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Cellular and Molecular Biology

Lipophagy-ICAM-1 pathway associated with fatty acid and oxygen deficiencies is involved in poor prognoses of ovarian clear cell carcinoma

British Journal of Cancer volume 127, pages 462–473 (2022)Cite this article

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Abstract

Background

Serum starvation and hypoxia (SSH) mimics a stress condition in tumours. We have shown that intercellular adhesion molecule-1 (ICAM-1) protein is synergistically expressed in ovarian clear cell carcinoma (CCC) cells under SSH in response to an insufficient supply of fatty acids (FAs). This ICAM-1 expression is responsible for resistance against the lethal condition, thereby promoting tumour growth. However, the underlying mechanisms that link SSH-driven ICAM1 gene expression to impaired FA supply and its clinical relevance are unclear.

Methods

The underlying mechanisms of how FA deficiency induces ICAM-1 expression in cooperation with hypoxia were analysed in vitro and in vivo. Clinical significance of CCC cell-derived ICAM-1 and the mechanism associated with the transcriptional synergism were also investigated.

Results

ICAM-1 expression was mediated through lipophagy-driven lipid droplet degradation, followed by impaired FA-lipid droplet flow. Lipophagy induced ICAM1 expression through stabilisation of NFκB binding to the promoter region via Sam68 and hTERT. Analyses of clinical specimens revealed that expression of ICAM-1 and LC3B, an autophagy marker associated with lipophagy, significantly correlated with poor prognoses of CCC.

Conclusions

The lipophagy-ICAM-1 pathway induced under a tumour-like stress conditions contributes to CCC progression and is a potential therapeutic target for this aggressive cancer type.

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Fig. 1: ICAM-1 level in cancer cells is associated with poor prognoses of CCC patients.
Fig. 2: Impairment of FA-LD flow is associated with synergistic ICAM-1 expression and decreased cell viability under SSH.
Fig. 3: Lipophagy is responsible for SSH-driven ICAM-1 expression and associated with an LD decrease in CCC cells.
Fig. 4: hTERT and Sam68 contribute to NFκB binding to ICAM1 under SSH.
Fig. 5: Lipophagy-ICAM-1 pathway is involved in aggressiveness of CCC through resistance against cell death.

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Data availability

All data generated in this study are included in this manuscript.

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Acknowledgements

We thank Mitchell Arico from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This study was partially supported by JSPS KAKENHI Grant Number 26430135.

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Authors and Affiliations

  1. Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, 241-8515, Japan

    Shiro Koizume, Tomoko Takahashi, Yoshiyasu Nakamura, Mitsuyo Yoshihara, Yukihide Ota, Shinya Sato, Hiroko Tadokoro & Yohei Miyagi

  2. Department of Pathology, Kanagawa Cancer Center Hospital, Yokohama, 241-8515, Japan

    Shiro Koizume, Shinya Sato, Tomoyuki Yokose & Yohei Miyagi

  3. Department of Obstetrics, Gynecology, and Molecular Reproductive Science, Yokohama City University, Graduate School of Medicine, Yokohama, 236-0004, Japan

    Yukihide Ota & Etsuko Miyagi

  4. Department of Gynecology, Kanagawa Cancer Center Hospital, Yokohama, 241-8515, Japan

    Hisamori Kato

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Contributions

SK designed the study, performed experiments, wrote the manuscript, and supervised the project. TT performed experiments. YN and MY contributed to IHC. YO contributed to animal experiments. SS, HT, and EM contributed to data interpretation. TY diagnosed cancer patients. HK contributed to TMA preparation. YM contributed to drafting the manuscript and supervised the project. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Shiro Koizume or Yohei Miyagi.

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The authors declare no competing interests.

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For human samples, written consent was obtained from all patients. The study was approved by our institutional review board (Kanagawa Cancer Center Research Institute) (approval No. 177). Animal studies were also reviewed and approved by our institutional review board.

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Koizume, S., Takahashi, T., Nakamura, Y. et al. Lipophagy-ICAM-1 pathway associated with fatty acid and oxygen deficiencies is involved in poor prognoses of ovarian clear cell carcinoma. Br J Cancer 127, 462–473 (2022). https://doi.org/10.1038/s41416-022-01808-4

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