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Pancreatic neuroendocrine tumor progression and resistance to everolimus: the crucial role of NF-kB and STAT3 interplay

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Abstract

Purpose

The finding of mTOR overactivation in patients affected by pancreatic neuroendocrine tumors (Pa-NETs) led to their treatment with the mTOR inhibitor everolimus. Unfortunately, the efficacy of everolimus is restricted by the occurrence of resistance. The mechanisms leading to Pa-NETs’ progression and resistance are not well understood. Notably, chronic inflammation is implicated in NET development. NF-kB is involved in inflammation and drug resistance mechanisms through the activation of several mediators, including STAT3. In this respect, NF-κB and STAT3 interaction is implicated in the crosstalk between inflammatory and tumor cells.

Methods

We investigated the expression of NF-kB in different Pa-NETs by RT-qPCR and immunohistochemistry. Then, we studied the role of NF-κB and STAT3 interplay in QGP-1 cells. Subsequently, we assessed the impact of NF-κB and STAT3 inhibitors in QGP-1 cell proliferation and spheroids growth. Finally, we evaluated the implication of the NF-kB pathway in everolimus-resistant Pa-NET cells.

Results

We found that the increased NF-kB expression correlates  with a higher grade in Pa-NETs. The activation of the STAT3 pathway induced by TNFα is mediated by NF-kB p65. NF-kB p65 and STAT3 inhibitors decrease QGP-1 viability, spheroids growth, and Pa-NETs cell proliferation. These effects are maintained in everolimus-resistant QGP-1R cells. Interestingly, we found that NF-kB, STAT3, IL-8, and SOCS3 are overexpressed in QGP-1R compared to QGP-1.

Conclusion

Since the NF-kB pathway is implicated in Pa-NETs’ progression and resistance to everolimus, these data could explain the potential use of NF-kB as a novel therapeutic target in Pa-NET patients.

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Data availability

The data that support the findings of this study are available upon reasonable request in Zenodo repository (https://zenodo.org/deposit/8411582).

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Funding

This work has been supported by PRIN 2022CZR88M and P20227KXJK.

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Authors and Affiliations

  1. Laboratory of Cellular and Molecular Endocrinology, IRCCS Humanitas Research Hospital, Manzoni 56, 20089, Rozzano, Milan, Italy

    E. Vitali, G. Valente & A. Panzardi

  2. Oncology Unit, IRCCS Humanitas Research Hospital, Manzoni 56, 20089, Rozzano, Milan, Italy

    A. Laffi

  3. Department of Biomedical Sciences, Humanitas University, Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy

    A. Zerbi, S. Uccella, G. Mazziotti & A. Lania

  4. Surgery Unit, IRCCS Humanitas Research Hospital, Manzoni 56, 20089, Rozzano, Milan, Italy

    A. Zerbi

  5. Pathology Unit, IRCCS Humanitas Research Hospital, Manzoni 56, 20089, Rozzano, ilan, Italy

    S. Uccella

  6. Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Manzoni 54, 20089, Rozzano, Milan, Italy

    G. Mazziotti & A. Lania

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  1. E. Vitali
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Correspondence to E. Vitali.

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Vitali, E., Valente, G., Panzardi, A. et al. Pancreatic neuroendocrine tumor progression and resistance to everolimus: the crucial role of NF-kB and STAT3 interplay. J Endocrinol Invest 47, 1101–1117 (2024). https://doi.org/10.1007/s40618-023-02221-1

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