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EPAS1 promotes peritoneal carcinomatosis of non-small-cell lung cancer by enhancing mesothelial–mesenchymal transition

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Abstract

Background

Non-small-cell lung cancer (NSCLC) is a major cause of cancer-related death globally. Endothelial PAS domain-containing protein 1 (EPAS1) is a homolog of the hypoxia-inducible factor 1α and has been reported to confer tyrosine kinase inhibitor (TKI) resistance in NSCLC, but its role in peritoneal carcinomatosis of NSCLC is unknown.

Methods

PC14HM, a high metastatic potential subline of NSCLC cell line PC14, was derived. Stable shRNA knockdown of EPAS1 was then established in PC14HM cells and subjected to assessment regarding the effects on proliferation and viability, xenograft tumor growth, metastatic potential, mesothelial–mesenchymal transition (MMT)-related characteristics and peritoneal carcinomatosis in a mouse model.

Results

EPAS1 expression was elevated in PC14HM cells. Knockdown of EPAS1 inhibited the proliferation and viability of PC14HM cells in vitro and suppressed tumorigenesis in vivo. In addition, the metastatic features and in vitro productions of MMT-inducing factors in PC14HM cells was also associated with EPAS1. More importantly, knockdown of EPAS1 drastically suppressed peritoneal carcinomatosis of PC14HM cells in vivo.

Conclusion

EPAS1 promotes peritoneal carcinomatosis of NSCLC through enhancement of MMT and could therefore serve as a prognostic marker or a therapeutic target in treating NSCLC, particularly in patients with peritoneal carcinomatosis.

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Abbreviations

EGFR:

Epidermal growth factor receptor

ELISA:

Enzyme-linked immunosorbent assay

EPAS1:

Endothelial PAS domain-containing protein 1

HGF:

Hepatocyte growth factor

IL:

Interleukin

MET:

Hepatocyte growth factor receptor

MMT:

Mesothelial–mesenchymal transition

NSCLC:

Non-small-cell lung cancer

PCI:

Peritoneal carcinomatosis index

PCR:

Polymerase chain reaction

SCLC:

Small-cell lung cancer

SD:

Standard deviation

TGF-β1:

Transforming growth factor-β1

TKI:

Tyrosine kinase inhibitor

TNF‑α:

Tumour necrosis factor‑α

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Funding

This work was funded by the Natural Science Foundation of Hebei Province (H2019106033).

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Authors and Affiliations

  1. Department of Thoracic Surgery, Shijiazhuang No. 1 Hospital, 36 Fanxi Road, 050011, Shijiazhuang, Hebei, China

    Qiang Zhen, Yaxiao Zhang, Renfeng Wang, Weiwei Chu, Xiaojian Zhao, Zhe Li, Huixian Li, Bing Zhang, Baolei Lv & Jiabao Liu

  2. Central Supply Room, Hebei General Hospital, No. 348 Heping West Road, 050051, Shijiazhuang, Hebei, China

    Lina Gao

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  1. Qiang Zhen
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  2. Yaxiao Zhang
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Correspondence to Yaxiao Zhang.

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Conflict of interest

Q. Zhen, Y. Zhang, L. Gao, R. Wang, W. Chu, X. Zhao, Z. Li, H. Li, B. Zhang, B. Lv, and J. Liu declare that they have no competing interests.

Caption Electronic Supplementary Material

Figure S1. HIF1α expression is unchanged between PC14 and PC14HM cell lines.

Expression levels of (A) HIF1α mRNA and (B) protein were examined in PC14 and PC14HM cells, respectively. Values were mean ± SD from at least three biological replicates. n p > 0.05, PC14 vs PC14HM

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Zhen, Q., Zhang, Y., Gao, L. et al. EPAS1 promotes peritoneal carcinomatosis of non-small-cell lung cancer by enhancing mesothelial–mesenchymal transition. Strahlenther Onkol 197, 141–149 (2021). https://doi.org/10.1007/s00066-020-01665-1

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