated genes and possible associated pathways. Overall, these data suggest that Sestrin2 expression has prognostic value and that it is a possible therapeutic target in lung cancer.
Highlights
Cancer, one of the leading causes of death in modern society, poses a threat to human health worldwide
RsiTg-nPiCfiRcarnetvlyearleeddutcheadt tihne Seexsptrriens2sioknnoocfkEdMowT nmacrekllesrsco(Vmimpaernetdin,toSntahial,tZinEBs1c)rwamasblseigcneilfilsc.anOtlvyerreadllu, cwede isnuSgegsetsrtint2hkatnoSceksdtroinw2n ecxepllrsescsoimonpiasrreedlattoedthtaotsiunrvscivraaml abnlde cmeliglsr.atOiovnerinallt,hwe Ae 5s4u9ggluenstgtchaantcSeerscterillnl2ineex.pression is related to survival and migration in the A549 lung cancer cell line
The increase in reactive oxygen species (ROS) levels was indicated by flow cytometry (Figure 3C). These results suggest that Sestrin2 affects the regulation of the NF-E2-related factor 2 (NRF2)-HO-1 pathway and ROS level in A549 cancer cells
Summary
One of the leading causes of death in modern society, poses a threat to human health worldwide. Called p53-activated gene 26 (PA26), is involved in the growth arrest and DNA damage response pathways [4]. Known as hypoxia-inducible gene 95 (Hi95), is involved in mediating the response to hypoxia and is upregulated by other stressors, such as DNA damage and oxidative stress [5,6]. As well as Sestrin, is known to mediate the regulation of mammalian target of rapamycin 1 (mTORC1) and Akt activation [7,8]. Expression of these genes decreases the levels of intracellular reactive oxygen species (ROS) and promotes resistance against oxidative stress [9,10]. Since sestrins can modulate pathways of cellular metabolism, sestrin expression seems to play an important role in prolonging life and inhibiting aging [2]
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