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C1QBP forms a positive feedback loop with the PAICS/FAK/C-MYC axis to promote cancer cell proliferation

Oncogene volume 44, pages 4363–4376 (2025)Cite this article

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Abstract

The cell membrane, as the boundary of the cellular system, plays an extremely important role in the regulation of cellular metabolism, substance transport, information exchange and cellular immunity. Complement component 1q subcomponent binding protein (C1QBP) is a ubiquitously expressed cellular protein, and although multiple studies have suggested that C1QBP may play an important role in cancer, the functions and mechanisms of C1QBP in the progression of many tumors remain unknown. We performed bioinformatics analysis and found that C1QBP was significantly overexpressed in a variety of tumor tissues and that high C1QBP expression correlates strongly with poor prognosis in tumor patients. Further validation in cholangiocarcinoma(CCA) revealed that C1QBP is the most upregulated membrane protein in CCA, where it is involved in energy metabolism, DNA repair, and tolerance to platinum-based chemotherapeutic agents. It also correlates strongly with CCA proliferation and poor prognosis, while silencing of C1QBP significantly inhibits CCA growth in mice. Mechanistic studies further demonstrated that c-MYC can upregulate C1QBP expression at the transcriptional level, subsequently influencing PAICS/FAK expression and promoting CCA growth. Interestingly, C1QBP also regulates c-MYC expression by increasing FAK phosphorylation, establishing a positive feedback loop that drives tumor progression. Additionally, we developed a novel siRNA delivery system, HA gel-siC1QBP, by encapsulating siC1QBP within hyaluronic acid-dopamine hydrogel-coated liposomes. In vivo experiments confirmed its ability to provide prolonged and stable C1QBP inhibition along with enhanced antitumor efficacy. In conclusion, our study suggests that C1QBP may serve as a valuable biomarker for tumour prognosis and that silencing C1QBP using HA gel-siC1QBP —either alone or combined with targeted/ immunotherapies —represents a promising therapeutic strategy against tumors.

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Fig. 1: C1QBP is elevated in a variety of tumors and associated with poor prognosis.
Fig. 2: C1QBP is associated with poor prognosis in CCA.
Fig. 3: C1QBP promotes the proliferation of CCA cells.
Fig. 4: C1QBP is involved in energy metabolism, DNA repair, and platinum resistance in CCA.
Fig. 5: C1QBP promotes CCA progression by activating the PAICS/FAK signaling pathway.
Fig. 6: C-MYC upregulates C1QBP at the transcriptional level.
Fig. 7: C1QBP regulates c-MYC expression through FAK to form a positive feedback loop that promotes CCA cell proliferation.
Fig. 8: The synthesized HA gel-siC1QBP effectively targets C1QBP both in vivo.

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Data availability

The datasets analysed during the current study are available in the [GEO] repository.

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Acknowledgements

This study was supported by Natural Science Foundation of Hubei Province (Grants: 2023AFB1020(X.C.)). This study was supported by Natural Science Foundation of Hunan Province (Grant: 2023JJ60453 (B.T.)) and Hunan Provincial Health Commission Scientific Research Program (Grant :D202302085994 (B.T.)). This study was supported by National Natural Science Foundation of China (Grants: 82302971 (J.Z.)) and Hubei Provincial Natural Science Foundation of China(Grants: 2023AFB190 (J.Z.)). This study was supported by Natural Science Foundation of Hubei Province (Grants: 2024AFB667 (C.Z.)). This study was supported by National Natural Science Foundation of China (Grants: 81772800(P.L.) and 82072945(P.L.)).

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Author notes

  1. These authors contributed equally: Xiang Cheng, Mengmeng Wang.

Authors and Affiliations

  1. Cancer center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Xiang Cheng, Mengmeng Wang & Pian Liu

  2. Department of Digestive Surgical Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Xiang Cheng

  3. Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Mengmeng Wang & Pian Liu

  4. Hubei Key Laboratory of Precision Radiation Oncology, Hubei, 430022, China

    Mengmeng Wang & Pian Liu

  5. Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, 410011, China

    Wei Li

  6. Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, Changsha, Hunan Province, China

    Bingzhang Tian

  7. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Jing Zhang

  8. Liver Transplant Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Chen Zhang

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Contributions

XC: Methodology, Investigation. MW: Methodology, Investigation. WL:Methodology, Visualization. BT: Methodology, Visualization. JZ:Visualization, Conceptualization. CZ: Visualization, Conceptualization. PL: Project administration, Conceptualization, Investigation.

Corresponding authors

Correspondence to Jing Zhang, Chen Zhang or Pian Liu.

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The authors declare no competing interests.

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The study was conducted in accordance with the principles of the Declaration of Helsinki principles. It was approved by the Animal Use and Care Committees at the Second Xiangya hospital, Central South University (approval number 20241070). All subjects have written informed consent.

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Cheng, X., Wang, M., Li, W. et al. C1QBP forms a positive feedback loop with the PAICS/FAK/C-MYC axis to promote cancer cell proliferation. Oncogene 44, 4363–4376 (2025). https://doi.org/10.1038/s41388-025-03568-w

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