Article| Volume 46, ISSUE 3, P425-435, March 2023

Progranulin promotes proliferation, migration and invasion via the PI3K/Akt signalling pathway in a model of endometriosis

Published:November 17, 2022DOI:


      • High-purity primary eutopic endometrial stromal cells were successfully isolated
      • The levels of PGRN expression were significantly elevated in endometriosis tissue samples
      • PGRN promoted the proliferation, migration and invasion of endometrial stromal cells
      • These effects are achieved via the PI3K/Akt signalling pathway


      Research question

      What are the levels of progranulin (PGRN) expression in primary endometrial stromal cells (ESC) and endometrial tissue in patients with endometriosis (EMS)? What is the role and mechanism of action of PGRN in EMS?


      Endometrial tissue was collected from 30 patients, 15 with EMS (EMS group) and 15 without EMS (non-EMS group). PGRN expression in endometrial tissue and ESC was analysed by immunohistochemistry, immunofluorescence, western blotting and quantitative reverse transcription polymerase chain reaction. PGRN overexpression and silencing ESC were established with lentivirus to detect the effect on proliferation, invasion and migration. The relationship between PGRN and the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signalling pathway was verified by western blotting. A rescue assay was performed with PI3K inhibitor treatment.


      The PGRN expression was significantly higher in EMS samples. PGRN up-regulation promoted proliferation (P = 0.007), migration (P = 0.002) and invasion (P < 0.001) of eutopic endometrial stromal cells (EUESC). The ratio of p-AKT/AKT was higher in the overexpression PGRN (ovPGRN) group than in the overexpression-NC (ovNC) group (P = 0.004). Silencing PGRN produced the opposite results, and LY2940002 addition reversed the effect of PGRN up-regulation on the proliferation, invasion and migration of EUESC.


      PGRN might promote the proliferation, invasion and migration of EUESC via the PI3K/Akt signalling pathway. These preliminary in-vitro findings may present a new perspective and inspire further study of the mechanism of EMS.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Reproductive BioMedicine Online
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Becker C.M.
        • Bokor A.
        • Heikinheimo O.
        • Horne A.
        • Jansen F.
        • Kiesel L.
        • King K.
        • Kvaskoff M.
        • Nap A.
        • Petersen K.
        • Saridogan E.
        • Tomassetti C.
        • van Hanegem N.
        • Vulliemoz N.
        • Vermeulen N.
        ESHRE Endometriosis Guideline Group. ESHRE guideline: endometriosis.
        Hum. Reprod. Open. 2022; 2022: hoac009
        • Brown J.
        • Farquhar C.
        Endometriosis: an overview of Cochrane Reviews.
        Cochrane Database Syst. Rev. 2014; 2014Cd009590
        • Cao Y.
        • Ye Q.
        • Zhuang M.
        • Xie S.
        • Zhong R.
        • Cui J.
        • Zhou J.
        • Zhu Y.
        • Zhang T.
        • Cao L.
        Ginsenoside Rg3 inhibits angiogenesis in a rat model of endometriosis through the VEGFR-2-mediated PI3K/Akt/mTOR signaling pathway.
        PLoS One. 2017; 12e0186520
        • Clement P.B.
        The pathology of endometriosis: a survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects.
        Adv. Anat. Pathol. 2007; 14: 241-260
        • Daniel R.
        • He Z.
        • Carmichael K.P.
        • Halper J.
        • Bateman A.
        Cellular localization of gene expression for progranulin.
        J. Histochem Cytochem. 2000; 48: 999-1009
        • Diao R.
        • Wei W.
        • Zhao J.
        • Tian F.
        • Cai X.
        • Duan Y.G.
        CCL19/CCR7 contributes to the pathogenesis of endometriosis via PI3K/Akt pathway by regulating the proliferation and invasion of ESCs.
        Am. J. Reprod. Immunol. 2017; 78
        • Dong D.
        • Zhang W.
        • Xiao W.
        • Wu Q.
        • Cao Y.
        • Gao X.
        • Huang L.
        • Wang Y.
        • Chen J.
        • Wang W.
        • Zhan Q.
        A GRN autocrine-dependent FAM135B/AKT/mTOR feedforward loop promotes esophageal squamous cell carcinoma progression.
        Cancer Res. 2021; 81: 910-922
        • Dong T.
        • Yang D.
        • Li R.
        • Zhang L.
        • Zhao H.
        • Shen Y.
        • Zhang X.
        • Kong B.
        • Wang L.
        PGRN promotes migration and invasion of epithelial ovarian cancer cells through an epithelial mesenchymal transition program and the activation of cancer associated fibroblasts.
        Exp. Mol. Pathol. 2016; 100: 17-25
        • Fang W.
        • Zhou T.
        • Shi H.
        • Yao M.
        • Zhang D.
        • Qian H.
        • Zeng Q.
        • Wang Y.
        • Jin F.
        • Chai C.
        • Chen T.
        Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8+ T cell exclusion.
        J. Exp. Clin. Cancer Res. 2021; 40: 4
        • Feng T.
        • Zheng L.
        • Liu F.
        • Xu X.
        • Mao S.
        • Wang X.
        • Liu J.
        • Lu Y.
        • Zhao W.
        • Yu X.
        • Tang W.
        Growth factor progranulin promotes tumorigenesis of cervical cancer via PI3K/Akt/mTOR signaling pathway.
        Oncotarget. 2016; 7: 58381-58395
        • Gonçalves G.A.
        • Camargo-Kosugi C.M.
        • Bonetti T.C.
        • Invitti A.L.
        • Girão M.J.
        • Silva I.D.
        • Schor E.
        p27kip1 overexpression regulates VEGF expression, cell proliferation and apoptosis in cell culture from eutopic endometrium of women with endometriosis.
        Apoptosis. 2015; 20: 327-335
        • Guha R.
        • Yue B.
        • Dong J.
        • Banerjee A.
        • Serrero G.
        Anti-progranulin/GP88 antibody AG01 inhibits triple negative breast cancer cell proliferation and migration.
        Breast Cancer Res. Treat. 2021; 186: 637-653
        • Holzer I.
        • Machado Weber A.
        • Marshall A.
        • Freis A.
        • Jauckus J.
        • Strowitzki T.
        • Germeyer A.
        GRN, NOTCH3, FN1, and PINK1 expression in eutopic endometrium – potential biomarkers in the detection of endometriosis – a pilot study.
        J. Assist. Reprod. Genet. 2020; 37: 2723-2732
        • Hung S.W.
        • Zhang R.
        • Tan Z.
        • Chung J.P.W.
        • Zhang T.
        • Wang C.C.
        Pharmaceuticals targeting signaling pathways of endometriosis as a potential new medical treatment: a review.
        Med. Res. Rev. 2021; 41: 2489-2564
        • Laganà A.S.
        • Garzon S.
        • Götte M.
        • Viganò P.
        • Franchi M.
        • Ghezzi F.
        • Martin D.C.
        The pathogenesis of endometriosis: molecular and cell biology insights.
        Int. J. Mol. Sci. 2019; 20: 5615
        • Lang J.H.
        History, current situation and development of understanding of endometriosis.
        Chin. J. Pract. Gynecol. Obstet. 2020; 36: 193-196
        • Liu Y.
        • Qin X.
        • Lu X.
        • Jiang J.
        Effects of inhibiting the PI3K/Akt/mTOR signaling pathway on the pain of sciatic endometriosis in a rat model.
        Can. J. Physiol. Pharmacol. 2019; 97: 963-970
        • Ma T.
        • Liu P.
        • Wei J.
        • Zhao M.
        • Yao X.
        • Luo X.
        • Xu S.
        Imperatorin alleviated endometriosis by inhibiting the activation of PI3K/Akt/NF-κB pathway in rats.
        Life Sci. 2021; 274119291
        • Madanes D.
        • Bilotas M.A.
        • Bastón J.I.
        • Singla J.J.
        • Meresman G.F.
        • Barañao R.I.
        • Ricci A.G.
        PI3K/AKT pathway is altered in the endometriosis patient's endometrium and presents differences according to severity stage.
        Gynecol. Endocrinol. 2020; 36: 436-440
        • Ornek T.
        • Fadiel A.
        • Tan O.
        • Naftolin F.
        • Arici A.
        Regulation and activation of ezrin protein in endometriosis.
        Hum. Reprod. 2008; 23: 2104-2112
        • Romano A.
        • Xanthoulea S.
        • Giacomini E.
        • Delvoux B.
        • Alleva E.
        • Vigano P.
        Endometriotic cell culture contamination and authenticity: a source of bias in in vitro research?.
        Hum. Reprod. 2020; 35: 364-376
        • Sampson J.A.
        Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation.
        Am. J. Pathol. 1927; 3 (93–110.43)
        • Xu Z.
        • Zhang L.
        • Yu Q.
        • Zhang Y.
        • Yan L.
        • Chen Z.J.
        The estrogen-regulated lncRNA H19/miR-216a-5p axis alters stromal cell invasion and migration via ACTA2 in endometriosis.
        Mol. Hum. Reprod. 2019; 25: 550-561
        • Yip C.W.
        • Lam C.Y.
        • Poon T.C.W.
        • Cheung T.T.
        • Cheung P.F.Y.
        • Fung S.W.
        • Wang X.Q.
        • Leung I.C.Y.
        • Ng L.W.C.
        • Lo C.M.
        • Tsao G.S.W.
        • Cheung S.T.
        Granulin-epithelin precursor interacts with 78-kDa glucose-regulated protein in hepatocellular carcinoma.
        BMC Cancer. 2017; 17: 409
        • Yotova I.
        • Quan P.
        • Gaba A.
        • Leditznig N.
        • Pateisky P.
        • Kurz C.
        • Tschugguel W.
        Raf-1 levels determine the migration rate of primary endometrial stromal cells of patients with endometriosis.
        J. Cell. Mol. Med. 2012; 16: 2127-2139
        • Zeitvogel A.
        • Baumann R.
        • Starzinski-Powitz A.
        Identification of an invasive, N-cadherin-expressing epithelial cell type in endometriosis using a new cell culture model.
        Am. J. Pathol. 2001; 159: 1839-1852
        • Zhan H.
        • Ma J.
        • Ruan F.
        • Bedaiwy M.A.
        • Peng B.
        • Wu R.
        • Lin J.
        Elevated phosphatase of regenerating liver 3 (PRL-3) promotes cytoskeleton reorganization, cell migration and invasion in endometrial stromal cells from endometrioma.
        Hum. Reprod. 2016; 31: 723-733
        • Zhou C.
        • Huang Y.
        • Wu J.
        • Wei Y.
        • Chen X.
        • Lin Z.
        • Nie S.
        A narrative review of multiple mechanisms of progranulin in cancer: a potential target for anti-cancer therapy.
        Transl. Cancer Res. 2021; 10: 4207-4216


      Aiping Qin, PhD, is a gynaecologist subspecializing in reproductive medicine. She is a member of the Reproductive Medicine Branch of the Chinese Medical Association. Her research interests include fertility protection and abnormal endometrial receptivity. She has published more than 50 articles.
      Key message
      The role and mechanism of PGRN in endometriosis is unclear. The results of this study suggest that PGRN is highly expressed in the eutopic endometrium of endometriosis patients and that up-regulation of PGRN may promote proliferation, invasion and migration of EUESC, which may be achieved through the PI3K/Akt signalling pathway.