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More importantly, Srsf3 KO reduced the expression of hepatocyte ER\u03b1 and transcription factor Foxa family genes essential for sexual dimorphism in liver cancer and their downstream targets leukemia inhibitory factor receptor Lifr and epidermal growth factor receptor Egfr, but increased the expression of Myc. We further evidenced that SRSF3 binds to FOXA1 promoter and is responsible for FOXA1 promoter activity and FOXA1 expression in liver cancer cells. Together, our data highlight a functional paradigm of SRSF3 at its physiological level in tissue context-dependent gene regulation and in facilitating hepatocyte ER\u03b1 and FOXA1 expression for sex disparity in liver cancer development.<\/jats:p>","DOI":"10.1073\/pnas.2536317123","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:18:26Z","timestamp":1790698706000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["SRSF3 plays a key role in liver cancer sex disparity by facilitating hepatocyte expression of ER\u03b1 and FOXA"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0309-9520","authenticated-orcid":false,"given":"Lulu","family":"Yu","sequence":"first","affiliation":[{"name":"Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, NIH","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Ajiro","sequence":"additional","affiliation":[{"name":"Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, NIH","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2907-4583","authenticated-orcid":false,"given":"Vladimir","family":"Majerciak","sequence":"additional","affiliation":[{"name":"Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, NIH","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei","family":"Lobanov","sequence":"additional","affiliation":[{"name":"Center for Cancer Research Collaborative Bioinformatics Resource, National Cancer Institute, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafeng","family":"He","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung, and Blood Institute, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Cam","sequence":"additional","affiliation":[{"name":"Center for Cancer Research Collaborative Bioinformatics Resource, National Cancer Institute, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9604-9762","authenticated-orcid":false,"given":"Baktiar","family":"Karim","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03v6m3209","id-type":"ROR","asserted-by":"publisher"}],"name":"Frederick National Laboratory for Cancer Research","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6581-8171","authenticated-orcid":false,"given":"Deanna","family":"Gotte","sequence":"additional","affiliation":[{"name":"Tumor Virus RNA Biology Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, NIH","place":["Frederick"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuxia","family":"Deng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03hz5th67","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Synthetic Biology, Shenzhen University of Advanced Technology","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5559-6233","authenticated-orcid":false,"given":"Keji","family":"Zhao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung, and Blood Institute, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas R.","family":"Lowy","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J. 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