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Androgen-regulated stromal complement component 7 (C7) suppresses prostate cancer growth

Oncogene volume 42, pages 2428–2438 (2023)Cite this article

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Abstract

The complement system is a major component of the innate immune system that works through the cytolytic effect of the membrane attack complex (MAC). Complement component 7 (C7) is essential for MAC assembly and its precisely regulated expression level is crucial for the cytolytic activity of MAC. We show that C7 is specifically expressed by the stromal cells in both mouse and human prostates. The expression level of C7 inversely correlates with clinical outcomes in prostate cancer. C7 is positively regulated by androgen signaling in the mouse prostate stromal cells. The androgen receptor directly transcriptionally regulates the mouse and human C7. Increasing C7 expression in the C57Bl/6 syngeneic RM-1 and Pten-Kras allografts suppresses tumor growth in vivo. Conversely, C7 haploinsufficiency promotes tumor growth in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Interestingly, replenishing C7 in androgen-sensitive Pten-Kras tumors during androgen depletion only slightly enhances cellular apoptosis, highlighting the diverse mechanisms employed by tumors to counteract complement activity. Collectively, our research indicates that augmenting complement activity could be a promising therapeutic approach to impede the development of castration resistance in prostate cancer.

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Fig. 1: C7 is expressed by stromal cells in mouse and human prostates.
Fig. 2: Stromal C7 expression inversely correlates with prostate cancer progression.
Fig. 3: C7 is regulated by androgen receptor signaling.
Fig. 4: C7 suppresses prostate tumor growth in vivo.
Fig. 5: C7 haploinsufficiency promotes tumor growth in TRAMP model.
Fig. 6: Restoring C7 expression enhances the response of Pten-Kras to androgen deprivation.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We thank the patients and their families for supporting this research, Brenda Nghiem and Lori Kollath for sample identification and processing, and Dr. Xiaomu Zhang for maintaining the C7 mice. This work is supported by W81XWH-20-1-0218 (L.X.), R01CA190378 (L.X.), the Pritt Family Endowment, P50CA97186, P01CA163227, and the Institute for Prostate Cancer Research (IPCR).

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DoD, NCI.

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Author notes

  1. These authors contributed equally: Zhicheng Zhou, Deyong Jia.

Authors and Affiliations

  1. Department of Urology, University of Washington, Seattle, WA, USA

    Zhicheng Zhou, Deyong Jia, Ohjoon Kwon, Martine P. Roudier, Daniel W. Lin, Colm Morrissey & Li Xin

  2. Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Shan Li, Huiyun Sun & John K. Lee

  3. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA

    Lawrence True

  4. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Chad J. Creighton

  5. Institute of Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA

    Li Xin

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Contributions

Conceptualization, LX and ZZ; Investigation, ZZ, DJ, OK, SL, HS, and MR; Formal analysis: ZZ, MR, CJC, and LX; Writing, LX, CJC, and ZZ; Resources, DL, LT, and CM; Funding Acquisition, LX and JKL; Supervision, LX and JKL.

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Correspondence to Li Xin.

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Zhou, Z., Jia, D., Kwon, O. et al. Androgen-regulated stromal complement component 7 (C7) suppresses prostate cancer growth. Oncogene 42, 2428–2438 (2023). https://doi.org/10.1038/s41388-023-02759-7

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