Oxygen Deprivation and Lung Cancer: The Deadly Link You Need to Know

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. It often experiences hypoxia, which is a condition of oxygen deprivation. This lack of oxygen leads to genetic instability, increased aggressiveness of tumor cells, development of metastasis, and resistance to treatment. The molecular processes through which hypoxia affects lung carcinogenesis are fragmented. Based on previous carcinomas, one can speculate that hypoxia might interfere with the RASSF1A (Ras association domain family 1 isoform A). It has been suggested that YAP is active in a number of hypoxic tumors. As the overall form of TAZ in ovarian cancer grows strongly concurrently under hypoxic conditions, the phosphorylation/inactivation of YAP diminishes. To increase pancreatic ductal adenocarcinoma invasion via epithelial-mesenchymal transition, hypoxia causes YAP to interact with hypoxia-inducible factor-1 (HIF-1A) and to nuclear translocate, making YAP an independent prognostic predictor of survival for these patients. In keeping with this, it has been demonstrated that YAP binds to HIF-1A and maintains the protein’s stability to encourage glycolysis in hepatocellular carcinoma cells under hypoxic stress.

Lung Cancer

Lung Cancer

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The Hippo pathway is altered due to RASSF1A loss

This theory that hypoxia could disrupt the RASSF1A or Hippo signaling pathway in NSCLC is particularly interesting because it is already known that the Hippo pathway is altered as a result of RASSF1A loss, which affects 25% of patients with NSCLC and results in aberrant activation of the Hippo kinase NDR2 and the Hippo effector YAP, which supports the subsequent initiation and spread of NSCLC. In a study conducted by a group of scientists, they sought to understand the relationship between HIF-1A/YAP/TAZ in the context of the presence or absence of RASSF1A in Human Bronchial Epithelial Cells (HBEC) lines grown under severe (0.2% O2) and prolonged (48h) hypoxia, i.e., conditions similar to those present in lung tumor, where the median tumor pO2 ranged from 0.7 to 46 mm Hg (median,16.6), equating to 0.09 to 6.09% O2 (median, 2.2%), to find new tools to establish tumor metastasis score.

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It was discovered that the CAIX H-Score is comparable between the main tumor and the brain metastasis in individuals with localized NSCLC as well as between those with metastatic NSCLC. Also, Results show that HBEC lines undergo apoptosis when exposed to hypoxia, yet regardless of whether they express RASSF1A, they are still able to survive and even multiply in this adverse environment. Furthermore, the transcription of one of its target genes (ANKDR1) revealed that hypoxia resulted in the inactivation of TAZ in HBEC-3 cells cultivated for 48 hours at 0.2% oxygen and the accumulation of active (dephosphorylated) nuclear YAP.

Clinical significance

The findings as a whole showed that NDR2 kinase is excessively active in NSCLC caused by hypoxia and promotes brain metastases development. Hence, NDR2 expression is a helpful biomarker to assess the likelihood of metastases in patients with NSCLC and is regularly detectable by immunohistochemistry on tumor samples. By pharmacologically attacking these new targets, cancer may be stopped in its tracks, and patients with NSCLC may have better chances of surviving the disease.

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Conclusion

Studies on how hypoxia affects the RASSF1A/Hippo pathway in bronchial cell lines are progressing quite well. The findings show that hypoxia is an exacerbating factor in the development of bronchial carcinogenesis.

References

Hypoxia-induced activation of NDR2 underlies brain metastases from Non-Small Cell Lung Cance

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