{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:14:50Z","timestamp":1787066090462,"version":"build-2736575974"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014220","name":"National Natural Science Foundation of China-Henan Joint Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014220","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014220","name":"National Natural Science Foundation of China-Henan Joint Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014220","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Adenomyosis (AM) is a disease in which endometrial tissue invades the myometrium and has a 10\u201360% prevalence in reproductive-aged women. TSC2 regulates autophagy\n                    <jats:italic>via<\/jats:italic>\n                    mTOR1 signalling in colorectal cancer and endometrial carcinoma. Dysregulation of autophagy is implicated in adenomyosis pathogenesis. However, whether TSC2 participates in adenomyosis\n                    <jats:italic>via<\/jats:italic>\n                    autophagy remains obscure. Here, we found that the expression of TSC2 in adenomyosis was significantly decreased than that in normal endometrium during the secretory phase. Moreover, TSC2 and autophagy marker expression was significantly lower in ectopic lesions than in eutopic samples. TSC2 downregulation inhibited autophagy through mTOR1 signalling pathway activation in endometrial cells, leading to excessive proliferation, migration, and EMT; TSC2 overexpression induced the opposite effects. Rapamycin treatment suppressed cell proliferation, migration and EMT in the absence of TSC2. In parallel, an autophagy-specific inhibitor (SAR-405) restored migration and EMT under rapamycin treatment in TSC2-knockdown Ishikawa cells. Finally, SAR-405 treatment promoted EMT and migration of overexpressing cells. Collectively, our results suggest that TSC2 controls endometrial epithelial cell migration and EMT by regulating mTOR1-autophagy axis activation and that hypo-expression of TSC2 in the endometrium might promote adenomyosis.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2021.710407","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T04:30:57Z","timestamp":1627533057000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Hypo-Expression of Tuberin Promotes Adenomyosis via the mTOR1-Autophagy Axis"],"prefix":"10.3389","volume":"9","author":[{"given":"Ni-Hao","family":"Gu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing-Xin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1093\/molehr\/gap092","article-title":"Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles.","volume":"15","author":"Adhikari","year":"2009","journal-title":"Mol. Hum. Reprod."},{"key":"B2","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.mce.2011.10.035","article-title":"Mechanisms of endometrial progesterone resistance.","volume":"358","author":"Al-Sabbagh","year":"2012","journal-title":"Mol. Cell Endocrinol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1093\/humupd\/dmz049","article-title":"Diagnosing adenomyosis: an integrated clinical and imaging approach.","volume":"26","author":"Chapron","year":"2020","journal-title":"Hum. Reprod. Update"},{"key":"B4","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1002\/path.2761","article-title":"Oestrogen-induced epithelial-mesenchymal transition of endometrial epithelial cells contributes to the development of adenomyosis.","volume":"222","author":"Chen","year":"2010","journal-title":"J. Pathol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1093\/molehr\/gat091","article-title":"Differential induction of autophagy by mTOR is associated with abnormal apoptosis in ovarian endometriotic cysts.","volume":"20","author":"Choi","year":"2014","journal-title":"Mol. Hum. Reprod."},{"key":"B6","doi-asserted-by":"crossref","DOI":"10.1095\/biolreprod.111.096206","article-title":"The role of autophagy in human endometrium.","volume":"86","author":"Choi","year":"2012","journal-title":"Biol. Reprod."},{"key":"B7","first-page":"99","article-title":"Hereditary renal adenomas and adenocarcinomas in rats.","volume":"4","author":"Eker","year":"1981","journal-title":"Diagn. Histopathol."},{"key":"B8","doi-asserted-by":"crossref","DOI":"10.1186\/s12958-019-0510-y","article-title":"Comparative analysis of mammalian sperm ultrastructure reveals relationships between sperm morphology, mitochondrial functions and motility.","volume":"17","author":"Gu","year":"2019","journal-title":"Reprod. Biol. Endocrinol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1038\/onc.2016.237","article-title":"Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy.","volume":"36","author":"Gugnoni","year":"2017","journal-title":"Oncogene"},{"key":"B10","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1093\/humrep\/dey022","article-title":"Decreased PECAM1-mediated TGF-beta1 expression in the mid-secretory endometrium in women with recurrent implantation failure.","volume":"33","author":"Guo","year":"2018","journal-title":"Hum. Reprod."},{"key":"B11","doi-asserted-by":"crossref","DOI":"10.1038\/nrdp.2016.35","article-title":"Tuberous sclerosis complex.","volume":"2","author":"Henske","year":"2016","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B12","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1007\/s43032-019-00035-2","article-title":"High-expression of neuropilin 1 correlates to estrogen-induced epithelial-mesenchymal transition of endometrial cells in adenomyosis.","volume":"27","author":"Hu","year":"2020","journal-title":"Reprod. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"7438","DOI":"10.1073\/pnas.0605874104","article-title":"Akt1 governs breast cancer progression in vivo.","volume":"104","author":"Ju","year":"2007","journal-title":"Proc.Natl. Acad. Sci. U.S.A."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1093\/molehr\/gau077","article-title":"Hyperplasia and fibrosis in mice with conditional loss of the TSC2 tumor suppressor in mullerian duct mesenchyme-derived myometria.","volume":"20","author":"Kaneko-Tarui","year":"2014","journal-title":"Mol. Hum. Reprod."},{"key":"B15","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1172\/jci73939","article-title":"mTOR: a pharmacologic target for autophagy regulation.","volume":"125","author":"Kim","year":"2015","journal-title":"J. Clin. Investig."},{"key":"B16","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1056\/nejmcibr1406613","article-title":"Molecular basis of giant cells in tuberous sclerosis complex.","volume":"371","author":"Kwiatkowski","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2725","DOI":"10.1093\/humrep\/17.10.2725","article-title":"Endometriosis results from the dislocation of basal endometrium.","volume":"17","author":"Leyendecker","year":"2002","journal-title":"Hum. Reprod."},{"key":"B18","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.cmet.2014.01.001","article-title":"Rapamycin: one drug, many effects.","volume":"19","author":"Li","year":"2014","journal-title":"Cell Metab."},{"key":"B19","doi-asserted-by":"publisher","first-page":"286","DOI":"10.2174\/1566523218666181008155039","article-title":"An observation of the role of autophagy in patients with endometriosis of different stages during secretory phase and proliferative phase.","volume":"18","author":"Li","year":"2018","journal-title":"Curr. Gene Ther."},{"key":"B20","article-title":"The novel testicular enrichment protein Cfap58 is required for Notch-associated ciliogenesis.","volume":"40","author":"Li","year":"2020","journal-title":"Biosci. Rep."},{"key":"B21","doi-asserted-by":"crossref","DOI":"10.1016\/j.jri.2020.103120","article-title":"Activating transcription factor 6 regulated cell growth, migration and inhibiteds cell apoptosis and autophagy via MAPK pathway in cervical cancer.","volume":"139","author":"Liu","year":"2020","journal-title":"J. Reprod. Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"2865","DOI":"10.2147\/ott.s95267","article-title":"PI3K\/AKT\/mTOR pathway promotes progestin resistance in endometrial cancer cells by inhibition of autophagy.","volume":"10","author":"Liu","year":"2017","journal-title":"Oncol. Targets Ther."},{"key":"B23","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/978-3-642-18930-2_8","article-title":"TOR action in mammalian cells and in Caenorhabditis elegans.","volume":"279","author":"Long","year":"2004","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2543","DOI":"10.1158\/1078-0432.ccr-07-0321","article-title":"Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma.","volume":"14","author":"Lu","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/s1097-2765(02)00568-3","article-title":"Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase\/akt pathway.","volume":"10","author":"Manning","year":"2002","journal-title":"Mol. Cell"},{"key":"B26","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1016\/0002-9378(78)90119-9","article-title":"Menstruation in intraocular endometrial transplants in the Rhesus monkey.","volume":"131","author":"Markee","year":"1978","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1093\/humupd\/dmv060","article-title":"Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics.","volume":"22","author":"McKinnon","year":"2016","journal-title":"Hum. Reprod. Update"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1677","DOI":"10.1093\/humrep\/dev100","article-title":"Estrogen promotes the survival of human secretory phase endometrial stromal cells via CXCL12\/CXCR4 up-regulation-mediated autophagy inhibition.","volume":"30","author":"Mei","year":"2015","journal-title":"Hum. Reprod."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1038\/nature06639","article-title":"Autophagy fights disease through cellular self-digestion.","volume":"451","author":"Mizushima","year":"2008","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1002\/path.4224","article-title":"beta-Catenin activation contributes to the pathogenesis of adenomyosis through epithelial-mesenchymal transition.","volume":"231","author":"Oh","year":"2013","journal-title":"J. Pathol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2019.04.012","article-title":"Increased expression of YAP is associated with decreased cell autophagy in the eutopic endometrial stromal cells of endometriosis.","volume":"491","author":"Pei","year":"2019","journal-title":"Mol. Cell Endocrinol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1210\/me.2013-1059","article-title":"Uterine-specific loss of Tsc2 leads to myometrial tumors in both the uterus and lungs.","volume":"27","author":"Prizant","year":"2013","journal-title":"Mol. Endocrinol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.tem.2009.10.001","article-title":"Mechanisms maintaining the dormancy and survival of mammalian primordial follicles.","volume":"21","author":"Reddy","year":"2010","journal-title":"Trends Endocrinol. Metab."},{"key":"B34","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1007\/s00404-009-1280-0","article-title":"Decreased expression of Beclin 1 in eutopic endometrium of women with adenomyosis.","volume":"282","author":"Ren","year":"2010","journal-title":"Arch. Gynecol. Obstet."},{"key":"B35","doi-asserted-by":"crossref","DOI":"10.1038\/cddis.2015.361","article-title":"Effect of hydroxychloroquine and characterization of autophagy in a mouse model of endometriosis.","volume":"7","author":"Ruiz","year":"2016","journal-title":"Cell Death Dis."},{"key":"B36","doi-asserted-by":"publisher","first-page":"6112","DOI":"10.1210\/jc.2004-0892","article-title":"Prostaglandin E2 mediates phosphorylation and down-regulation of the tuberous sclerosis-2 tumor suppressor (tuberin) in human endometrial adenocarcinoma cells via the Akt signaling pathway.","volume":"89","author":"Sales","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B37","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.rbmo.2017.06.016","article-title":"Pathogenesis of adenomyosis: an update on molecular mechanisms.","volume":"35","author":"Vannuccini","year":"2017","journal-title":"Reprod. Biomed. Online"},{"key":"B38","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1093\/humrep\/deu041","article-title":"Uterine adenomyosis and in vitro fertilization outcome: a systematic review and meta-analysis.","volume":"29","author":"Vercellini","year":"2014","journal-title":"Hum. Reprod."},{"key":"B39","doi-asserted-by":"crossref","DOI":"10.1007\/s43032-021-00513-6","article-title":"Immunoreactivity of plasminogen activator inhibitor 1 and its correlation with dysmenorrhea and lesional fibrosis in adenomyosis.","author":"Yang","year":"2021","journal-title":"Reprod. Sci."},{"key":"B40","doi-asserted-by":"crossref","DOI":"10.1186\/s13046-020-01696-7","article-title":"NUCKS promotes cell proliferation and suppresses autophagy through the mTOR-Beclin1 pathway in gastric cancer.","volume":"39","author":"Zhao","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1111\/jcmm.13457","article-title":"Outer dense fibers stabilize the axoneme to maintain sperm motility.","volume":"22","author":"Zhao","year":"2018","journal-title":"J. Cell Mol. Med."},{"key":"B42","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1016\/j.bbrc.2018.01.184","article-title":"ILK-induced epithelial-mesenchymal transition promotes the invasive phenotype in adenomyosis.","volume":"497","author":"Zhou","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."}],"container-title":["Frontiers in Cell and Developmental Biology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.710407\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T04:31:09Z","timestamp":1627533069000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcell.2021.710407\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,29]]},"references-count":42,"alternative-id":["10.3389\/fcell.2021.710407"],"URL":"https:\/\/doi.org\/10.3389\/fcell.2021.710407","relation":{},"ISSN":["2296-634X"],"issn-type":[{"value":"2296-634X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,29]]},"article-number":"710407"}}