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ERBB3-induced furin promotes the progression and metastasis of ovarian cancer via the IGF1R/STAT3 signaling axis

Oncogene volume 39, pages 2921–2933 (2020)Cite this article

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Abstract

High-grade serous carcinoma, accounts for up to 70% of all ovarian cases. Furin, a proprotein convertase, is highly expressed in high-grade serous carcinoma of ovarian cancer patients, and its expression is even higher in tumor omentum than in normal omentum, the preferred site of ovarian cancer metastasis. The proteolytic actions of this cellular endoprotease help the maturation of several important precursors of protein substrates and its levels increase the risk of several cancer. We show that furin activates the IGF1R/STAT3 signaling axis in ovarian cancer cells. Conversely, furin knockdown downregulated IGF1R-β and p-STAT3 (Tyr705) expression. Further, silencing furin reduced tumor cell migration and invasion in vitro and tumor growth and metastasis in vivo. Collectively, our findings show that furin can be an effective therapeutic target for ovarian cancer prevention or treatment.

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Fig. 1: Furin was regulated by NRG1 stimulation through ERBB receptors.
Fig. 2: Furin is highly expressed in ovarian cancer patients.
Fig. 3: Cell migration, cell invasion, and spheroid formation were reduced by furin knockdown.
Fig. 4: IGF1R-β was downregulated by furin knockdown.
Fig. 5: p-STAT3 (Tyr705) was reduced by furin knockdown.
Fig. 6: Knockdown of furin reduces tumor growth in vivo.

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Acknowledgements

SP is supported by the Ovarian Cancer Research Fund Alliance (OCRFA) and by research funds from the Women’s Health Research Program (WHRP) in the Department of Obstetrics and Gynecology at the Medical College of Wisconsin (MCW). PCR is supported by the 1R01CA229907, OCRFA, and WHRP as well as by the DoD Breast Cancer Research Program (W81XWH-18-1-0024). RR is supported by Children’s Research Institute, Department of Pediatrics, Department of OBGYN and funds from NIH grants. Authors acknowledge Dr Anil Sood for providing tissue slides collected from the nude mice, treated with NRG1 siRNA-encapsulated nanoparticle.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Changliang Chen, Prachi Gupta, Deepak Parashar, Gopakumar G. Nair, Jasmine George, Anjali Geethadevi, Shirng-Wern Tsaih, William Bradley, Ramani Ramchandran, Janet S. Rader, Pradeep Chaluvally-Raghavan & Sunila Pradeep

  2. Metrohealth Medical Research Center, Case Western Reserve University, Cleveland, OH, USA

    Wei Wang

  3. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Ramani Ramchandran

  4. Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Janet S. Rader, Pradeep Chaluvally-Raghavan & Sunila Pradeep

  5. Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Pradeep Chaluvally-Raghavan & Sunila Pradeep

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  1. Changliang Chen
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Chen, C., Gupta, P., Parashar, D. et al. ERBB3-induced furin promotes the progression and metastasis of ovarian cancer via the IGF1R/STAT3 signaling axis. Oncogene 39, 2921–2933 (2020). https://doi.org/10.1038/s41388-020-1194-7

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