{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T12:40:39Z","timestamp":1777552839747,"version":"3.51.4"},"reference-count":31,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T00:00:00Z","timestamp":1643673600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["DNA and Cell Biology"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:p>\n                    Hepatocellular carcinoma (HCC) is an aggressive disease with a high degree of tumor heterogeneity. Genetic lesions of mTOR-related genes, including\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    and hyperactivation of mTOR signaling, are common in HCC. However, the association of genetic alterations with hepatocarcinogenesis remains unclear. In this study, continuous truncating mutations occurred within or upstream of the\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    Rap_GAP domain in clinical HCC samples. To elucidate whether hyperactivation of mTOR signaling in HCC is caused by\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    truncating mutations, HCC cell models carrying the\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    deletion (CRISPR\/Cas9) or the\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    truncating mutation (mutagenesis) were established. Our findings showed that either\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    deletion or\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    mutant could lead to\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    loss-of-function and hyperactivation of mTOR signaling. Furthermore, hyperactivation of mTOR signaling was relieved by rapamycin. Immunohistochemistry of clinical samples confirmed frequent\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    loss in HCC. Thus, our study revealed that genetic alterations cause\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    loss of function and result in the hyperactivation of mTOR, and high frequency of\n                    <jats:italic toggle=\"yes\">TSC2<\/jats:italic>\n                    truncating mutations around RAP_GAP domain may be one of the reasons for the hyperactivation of mTOR in HCC patients.\n                  <\/jats:p>","DOI":"10.1089\/dna.2021.0769","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T16:10:45Z","timestamp":1644509445000},"page":"215-224","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":1,"title":["Rap_GAP Domain of\n                    <i>TSC2<\/i>\n                    Contributes to Tumor Suppression Through mTOR Signaling in Human Hepatocellular Carcinoma"],"prefix":"10.1177","volume":"41","author":[{"given":"Mengying","family":"Cui","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, P.R. China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weibo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Orthopedic, The Second Hospital of Jilin University, Changchun, P.R. China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiyao","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, P.R. China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiacheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, P.R. China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3619-2222","authenticated-orcid":false,"given":"Xuewen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, P.R. China."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2022,2,9]]},"reference":[{"key":"e_1_3_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4887"},{"key":"e_1_3_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23963"},{"key":"e_1_3_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0383-1"},{"key":"e_1_3_6_5_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.887201"},{"key":"e_1_3_6_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0929"},{"key":"e_1_3_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2256"},{"key":"e_1_3_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1902"},{"key":"e_1_3_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.35"},{"key":"e_1_3_6_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-312734"},{"key":"e_1_3_6_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.25.2899"},{"key":"e_1_3_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2391"},{"key":"e_1_3_6_13_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20080281"},{"key":"e_1_3_6_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-14-0768"},{"key":"e_1_3_6_15_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1110003"},{"key":"e_1_3_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80657-1"},{"key":"e_1_3_6_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.2.406"},{"key":"e_1_3_6_18_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.154492.113"},{"key":"e_1_3_6_19_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.01.053"},{"key":"e_1_3_6_20_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2018.08.065"},{"key":"e_1_3_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12912"},{"key":"e_1_3_6_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2006.02932.x"},{"key":"e_1_3_6_23_1","first-page":"ra24","article-title":"Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice","author":"Menon S.","year":"2012","unstructured":"Menon S., , Yecies J.L., , Zhang H.H., , Howell J.J., , Nicholatos J., , Harputlugil E., et al. 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