Differential molecular alterations promoting non-small cell lung cancer under hypoxia

Abstract

Hypoxia is one of the hallmarks of the solid cancer microenvironment that dominates cancer progression and exacerbation. Under the oxygen-deprived condition, cancer resists and circumvents all interventions for permanence. Genomic and genetic instability of hypoxic cancer remains to be insightfully investigated and interpreted, as in lung adenocarcinoma. Herein, non-small cell lung cancer (NSCLC) cell line A549 was exposed to hypoxic shots parallel with running non-hypoxic (normoxic) A549 cells. Based on the isolated total RNA, gene transcriptomic profiling was identified using microarray and analysed via Ingenuity Pathway Analysis (IPA). As well, wound healing and cytotoxicity of doxorubicin were performed to assess hypoxic lung cancer cell response. Gene expression analysis revealed that TP53 (p53) is the most activated signaling, along with suppression of chromosomal signalings (DNA replication and repair). Besides, TP53 and its dependent target CDKN1A/p21 (cell cycle down-regulator) were identified as the topmost significant upstream transcriptional regulators, commanding a 37-gene targetable panel for cancer survival. In addition, hypoxic A549 cells were more chemo-resistant and higher motile. Notably, other emerging alterations were detected regarding efflux transporters (ABC-As and ABC-G1) that have been selectively up-regulated over the rest of under-transcribed (ABC) transporters subfamilies. Together, these  involved findings suggest that the p53 signaling could be a potential survival mediator of hypoxic NSCLC cells (A549), which triggered the prominent cell cycle down-regulation to frustrate apoptotic response in hypoxic NSCLC. Coupled with the impairing of DNA replication and repair signalings that promoted molecular alterations for survival. Represented by the remarkable epithelial-mesenchymal transition of hypo-proliferating hypoxic A549 cells by which was described at the transcriptional level alongside phenotypic level. Consequently, hypoxic A549 cells showed higher resistance to doxorubicin targeting DNA replication, regardless of any transcriptionally down-regulated (ABC) transporters.

Funding

Deanship of Academic Research, University of Jordan