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Heparanase interacting BCLAF1 to promote the development and drug resistance of ICC through the PERK/eIF2α pathway

Cancer Gene Therapy (2024)Cite this article

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Abstract

Intrahepatic cholangiocarcinoma (ICC) is a primary epithelial carcinoma known for its aggressive nature, high metastatic potential, frequent recurrence, and poor prognosis. Heparanase (HPSE) is the only known endogenous β-glucuronidase in mammals. In addition to its well-established enzymatic roles, HPSE critically exerts non-catalytic function in tumor biology. This study herein aimed to investigate the non-enzymatic roles of HPSE as well as relevant regulatory mechanisms in ICC. Our results demonstrated that HPSE was highly expressed in ICC and promoted the proliferation of ICC cells, with elevated HPSE levels implicating a poor overall survival of ICC patients. Notably, HPSE interacted with Bcl-2-associated factor 1 (BCLAF1) to upregulate the expression of Bcl-2, which subsequently activated the PERK/eIF2α-mediated endoplasmic reticulum (ER) stress pathway to promote anti-apoptotic effect of ICC. Moreover, our in vivo experiments revealed that concomitant administration of gemcitabine and the Bcl-2 inhibitor navitoclax enhanced the sensitivity of ICC cells with highly expressed HPSE to chemotherapy. In summary, our findings revealed that HPSE promoted the development and drug resistance of ICC via its non-enzymatic function. Bcl-2 may be considered as an effective target with therapeutic potential to overcome ICC chemotherapy resistance induced by HPSE, presenting valuable insights into the development of novel therapeutic strategies against ICC.

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Fig. 1: Overexpression of HPSE in ICC.
Fig. 2: HPSE promoted ICC progression.
Fig. 3: HPSE activated the PERK/eIF2α pathway in ICC.
Fig. 4: The interaction between HPSE and BCLAF1 promoted the anti-apoptosis of ICC cells.
Fig. 5: Combined application of gemcitabine with Bcl-2 inhibitor navitoclax inhibited progression of ICC.
Fig. 6: HPSE is highly expressed in ICC and is positively associated with poor prognosis.

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Data availability

The data and materials that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The results shown in Fig. 1A are in part based on data generated by the TCGA Research Network (https://ualcan.path.uab.edu/). The results in Supplementary Fig. 1 were obtained from the R2 bioinformatics database (https://hgserver1.amc.nl).

Funding

This work was supported by Grants from the National Natural Science Foundation of China (81874193), the High-Level Talents Converging Program of Hunan Province (2019RS1041), Natural Science Foundation of Hunan Province (2021JJ30465), the Research Team for Reproduction Health and Translational Medicine of Hunan Normal University (2023JC101), and Developmental Biology and Breeding (2022XKQ0205).

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Authors and Affiliations

  1. Department of Basic Medical Sciences, School of Medicine, Hunan Normal University, Changsha, China

    Fengyan Yuan, Huiqin Zhou, Chongyang Liu, Yi Wang, Jing Quan, Jie Liu & Xing Yu

  2. Key Laboratory of Model Animals and Stem Cell Biology of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China

    Fengyan Yuan, Huiqin Zhou, Chongyang Liu, Yi Wang, Jing Quan, Jie Liu & Xing Yu

  3. Research Center of Reproduction and Translational Medicine of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China

    Fengyan Yuan, Huiqin Zhou, Chongyang Liu, Yi Wang, Jing Quan, Jie Liu & Xing Yu

  4. Biliary Tract Surgery Laboratory, Department of Hepatobiliary Surgery, Hunan Provincial People’s Hospital, the First Affiliated Hospital of Hunan Normal University, Changsha, China

    Hao Li

  5. Hunan Research Center of Biliary Disease, the First Affiliated Hospital of Hunan Normal University, Changsha, China

    Hao Li

  6. Key Laboratory of Biliary Disease Prevention and treatment, the First Affiliated Hospital of Hunan Normal University,, Changsha, China

    Hao Li

  7. Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, QLD, Australia

    Mark von Itzstein

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Contributions

XY, HL, and MvI conceived and designed the study. Data acquisition was performed by FY, HZ, CL, YW, JQ, and JL, and all authors contributed to data interpretation. FY wrote the first draft and XY, HL, and MvI critically revised the manuscript for important intellectual contents. All authors revised further drafts and approved the submission.

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Correspondence to Hao Li, Mark von Itzstein or Xing Yu.

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Animal Studies: All animal care and experimental protocols were approved by the Ethics Committee of Hunan Normal University (D2020281).

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Yuan, F., Zhou, H., Liu, C. et al. Heparanase interacting BCLAF1 to promote the development and drug resistance of ICC through the PERK/eIF2α pathway. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00754-y

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