Sex disparities in non-small cell lung cancer: mechanistic insights from a cRaf transgenic disease model

Zhong, Shen; Borlak, Jürgen

doi:10.1016/j.ebiom.2023.104763

Cited by 1 publication

(2 citation statements)

References 153 publications

(176 reference statements)

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“…Therefore, we regard its fourfold upregulation in tobacco smoke exposed transgenic animals (both sexes) as an adaptive response to the detrimental effects of cRaf hyperactivity and tobacco smoke. Moreover, Meg3 is also upregulated in sham exposed transgenic animals (Zhong and Borlak 2023 ), while the repression of repetin in transgenic males and females supports epithelial cell dedifferentiation (Supplementary Table S3) (Huber et al 2005 ; Krieg et al 1997 ). Interestingly, in sham exposed transgenic males but not in females, gastrokine 2 is highly induced (17-fold).…”

Section: Resultsmentioning

confidence: 99%

“…We performed whole genome miRNA profiling of lung tissue of cRaf transgenic mice as described before (Vescovo et al 2013 , Zhong and Borlak 2023 ). We used the following protocol for the Affymetrix platform: from each lung we isolated 200 ng of total RNA and labeled nucleic acids with the FlashTag Biotin HSR labeling kit according to the manufacturer’s instructions (Genisphere, Hatfield, PA, USA, http://media.affymetrix.com/support/downloads/manuals/mirna_flashtag_manual.pdf ).…”

Section: Methodsmentioning

confidence: 99%

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Sex differences in the tumor promoting effects of tobacco smoke in a cRaf transgenic lung cancer disease model

Zhong,

Borlak

2024

Arch Toxicol

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Tobacco smoke (TS) is the leading cause for lung cancer (LC), and female smokers are at a greater risk for LC. Yet, the underlying causes are unknown. We performed whole genome scans in TS exposed wild type and histologically characterized tumor lesions of cRaf transgenic mice. We constructed miRNA-gene and transcription factor-miRNA/gene regulatory networks and determined sex-specific gene regulations by evaluating hormone receptor activities. We validated the findings from TS exposed cRaf mice in a large cohort of smoking and never-smoking LC patients. When compared to males, TS prompted a sevenfold increase in tumor multiplicity in cRaf females. Genome-wide scans of tumor lesions identified 161 and 53 genes and miRNAs, which code for EGFR/MAPK signaling, cell proliferation, oncomirs and oncogenes, and 50% of DEGs code for immune response and tumor evasion. Outstandingly, in transgenic males, TS elicited upregulation of 20 tumor suppressors, some of which are the targets of the androgen and estrogen receptor. Conversely, in females, 18 tumor suppressors were downregulated, and five were specifically repressed by the estrogen receptor. We found TS to perturb the circadian clock in a sex-specific manner and identified a female-specific regulatory loop that consisted of the estrogen receptor, miR-22-3p and circadian genes to support LC growth. Finally, we confirmed sex-dependent tumor promoting effects of TS in a large cohort of LC patients. Our study highlights the sex-dependent genomic responses to TS and the interplay of circadian clock genes and hormone receptors in the regulation of oncogenes and oncomirs in LC growth.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%