Skip to main content
SpringerLink
Log in

Gene expression related to lung cancer altered by PHMG-p treatment in PBTE cells

  • Original Article
  • Published:
Molecular & Cellular Toxicology Aims and scope Submit manuscript

Abstract

Background

Humidifier disinfectants (HDs), including polyhexamethylene guanidine phosphate (PHMG-p), are commonly used in Korea to prevent microbial growth. Epidemiological studies show that PHMG-p causes severe lung injury, accompanied by pulmonary inflammation and fibrosis. Several studies have examined humidifier disinfectant-associated lung injuries, but few have examined potential carcinogenic activity of PHMG-p. Our previous studies have shown that PHMG-p can induce lung cancer. However, gene expression changes in squamous cell carcinoma (SCC) caused by PHMG-p have not yet been studied.

Objectives

We aimed to determine the PHMG-p-induced changes in transcription levels of genes involved in SCC development and progression in primary bronchial/tracheal epithelial cells (PBTE cells).

Results

Genetic alterations induced by PHMG-p were designated as fold change (FC) values of greater than 2 or less than 0.5. RNA sequencing analysis revealed that two genes were upregulated and sixteen genes were downregulated in the short-term PHMG-p exposure group. Fourteen genes were upregulated and 3 genes were downregulated in the long-term PHMG-p exposure group.

Conclusion

Our data show that PHMG-p induces genetic changes associated with SCC progression in PBTE cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Bikkavilli RK et al (2015) Wnt7a is a novel inducer of β-catenin-independent tumor-suppressive cellular senescence in lung cancer. Oncogene 34:5317–5328

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chatterjee S, Sinha S, Kundu CN (2021) Nectin cell adhesion molecule-4 (NECTIN-4): a potential target for cancer therapy. Eur J Pharmacol 911:174516

    CAS  PubMed  Google Scholar 

  • Cui H et al (2015) Tissue inhibitor of metalloproteinases-1 induces a pro-tumourigenic increase of miR-210 in lung adenocarcinoma cells and their exosomes. Oncogene 34:3640–3650

    CAS  PubMed  Google Scholar 

  • Delpeut S, Noyce RS, Richardson CD (2014) The tumor-associated marker, PVRL4 (nectin-4), is the epithelial receptor for morbilliviruses. Viruses 6:2268–2286

    PubMed  PubMed Central  Google Scholar 

  • Fessart D et al (2021) Extracellular AGR2 triggers lung tumour cell proliferation through repression of p21CIP1. Biochim Biophys Acta (BBA)-Mol Cell Res 1868:118920

  • Gentleman RC et al (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5:1–16

    Google Scholar 

  • Hatakeyama J, Wald JH, Printsev I, Ho H-YH, Carraway KL (2014) Vangl1 and Vangl2: planar cell polarity components with a developing role in cancer. Endocr Relat Cancer 21:R345–R356

    CAS  PubMed  PubMed Central  Google Scholar 

  • He J, Fu Y, Hu J, Chen J, Lou G (2021) Hypomethylation-mediated AGR2 overexpression facilitates cell proliferation, migration, and invasion of lung adenocarcinoma. Cancer Manag Res 13:5177

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jeon B-H, Park YJ (2012) Frequency of humidifier and humidifier disinfectant usage in gyeonggi provine. Environ Health Toxicol 27

  • Jeong MH, Kim HR, Park YJ, Chung KH (2019) Akt and Notch pathways mediate polyhexamethylene guanidine phosphate-induced epithelial-mesenchymal transition via ZEB2. Toxicol Appl Pharmacol 380:114691

    CAS  PubMed  Google Scholar 

  • Jeong S-H et al (2021) MTF1 is essential for the expression of MT1B, MT1F, MT1G, and MT1H induced by PHMG, but not CMIT, in the human pulmonary alveolar epithelial cells. Toxics 9:203

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ji Z, Pan X, Shang Y, Ni D-T, Wu F-L (2019) KIF18B as a regulator in microtubule movement accelerates tumor progression and triggers poor outcome in lung adenocarcinoma. Tissue Cell 61:44–50

    CAS  PubMed  Google Scholar 

  • Jin SW, Lee GH, Pham HT, Choi JH, Jeong HG (2019) Polyhexamethylene guanidine phosphate damages tight junctions and the F-actin architecture by activating calpain-1 via the P2RX7/Ca2+ signaling pathway. Cells 9:59

    PubMed  PubMed Central  Google Scholar 

  • Ju Q et al (2020) Genome-wide analysis of prognostic-related lncRNAs, miRNAs and mRNAs forming a competing endogenous RNA network in lung squamous cell carcinoma. J Cancer Res Clin Oncol 146:1711–1723

    CAS  PubMed  Google Scholar 

  • Ju YJ et al (2021) A comprehensive study of deaths due to exposure to humidifier disinfectant in Korea: focusing on medical records, assessment of exposure to humidifier disinfectants, and causes of death. Epidemiol Health 43:e2021091. https://doi.org/10.4178/epih.e2021091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim C et al (2021a) Evaluation of the long-term effect of polyhexamethylene guanidine phosphate in a rat lung model using conventional chest computed tomography with histopathologic analysis. PLoS ONE 16:e0256756

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim C et al (2021b) Evaluation of polyhexamethylene guanidine-induced lung injuries by chest CT, pathologic examination, and RNA sequencing in a rat model. Sci Rep 11:1–12

    Google Scholar 

  • Kim H-C, Kim H, Mun E-C, Lee Y, Park S (2021c) Need for individual-based evaluation to determine the association between humidifier disinfectants and health injuries. Ann Occup Environ Med 33

  • Kim H-R, Hwang G-W, Naganuma A, Chung K-H (2016) Adverse health effects of humidifier disinfectants in Korea: lung toxicity of polyhexamethylene guanidine phosphate. J Toxicol Sci 41:711–717

    CAS  PubMed  Google Scholar 

  • Kim S-W et al (2007) Proteomics-based identification of proteins secreted in apical surface fluid of squamous metaplastic human tracheobronchial epithelial cells cultured by three-dimensional organotypic air-liquid interface method. Can Res 67:6565–6573

    CAS  Google Scholar 

  • Kim W-Y, Hong S-B (2017) Humidifier disinfectant-associated lung injury: six years after the tragic event. Tuberculos Respir Disease 80:351–357

    Google Scholar 

  • Koh HM et al (2019) Prognostic role of S100A8 and S100A9 protein expressions in non-small cell carcinoma of the lung. J Pathol Transl Med 53:13–22

    PubMed  Google Scholar 

  • Langmead B, Salzberg SL (2012) Fast gapped-read alignment with Bowtie 2. Nat Methods 9:357–359

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee H et al (2022) Analysis of lung cancer-related genetic changes in long-term and low-dose polyhexamethylene guanidine phosphate (PHMG-p) treated human pulmonary alveolar epithelial cells. BMC Pharmacol Toxicol 23:1–15

    CAS  Google Scholar 

  • McCarroll J, Wong SW, Hsu K, Geczy CL, Tedla N (2022) Intranasal delivery of recombinant S100A8 protein delays lung cancer growth by remodeling the lung immune microenvironment. Front Immunol 1874

  • Miao T-w, Yang D-q, Chen F-y, Zhu Q, Chen X (2022) A ferroptosis-related gene signature for overall survival prediction and immune infiltration in lung squamous cell carcinoma. Biosci Rep 42:BSR20212835

  • Mokhlesi A, Talkhabi M (2020) Comprehensive transcriptomic analysis identifies novel regulators of lung adenocarcinoma. J Cell Commun Signal 14:453–465

    PubMed  PubMed Central  Google Scholar 

  • Ohkubo Y et al (2010) Combining carbon ion radiotherapy and local injection of α-galactosylceramide–pulsed dendritic cells inhibits lung metastases in an in vivo murine model. Int J Radiat Oncol Biol Phys 78:1524–1531

  • Park D-U et al (2017) Types of household humidifier disinfectant and associated risk of lung injury (HDLI) in South Korea. Sci Total Environ 596:53–60

    PubMed  Google Scholar 

  • Park JS, Park YJ, Kim HR, Chung KH (2019) Polyhexamethylene guanidine phosphate-induced ROS-mediated DNA damage caused cell cycle arrest and apoptosis in lung epithelial cells. J Toxicol Sci 44:415–424

    CAS  PubMed  Google Scholar 

  • Peinado-Serrano J et al (2022) A six-gene prognostic and predictive radiotherapy-based signature for early and locally advanced stages in non-small-cell lung cancer. Cancers 14:2054

    CAS  PubMed  PubMed Central  Google Scholar 

  • Puissegur M et al (2011) miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ 18:465–478

    CAS  PubMed  Google Scholar 

  • Puvirajesinghe TM et al (2016) Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2–JNK signalling in breast cancer. Nat Commun 7:1–15

    Google Scholar 

  • Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26:841–842

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rodón L et al (2019) The CREB coactivator CRTC2 promotes oncogenesis in LKB1-mutant non–small cell lung cancer. Science advances 5:eaaw6455

  • Ryu SH et al (2019) Humidifier disinfectant and use characteristics associated with lung injury in Korea. Indoor Air 29:735–747

    CAS  PubMed  Google Scholar 

  • Savini A et al (2015) Squamous cell carcinoma of the lung: clinical criteria for treatment strategy. J Cancer Metastas Treatment 1:90–93

    Google Scholar 

  • Shi S et al (2018) CRTC2 promotes non-small cell lung cancer A549 migration and invasion in vitro. Thoracic Cancer 9:136–141

    CAS  PubMed  Google Scholar 

  • Shi X et al (2022) Integrative pan cancer analysis reveals the importance of CFTR in lung adenocarcinoma prognosis. Genomics 114:110279

    CAS  PubMed  Google Scholar 

  • Song C et al (2020) A prognostic nomogram combining immune-related gene signature and clinical factors predicts survival in patients with lung adenocarcinoma. Front Oncol 10:1300

    PubMed  PubMed Central  Google Scholar 

  • Song JA et al (2014) Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy. Food Chem Toxicol 69:267–275

    CAS  PubMed  Google Scholar 

  • Su W et al (2016) miR-135b reverses chemoresistance of non-small cell lung cancer cells by downregulation of FZD1. Biomed Pharmacother 84:123–129

    CAS  PubMed  Google Scholar 

  • Sun N et al (2022) A novel immune checkpoints-based signature to predict prognosis and response to immunotherapy in lung adenocarcinoma. J Transl Med 20:1–15

    CAS  Google Scholar 

  • Sun Q et al (2022b) Prognostic value and oncogenic effects of ubiquitin-specific protease 43 in lung squamous cell carcinoma. The Tohoku Journal of Experimental Medicine

  • Vitt A et al (2015) Antimicrobial activity of polyhexamethylene guanidine phosphate in comparison to chlorhexidine using the quantitative suspension method. Ann Clin Microbiol Antimicrob 14:1–9

    CAS  Google Scholar 

  • Wang J, Yang Q, Tang M, Liu W (2022) Validation and analysis of expression, prognosis and immune infiltration of WNT gene family in non-small cell lung cancer. Front Oncol 12

  • Wang R, Wang X, Zhang J, Liu Y (2021) LINC00942 promotes tumor proliferation and metastasis in lung adenocarcinoma via FZD1 upregulation. Technol Cancer Res Treat 20:1533033820977526

    CAS  PubMed  PubMed Central  Google Scholar 

  • Werynska B et al (2013) Metallothionein 1F and 2A overexpression predicts poor outcome of non-small cell lung cancer patients. Exp Mol Pathol 94:301–308

    CAS  PubMed  Google Scholar 

  • Xiong Y, Mingzhen L, Zhang P, Zhang L, Yue Y (2017) Study on genetype in lung squamous carcinoma by high-throughput of transcriptome sequence. Zhongguo Fei Ai Za Zhi 20

  • Xu F et al (2020a) A TP53-associated gene signature for prediction of prognosis and therapeutic responses in lung squamous cell carcinoma. Oncoimmunology 9:1731943

    PubMed  PubMed Central  Google Scholar 

  • Xu Z et al (2020b) Circ-IGF1R inhibits cell invasion and migration in non-small cell lung cancer. Thoracic Cancer 11:875–887

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xue Y et al (2021) Long noncoding RNAs PTPRG Antisense RNA 1 targets cyclin D1 to facilitate cell proliferation in lung adenocarcinoma. Cancer Biotherap Radiopharm

  • Yang J-W et al (2022) Tissue-level alveolar epithelium model for recapitulating SARS-CoV-2 infection and cellular plasticity. Commun Biol 5:1–12

    Google Scholar 

  • Yang Y et al (2019) Evidence for an oncogenic role of HOXC6 in human non-small cell lung cancer. PeerJ 7:e6629

    PubMed  PubMed Central  Google Scholar 

  • Zhang H et al (2022) QKI-6 Suppresses Cell Proliferation, Migration, and EMT in Non-Small Cell Lung Cancer. Frontiers in Oncology 12

  • Zhang Q-X et al (2021) The roles of risk model based on the 3-XRCC genes in lung adenocarcinoma progression. Transl Cancer Res 10:4413

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang W et al (2018) TRIM58/cg26157385 methylation is associated with eight prognostic genes in lung squamous cell carcinoma. Oncol Rep 40:206–216

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the National Institute of Environment Research (NIER) funded by the Ministry of Environment (MOE) of the Republic of Korea (grant number NIER-2022-04-03-001).

Author information

Author notes

  1. Yoon Hee Park and Sang Hoon Jeong have contributed equally to this work.

Authors and Affiliations

  1. Medical Science Research Center, Ansan Hospital, Korea University College of Medicine, Ansan-Si, Gyeonggi, Republic of Korea

    Yoon Hee Park, Sang Hoon Jeong, Hyejin Lee, Yoon Jeong Nam, Ja Young Kang, Jin Young Choi, Yu-Seon Lee, Su A. Park, Jaeyoung Kim & Hong Lee

  2. Department of Radiology, Ansan Hospital, Korea University College of Medicine, Ansan-Si, Gyeonggi, Republic of Korea

    Cherry Kim

  3. Department of Medical Humanities and Social Medicine, College of Medicine, Kosin University, Busan, Republic of Korea

    Eun-Kee Park

  4. Environmental Health Research Department, Humidifier Disinfectant Health Center, National Institute of Environmental Research, Incheon, Republic of Korea

    Yong-Wook Baek

  5. Department of Pathology, Ansan Hospital, Korea University College of Medicine, Ansan-Si, Gyeonggi, Republic of Korea

    Ju-Han Lee

Authors
  1. Yoon Hee Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sang Hoon Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hyejin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cherry Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoon Jeong Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ja Young Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jin Young Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu-Seon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Su A. Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jaeyoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eun-Kee Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yong-Wook Baek
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ju-Han Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

PYH and JSH analyzed the RNA sequencing data, searched references to genes and wrote this manuscript. KC, NYJ, KJ, PEK, and BYW performed the data analysis. LH1 performed RT-qPCR. KJY, CJY, LYS, and PSA contributed to searching references to this study. LH2 designed this study and edited the manuscript. LJH supervised the study and acquired the funding source. (LH1: Hyejin Lee, LH2: Hong Lee).

Corresponding authors

Correspondence to Hong Lee or Ju-Han Lee.

Ethics declarations

Conflict of interest

Yoon Hee Park declares that there are no conflicts of interest. Sang Hoon Jeong declares that there are no conflicts of interest. Hyejin Lee declares that there are no conflicts of interest. Cherry Kim declares that there are no conflicts of interest. Yoon Jeong Nam declares that there are no conflicts of interest. Ja Young Kang declares that there are no conflicts of interest. Jin Young Choi declares that there are no conflicts of interest. Yu-Seon Lee declares that there are no conflicts of interest. Su a Park declares that there are no conflicts of interest. Jaeyoung Kim declares that there are no conflicts of interest. Eun-Kee Park declares that there are no conflicts of interest. Yong-Wook Baek declares that there are no conflicts of interest. Hong Lee declares that there are no conflicts of interest. Ju-Han Lee declares that there are no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 14 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, Y.H., Jeong, S.H., Lee, H. et al. Gene expression related to lung cancer altered by PHMG-p treatment in PBTE cells. Mol. Cell. Toxicol. 19, 205–217 (2023). https://doi.org/10.1007/s13273-022-00319-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13273-022-00319-w

Keywords

Search

Navigation