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P-element-Induced Wimpy-Testis-Like Protein 1 Regulates the Activation of Pancreatic Stellate Cells Through the PI3K/AKT/mTOR Signaling Pathway

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Abstract

Aim

Pancreatic fibrosis is the main pathological characteristic of chronic pancreatitis (CP) and pancreatic cancer. Pancreatic stellate cells (PSCs) play a critical role in pancreatic fibrosis. Any targets that may have an impact on the activation of PSCs could become potential treatment candidates for CP and pancreatic cancer. Our goal was to investigate the effect of P-element-induced wimpy-testis (PIWI) protein 1 (PIWIL1) on PSC activation.

Methods

Lentivirus-based RNA interference (RNAi) and overexpression vector construction were used to knock down and over-express the PIWIL1 protein. Immunocytofluorescent staining, western blotting, wound healing assay, transwell assay, and phalloidin staining were used to investigate the effects of PIWIL1 on the secretion of extracellular matrix components (EMC), actin cytoskeleton, and on the invasion and migration abilities of primary PSCs isolated from C57BL/6 mice. Moreover, pancreatic fibrosis was induced by l-arginine in C57BL/6 mice. The expression of PIWIL1 and collagen deposition in vivo were tested by western blotting and Sirius red staining.

Results

Expression levels of collagen I, collagen III, and α-smooth muscle actin were significantly decreased in the LV-PIWIL1 group. Compared with the si-PIWIL1 group, significant differences were observed in the expression of desmin, p-PI3K, p-AKT, and p-mTOR in the LV-PIWIL1 group. Furthermore, PIWIL1 suppressed the PSCs’ invasion and migration abilities. In a rescue experiment, the PI3K/AKT/mTOR signaling pathway was found to be the underlying mechanism in PSCs activation mediated by PIWIL1.

Conclusions

Our findings suggest that PIWIL1 inhibits the activation of PSCs via the PI3K/AKT/mTOR signaling pathway. PIWIL1 is a potential therapeutic target for pancreatic fibrosis.

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Funding

The study was supported by the Fund for Fostering Young Scholars of Peking University Health Science Center (BMU2021PY010), National Natural Science Foundation of China (No. 82002461), and Medjaden Academy and Research Foundation for Young Scientists (MJR20211110).

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Author notes

  1. Ran Xue, Jun Zhou have contributed to this work equally.

Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Center, Peking University Cancer Hospital & Institute, Fucheng Road 52, Haidian District, 100142, Beijing, China

    Ran Xue, Jifang Gong & Lin Shen

  2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Fucheng Road 52, Haidian District, Beijing, 100142, China

    Jun Zhou, Jifang Gong & Lin Shen

  3. Department of Medical Oncology, Beijing You-An Hospital, Capital Medical University, Beijing, 100069, China

    Jing Wu & Qinghua Meng

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  1. Ran Xue
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  2. Jun Zhou
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  3. Jing Wu
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  4. Qinghua Meng
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Correspondence to Ran Xue.

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Xue, R., Zhou, J., Wu, J. et al. P-element-Induced Wimpy-Testis-Like Protein 1 Regulates the Activation of Pancreatic Stellate Cells Through the PI3K/AKT/mTOR Signaling Pathway. Dig Dis Sci 68, 1339–1350 (2023). https://doi.org/10.1007/s10620-022-07605-6

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  • DOI: https://doi.org/10.1007/s10620-022-07605-6

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