Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression

Hao, Shengyu; Zhu, Xiaodan; Liu, Zilong; Wu, Xiaodan; Li, Shanqun; Jiang, Pan; Jiang, Liyan

doi:10.1186/s12931-021-01655-6

Cited by 31 publications

(25 citation statements)

References 36 publications

(20 reference statements)

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“…However, the specific mechanisms underlying the elevation of Bach1 in lung CSCs have yet to be investigated. Previously, we reported that chronic intermittent hypoxia induced lung cancer stem cell-like properties through enhancing Bach1 expression [ 29 ]. In addition, we would further check the detailed mechanism that Bach1 induces lung tumor growth and reduces lung cancer cell death.…”

Section: Discussionmentioning

confidence: 99%

BTB and CNC homology 1 (Bach1) induces lung cancer stem cell phenotypes by stimulating CD44 expression

et al. 2021

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Background Growing evidence suggests that cancer stem cells (CSCs) are responsible for cancer initiation in tumors. Bach1 has been identified to contribute to several tumor progression, including lung cancer. The role of Bach1 in CSCs remains poorly known. Therefore, the function of Bach1 on lung CSCs was focused currently. Methods The expression of Bach1, CD133, CD44, Sox2, Nanog and Oct4 mRNA was assessed using Real-Time Quantitative Reverse Transcription PCR (RT-qPCR). Protein expression of Bach1, CD133, CD44, Sox2, Nanog, Oct4, p53, BCL2, BAX, p-p38, p-AKT1, c-Fos and c-Jun protein was analyzed by western blotting. 5-ethynyl-29-deoxyuridine (EdU), colony formation, Flow cytometry analysis and transwell invasion assay were carried out to analyze lung cancer cell proliferation, apoptosis and invasion respectively. Tumor sphere formation assay was utilized to evaluate spheroid capacity. Flow cytometry analysis was carried out to isolate CD133 or CD44 positive lung cancer cells. The relationship between Bach1 and CD44 was verified using ChIP-qPCR and dual-luciferase reporter assay. Xenograft tumor tissues were collected for hematoxylin and eosin (HE) staining and IHC analysis to evaluate histology and Ki-67. Results The ratio of CD44 + CSCs from A549 and SPC-A1 cells were significantly enriched. Tumor growth of CD44 + CSCs was obviously suppressed in vivo compared to CD44− CSCs. Bach1 expression was obviously increased in CD44 + CSCs. Then, via using the in vitro experiment, it was observed that CSCs proliferation and invasion were greatly reduced by the down-regulation of Bach1 while cell apoptosis was triggered by knockdown of Bach1. Loss of Bach1 was able to repress tumor-sphere formation and tumor-initiating CSC markers. A repression of CSCs growth and metastasis of shRNA-Bach1 was confirmed using xenograft models and caudal vein injection. The direct interaction between Bach1 and CD44 was confirmed by ChIP-qPCR and dual-luciferase reporter assay. Furthermore, mitogen-activated protein kinases (MAPK) signaling pathway was selected and we proved the effects of Bach1 on lung CSCs were associated with the activation of the MAPK pathway. As manifested, loss of Bach1 was able to repress p-p38, p-AKT1, c-Fos, c-Jun protein levels in lung CSCs. Inhibition of MAPK signaling remarkably restrained lung CSCs growth and CSCs properties induced by Bach1 overexpression. Conclusion In summary, we imply that Bach1 demonstrates great potential for the treatment of lung cancer metastasis and recurrence via activating CD44 and MPAK signaling.

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Section: Discussionmentioning

confidence: 99%

BTB and CNC homology 1 (Bach1) induces lung cancer stem cell phenotypes by stimulating CD44 expression

et al. 2021

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“…RR, risk ratio. exacerbate tumor progression, aggressiveness, and metastasis via multiple molecular mechanisms in lung cancer (Guo et al, 2019;Kang et al, 2020;Torres et al, 2020;Hao et al, 2021), experimental studies regarding the role of intermittent hypoxia on the pathogenesis of lung cancer remain lacking. Future studies are warranted for improving the understanding of the mechanisms involved.…”

Section: Discussionmentioning

confidence: 99%

Sleep-disordered breathing and risk of lung cancer: a meta-analysis longitudinal follow-up studies

Zhang

Han

et al. 2021

European Journal of Cancer Prevention

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Consensus remains lack regarding whether sleepdisordered breathing (SDB) is an independent risk factor for lung cancer. We therefore conducted a metaanalysis to clarify the relationship of SDB and lung cancer. Longitudinal follow-up studies investigating the association between SDB and incidence of lung cancer were included by search of electronic databases including PubMed, Embase, and Cochrane's Library. A randomeffects model was adopted to combine the results. Seven studies were included. Pooled results showed that presence of SDB was independently associated with higher incidence of lung cancer [adjusted risk ratio (RR): 1.28; 95% confidence interval (CI), 1.11-1.47; P < 0.001; I 2 = 37%]. Sensitivity analysis limited to studies with adjustment of smoking showed consistent results (three studies, RR: 1.34; 95% CI, 1.22-1.48; P < 0.001; I 2 = 8%). Subgroup analysis suggested that the association between SDB and higher risk of lung cancer was not significantly affected by study characteristics such as study design, source of population, sample size, evaluation methods for SDB, follow-up duration, methods for validation of lung cancer, or score of study quality (P values for subgroup difference all >0.05). No significant publication bias was observed (P for Egger's regression test = 0.258). These results suggested that SDB may be an independent risk factor of lung cancer in adult population. Intensive screening and prevention of lung cancer in subjects with SDB should be considered. European

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“…An important example of this association between cancer and the cyclic hypoxia might be appreciated in cancer patients suffering from obstructive sleep apnea (OSA); this association participates in increasing the incidence and mortality of cancer [ 33 ]. Several studies have confirmed that exposure to cyclic hypoxia increases cancer stem cell markers, as well as features related to metastasis [ 34 , 35 , 36 ]. It has even been suggested that the aggressiveness in melanoma can be mediated by TGF-β (a well-known pro-fibrotic cytokine) [ 37 ].…”

Section: Cancer Hallmarks Associated With Hypoxiamentioning

confidence: 99%

Hypoxia in Cancer and Fibrosis: Part of the Problem and Part of the Solution

Romero

Aquino‐Gálvez

2021

IJMS

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Adaptive responses to hypoxia are involved in the progression of lung cancer and pulmonary fibrosis. However, it has not been pointed out that hypoxia may be the link between these diseases. As tumors or scars expand, a lack of oxygen results in the activation of the hypoxia response, promoting cell survival even during chronic conditions. The role of hypoxia-inducible factors (HIFs) as master regulators of this adaptation is crucial in both lung cancer and idiopathic pulmonary fibrosis, which have shown the active transcriptional signature of this pathway. Emerging evidence suggests that interconnected feedback loops such as metabolic changes, fibroblast differentiation or extracellular matrix remodeling contribute to HIF overactivation, making it an irreversible phenomenon. This review will focus on the role of HIF signaling and its possible overlapping in order to identify new opportunities in therapy and regeneration.

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Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression

Cited by 31 publications

References 36 publications

BTB and CNC homology 1 (Bach1) induces lung cancer stem cell phenotypes by stimulating CD44 expression

BTB and CNC homology 1 (Bach1) induces lung cancer stem cell phenotypes by stimulating CD44 expression

Sleep-disordered breathing and risk of lung cancer: a meta-analysis longitudinal follow-up studies

Hypoxia in Cancer and Fibrosis: Part of the Problem and Part of the Solution

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