{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:00:53Z","timestamp":1760148053698,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T00:00:00Z","timestamp":1679961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Government of Thailand","award":["C9380\/A26813","C18342\/A23390"],"award-info":[{"award-number":["C9380\/A26813","C18342\/A23390"]}]},{"name":"Government of India","award":["C9380\/A26813","C18342\/A23390"],"award-info":[{"award-number":["C9380\/A26813","C18342\/A23390"]}]},{"name":"Newcastle University Research Fellowship","award":["C9380\/A26813","C18342\/A23390"],"award-info":[{"award-number":["C9380\/A26813","C18342\/A23390"]}]},{"name":"Cancer Research UK","award":["C9380\/A26813","C18342\/A23390"],"award-info":[{"award-number":["C9380\/A26813","C18342\/A23390"]}]},{"name":"Kidscan","award":["C9380\/A26813","C18342\/A23390"],"award-info":[{"award-number":["C9380\/A26813","C18342\/A23390"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC), the most common type of liver cancer, has very poor outcomes. Current therapies often have low efficacy and significant toxicities. Thus, there is a critical need for the development of novel therapeutic approaches for HCC. We have developed a novel bioinformatics pipeline, which integrates genome-wide DNA methylation and gene expression data, to identify genes required for the survival of specific molecular cancer subgroups but not normal cells. Targeting these genes may induce cancer-specific \u201csynthetic lethality\u201d. Initially, five potential HCC molecular subgroups were identified based on global DNA methylation patterns. Subgroup-2 exhibited the most unique methylation profile and two candidate subtype-specific vulnerability or SL-like genes were identified for this subgroup, including TIAM1, a guanine nucleotide exchange factor encoding gene known to activate Rac1 signalling. siRNA targeting TIAM1 inhibited cell proliferation in TIAM1-positive (subgroup-2) HCC cell lines\u00a0but had no effect on the normal hepatocyte HHL5 cell line. Furthermore, TIAM1-positive\/subgroup-2 cell lines were significantly more sensitive to the TIAM1\/RAC1 inhibitor NSC23766 compared with TIAM1-negative HCC lines or the normal HHL5 cell line. The results are consistent with a synthetic lethal role for TIAM1 in a methylation-defined HCC subgroup and suggest it may be a viable therapeutic target in this subset of HCC patients.<\/jats:p>","DOI":"10.3390\/ijms24076387","type":"journal-article","created":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T02:03:53Z","timestamp":1680055433000},"page":"6387","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of TIAM1 as a Potential Synthetic-Lethal-like Gene in a Defined Subset of Hepatocellular Carcinoma"],"prefix":"10.3390","volume":"24","author":[{"given":"Chalermsin","family":"Permtermsin","sequence":"first","affiliation":[{"name":"Biosciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H","family":"Lalchungnunga","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sirintra","family":"Nakjang","sequence":"additional","affiliation":[{"name":"Bioinformatics Support Unit, Newcastle University, Newcastle NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Casement","sequence":"additional","affiliation":[{"name":"Bioinformatics Support Unit, Newcastle University, Newcastle NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura Frances","family":"Ogle","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0359-9795","authenticated-orcid":false,"given":"Helen L.","family":"Reeves","sequence":"additional","affiliation":[{"name":"Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle NE2 4HH, UK"},{"name":"Liver Unit, Freeman Hospital, Newcastle-Upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne NE7 7DN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon","family":"Strathdee","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle NE2 4HH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruchi","family":"Shukla","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle NE2 4HH, UK"},{"name":"Department of Applied Sciences, Northumbria University, Newcastle NE1 8ST, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. 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