{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T06:34:59Z","timestamp":1778567699149,"version":"3.51.4"},"reference-count":33,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,6,1]]},"abstract":"<jats:p>Accumulating evidence has demonstrated that FHIT (fragile histidine triad) is a bona fide tumour suppressor gene in a large fraction of human tumours, including hepatocellular cancer. A virus-based delivery system has been developed to transfer the FHIT gene into many types\u00a0of cancer cells to inhibit growth or even induce apoptosis. However, a protein-based replacement strategy for FHIT has not been performed in cancer cells. Here, we used HIV-TAT (transactivator of transcription)-derived peptide to transfer the purified FHIT protein into HCC (hepatocellular carcinoma) cells and determine the biological effect of this fusion protein in inducing apoptosis. Affinity chromatography was used to purify TAT peptide-fused human FHIT (TAT\u2013FHIT) protein from BL21 Escherichia coli. Immunofluorescence staining and Western blot analysis were performed to identify the expression and internalization of TAT\u2013FHIT in HCC cells compared with the purified FHIT protein. Our study showed that TAT\u2013FHIT protein can translocate into cancer cells in 1\u00a0h after incubation at 37\u00b0C. Furthermore, the results of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay, Annexin-V staining and Western blotting demonstrated that TAT\u2013FHIT can robustly inhibit growth and induce apoptosis of HCC cells in vitro. In addition, a mechanistic study showed that both exogenous and intrinsic apoptotic pathways were involved in TAT\u2013FHIT-mediated apoptosis and this effect could be attenuated partially by a mitochondrial protector TAT-BH4, indicating that mitochondrion plays a critical role in TAT\u2013FHIT-mediated pro-apoptotic effect in cancer cells. Taken together, our study suggests that TAT\u2013FHIT is a potential pro-apoptotic molecule in HCC cells and strengthen the hypothesis of its therapeutic application against HCC.<\/jats:p>","DOI":"10.1042\/bsr20110033","type":"journal-article","created":{"date-parts":[[2011,7,4]],"date-time":"2011-07-04T15:56:58Z","timestamp":1309795018000},"page":"271-279","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["HIV-TAT-fused FHIT protein functions as a potential pro-apoptotic molecule in hepatocellular carcinoma cells"],"prefix":"10.1042","volume":"32","author":[{"given":"Gui-Rong","family":"Yu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Wei","family":"Qin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji-Peng","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"},{"name":"Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Hua","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Ling","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Immunology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Yan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin-Tao","family":"Jia","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"An-Gang","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China"},{"name":"Department of Immunology, Fourth Military Medical University, 710032 Xi'an, People's Republic of China."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2012,1,30]]},"reference":[{"key":"2021111618102697600_B1","doi-asserted-by":"crossref","first-page":"S302","DOI":"10.1016\/S1590-8658(10)60521-X","article-title":"Future perspectives in hepatocellular carcinoma","volume":"42","author":"Worns","year":"2010","journal-title":"Dig. Liver Dis."},{"key":"2021111618102697600_B2","doi-asserted-by":"crossref","first-page":"S264","DOI":"10.1016\/S1590-8658(10)60515-4","article-title":"Molecular approaches to treatment of hepatocellular carcinoma","volume":"42","author":"Lachenmayer","year":"2010","journal-title":"Dig. Liver Dis."},{"key":"2021111618102697600_B3","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.yexmp.2009.09.012","article-title":"Concordance of DNA methylation pattern in plasma and tumor DNA of Egyptian hepatocellular carcinoma patients","volume":"88","author":"Iyer","year":"2010","journal-title":"Exp. Mol. Pathol."},{"key":"2021111618102697600_B4","first-page":"273","article-title":"Influence of DNA methyltransferase 3b on FHIT expression and DNA methylation of the FHIT promoter region in hepatoma SMMC-7721 cells","volume":"8","author":"Wang","year":"2009","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"2021111618102697600_B5","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/S0092-8674(00)81034-X","article-title":"The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers","volume":"84","author":"Ohta","year":"1996","journal-title":"Cell"},{"key":"2021111618102697600_B6","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1038\/sj.bjc.6602182","article-title":"Development of spontaneous tumours and intestinal lesions in Fhit gene knockout mice","volume":"91","author":"Fujishita","year":"2004","journal-title":"Br. J. Cancer"},{"key":"2021111618102697600_B7","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1001\/jama.286.19.2441","article-title":"Potential cancer therapy with the fragile histidine triad gene: review of the preclinical studies","volume":"286","author":"Ishii","year":"2001","journal-title":"JAMA, J. Am. Med. Assoc."},{"key":"2021111618102697600_B8","first-page":"1049","article-title":"Alterations of the FHIT gene in human hepatocellular carcinoma","volume":"60","author":"Yuan","year":"2000","journal-title":"Cancer Res."},{"key":"2021111618102697600_B9","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/bjc.1998.66","article-title":"Aberrant FHIT transcripts in hepatocellular carcinomas","volume":"77","author":"Chen","year":"1998","journal-title":"Br. J. Cancer"},{"key":"2021111618102697600_B10","doi-asserted-by":"crossref","first-page":"228","DOI":"10.3748\/wjg.v11.i2.228","article-title":"Expression of fragile histidine triad in primary hepatocellular carcinoma and its relation with cell proliferation and apoptosis","volume":"11","author":"Nan","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"2021111618102697600_B11","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.coph.2006.04.004","article-title":"Cell-penetrating peptides as vectors for peptide, protein and oligonucleotide delivery","volume":"6","author":"Mae","year":"2006","journal-title":"Curr. Opin. Pharmacol."},{"key":"2021111618102697600_B12","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1111\/j.1440-1746.2010.06582.x","article-title":"Cell death and hepatocarcinogenesis: dysregulation of apoptosis signaling pathways","volume":"26","author":"Schattenberg","year":"2011","journal-title":"J. Gastroenterol. Hepatol."},{"key":"2021111618102697600_B13","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.pep.2008.01.020","article-title":"Purification of GFP fusion proteins with high purity and yield by monoclonal antibody-coupled affinity column chromatography","volume":"59","author":"Zhuang","year":"2008","journal-title":"Protein Expr. Purif."},{"key":"2021111618102697600_B14","doi-asserted-by":"crossref","first-page":"547","DOI":"10.4161\/cbt.7.4.5484","article-title":"A survivin double point mutant has potent inhibitory effect on the growth of hepatocellular cancer cells","volume":"7","author":"Zhang","year":"2008","journal-title":"Cancer Biol. Ther."},{"key":"2021111618102697600_B15","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/cgt.2009.68","article-title":"Survivin knockdown by short hairpin RNA abrogates the growth of human hepatocellular carcinoma xenografts in nude mice","volume":"17","author":"Zhang","year":"2010","journal-title":"Cancer Gene. Ther."},{"key":"2021111618102697600_B16","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1053\/j.gastro.2010.08.046","article-title":"HIV-Tat-mediated delivery of an LPTS functional fragment inhibits telomerase activity and tumorigenicity of hepatoma cells","volume":"140","author":"Chen","year":"2011","journal-title":"Gastroenterology"},{"key":"2021111618102697600_B17","doi-asserted-by":"crossref","first-page":"10250","DOI":"10.1073\/pnas.191345898","article-title":"The tumor spectrum in FHIT-deficient mice","volume":"98","author":"Zanesi","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111618102697600_B18","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/modpathol.3800102","article-title":"FHIT mRNA and protein expression in hepatocellular carcinoma","volume":"17","author":"Kannangai","year":"2004","journal-title":"Mod. Pathol."},{"key":"2021111618102697600_B19","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/mc.10044","article-title":"Alterations of the Fhit gene in hepatocellular carcinomas induced by N-nitrosodiethylamine in rats","volume":"34","author":"Tsujiuchi","year":"2002","journal-title":"Mol. Carcinog."},{"key":"2021111618102697600_B20","doi-asserted-by":"crossref","first-page":"3346","DOI":"10.1073\/pnas.061020098","article-title":"FHIT gene therapy prevents tumor development in Fhit-deficient mice","volume":"98","author":"Dumon","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021111618102697600_B21","first-page":"M65","article-title":"The FHIT gene, a multiple tumor suppressor gene encompassing the carcinogen sensitive chromosome fragile site, FRA3B","volume":"1332","author":"Huebner","year":"1997","journal-title":"Biochim. Biophys. 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U.S.A."},{"key":"2021111618102697600_B23","first-page":"3333","article-title":"Induction of apoptosis and inhibition of tumorigenicity and tumor growth by adenovirus vector-mediated fragile histidine triad (FHIT) gene overexpression","volume":"59","author":"Ji","year":"1999","journal-title":"Cancer Res."},{"key":"2021111618102697600_B24","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1096\/fj.03-0241fje","article-title":"Regression of upper gastric cancer in mice by FHIT gene delivery","volume":"17","author":"Ishii","year":"2003","journal-title":"FASEB J."},{"key":"2021111618102697600_B25","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1007\/s10529-007-9322-9","article-title":"Expression and simple, one-step purification of fragile histidine triad (Fhit) tumor suppressor mutant forms in Escherichia coli and their interaction with protoporphyrin IX","volume":"29","author":"Zawacka-Pankau","year":"2007","journal-title":"Biotechnol. Lett."},{"key":"2021111618102697600_B26","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1006\/prep.1999.1199","article-title":"Expression in Escherichia coli and simple purification of human Fhit protein","volume":"18","author":"Pawelczyk","year":"2000","journal-title":"Protein. Expr. Purif."},{"key":"2021111618102697600_B27","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.jconrel.2006.10.031","article-title":"The taming of the cell penetrating domain of the HIV Tat: myths and realities","volume":"117","author":"Chauhan","year":"2007","journal-title":"J. Control. Release"},{"key":"2021111618102697600_B28","doi-asserted-by":"crossref","first-page":"5286","DOI":"10.1038\/onc.2010.267","article-title":"Cell delivery of Met docking site peptides inhibit angiogenesis and vascular tumor growth","volume":"29","author":"Cantelmo","year":"2010","journal-title":"Oncogene"},{"key":"2021111618102697600_B29","doi-asserted-by":"crossref","first-page":"9102","DOI":"10.1038\/sj.onc.1208142","article-title":"The apoptotic pathway triggered by the Fhit protein in lung cancer cell lines is not affected by Bcl-2 or Bcl-x(L) overexpression","volume":"23","author":"Roz","year":"2004","journal-title":"Oncogene"},{"key":"2021111618102697600_B30","first-page":"1183","article-title":"Restoration of fragile histidine triad (FHIT) expression induces apoptosis and suppresses tumorigenicity in breast cancer cell lines","volume":"63","author":"Sevignani","year":"2003","journal-title":"Cancer Res."},{"key":"2021111618102697600_B31","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S0092-8674(00)81590-1","article-title":"Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis","volume":"94","author":"Li","year":"1998","journal-title":"Cell"},{"key":"2021111618102697600_B32","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/S0092-8674(00)81589-5","article-title":"BID, a Bcl2 interacting protein, mediates cytochrome c release from mitochondrion in response to activation of cell surface death receptors","volume":"94","author":"Luo","year":"1998","journal-title":"Cell"},{"key":"2021111618102697600_B33","doi-asserted-by":"crossref","first-page":"12753","DOI":"10.1073\/pnas.0906484106","article-title":"Intramitochondrial calcium regulation by the FHIT gene product sensitises to apoptosis","volume":"106","author":"Rimessi","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U.S.A."}],"container-title":["Bioscience Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/32\/3\/271\/474971\/bsr0320271.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/bioscirep\/article-pdf\/32\/3\/271\/474971\/bsr0320271.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T18:27:30Z","timestamp":1637087250000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/bioscirep\/article\/32\/3\/271\/55930\/HIV-TAT-fused-FHIT-protein-functions-as-a"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,1,30]]},"references-count":33,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2012,6,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bsr20110033","relation":{},"ISSN":["0144-8463","1573-4935"],"issn-type":[{"value":"0144-8463","type":"print"},{"value":"1573-4935","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,1,30]]}}}