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CISD2 promotes lung squamous carcinoma cell migration and invasion via the TGF-β1-induced Smad2/3 signaling pathway

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Abstract

Background

Although aberrant expression of CDGSH iron sulfur domain 2 (CISD2) contributes to the tumorigenesis and progression of numerous human cancers, the biological function of CISD2 and its specific prognostic value in lung squamous cell carcinoma (LUSC) have yet to be comprehensively explored. The current study aimed to elucidate the role of CISD2 in LUSC as well as the underlying molecular mechanisms.

Methods

Immunohistochemistry was conducted to detect the protein expression of CISD2 and analyze whether high expression of CISD2 affects the overall survival (OS) of LUSC patients. Cell proliferation, colony formation, wound healing and Transwell invasion assays were performed to clarify whether CISD2 contributes to LUSC cell proliferation and disease progression. Quantitative real-time reverse transcription-PCR and western blot assays were used to detect the levels of transcription factors and key epithelial-mesenchymal transition (EMT)-related markers in LUSC cells after CISD2 knockdown and overexpression to determine whether CISD2 regulates transforming growth factor-beta (TGF-β)-induced EMT in LUSC.

Results

Immunohistochemistry of human tissue microarrays containing 90 pairs of adjacent and cancerous tissues revealed that CISD2 is considerably overexpressed in LUSC and strongly linked to poor OS. Functional experiments suggested that silencing endogenous CISD2 inhibited the growth, colony formation, migration, and invasion of H2170 and H226 cell lines. Exogenous overexpression of CISD2 facilitated these phenotypes in SK-MES-1 and H2170 cells. Furthermore, CISD2 promoted EMT progression by increasing the expression of mesenchymal markers (N-cadherin, vimentin, Snail, and Slug) as well as SMAD2/3 and reducing the expression of the epithelial marker E-cadherin. Mechanistically, our studies provide the first evidence that CISD2 can promote EMT by enhancing TGF-β1-induced Smad2/3 expression in LUSC cells.

Conclusion

In conclusion, our research illustrates that CISD2 is highly expressed in LUSC and may facilitate LUSC proliferation and metastasis. Thus, CISD2 may serve as an independent prognostic marker and possible treatment target for LUSC.

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Data availability

The datasets produced for this work can be obtained from the corresponding author (QW) upon request.

Abbreviations

CISD2:

CDGSH iron sulfur domain 2

TGF-β:

Transforming growth factor-beta

NSCLC:

Non-small cell lung cancer

LUSC:

Lung squamous cell carcinoma

EMT:

Epithelial-mesenchymal transition

OS:

Overall survival

KD:

Knockdown

OE:

Overexpression

qRT‒PCR:

Quantitative real-time reverse transcription-PCR

WB:

Western blotting

IHC:

Immunohistochemistry

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Acknowledgements

We gratefully acknowledge Xifeng Xu for providing CISD2 KD plasmid information.

Funding

This study was funded by the Zhejiang Provincial Natural Science Foundation of China (Grant no. Q23H160038), the National Natural Science Foundation of China (Grant no. 81803042) and the Medical and Health Technology Project of Hangzhou (Grant no. A20220029).

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Author notes

  1. Jingjing Zhang and Lifang Pan contributed equally to this work.

Authors and Affiliations

  1. Integrated Traditional Chinese and Western Medicine Oncology Laboratory, Zhejiang Cancer Hospital, Hangzhou, 310022, China

    Lifang Pan & Qiong Wu

  2. Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, 310006, China

    Jingjing Zhang, Shirong Zhang & Yuhong Yang

  3. Department of Radiation Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China

    Jiafeng Liang & Shenglin Ma

Authors
  1. Jingjing Zhang
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  2. Lifang Pan
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  3. Shirong Zhang
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  5. Jiafeng Liang
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  7. Qiong Wu
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Contributions

QW, JZ and SM contributed to the study conception and design; QW, JZ and LP performed the experiments; QW, JZ, LP and JL analyzed and interpreted data and statistical analysis; SZ and YY edited the manuscript; QW and JZ wrote the manuscript.

Corresponding authors

Correspondence to Shenglin Ma or Qiong Wu.

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Conflict of interest

The authors declare no potential conflicts of interest.

Ethics approval

The ethics committee of Shanghai Outdo Biotech Company approved all study procedures, which were carried out according to the 1964 Helsinki Declaration.

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All patients in the study provided informed written consent.

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Zhang, J., Pan, L., Zhang, S. et al. CISD2 promotes lung squamous carcinoma cell migration and invasion via the TGF-β1-induced Smad2/3 signaling pathway. Clin Transl Oncol 25, 3527–3540 (2023). https://doi.org/10.1007/s12094-023-03222-5

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  • DOI: https://doi.org/10.1007/s12094-023-03222-5

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