{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T13:12:21Z","timestamp":1754485941447,"version":"3.37.3"},"reference-count":93,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T00:00:00Z","timestamp":1683676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001502","name":"Department of Atomic Energy, Government of India","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001502","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The pathogenesis of gallbladder cancer is complex, involving environmental and genetic risk factors. The matrix metallopeptidase 14 (MMP14) alters the tumor microenvironment and promotes tumorigenesis. In this study, we have characterized the role of the MMP14 promoter variants rs1004030 and rs1003049 in gallbladder cancer pathogenesis. Previously, we have shown the association of rs1004030 and rs1003049 with GBC and allele-specific differential expression of MMP14 in GBC patients. These variants reside within the cis-regulatory element (CRE) with high DNase and H3K4me3 signals, suggesting an active regulatory role in MMP14 expression. The luciferase-based reporter assay showed the role of promoter variants on expression levels in two GBC cell lines. Deleting the 119\u00a0bp promoter region surrounding the variants rs1004030 and rs1003049 by CRISPR-Cas9 genome editing resulted in reduced MMP14 expression in G415 cells. Electrophoretic mobility shift assay shows the presence of risk allele \u2018C\u2019\/\u2018G\u2019 at rs1004030 and rs1003049 and create binding sites for transcription factors SOX10 and MYB, respectively. Further, stable knockdown of these transcription factors in G415 and TGBC1TKB cells showed reduced expression of MMP14. However, in both GBC cells, ectopic expression of these transcription factors increased the expression of MMP14. Rescue of MYB and SOX10 expression levels showed a significant increase in luciferase activity only in risk allele-carrying constructs. In conclusion, our study unveils a mechanistic role of the MMP14 promoter variants rs1004030 and rs1003049 in gallbladder cancer.<\/jats:p>","DOI":"10.1093\/hmg\/ddad077","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T06:52:00Z","timestamp":1683787920000},"page":"2357-2372","source":"Crossref","is-referenced-by-count":2,"title":["Gallbladder cancer-associated genetic variants rs1003349 and rs1004030 regulate MMP14 expression by altering SOX10- and MYB-binding sites"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3662-8815","authenticated-orcid":false,"given":"Vinay","family":"J","sequence":"first","affiliation":[{"name":"School of Biological Sciences, National Institute of Science Education and Research , Bhubaneswar, Odisha 752050 , India"},{"name":"Training School Complex, Homi Bhabha National Institute , Anushakti Nagar, Mumbai 400094 , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ananya","family":"Palo","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, National Institute of Science Education and Research , Bhubaneswar, Odisha 752050 , India"},{"name":"Training School Complex, Homi Bhabha National Institute , Anushakti Nagar, Mumbai 400094 , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kusumbati","family":"Besra","sequence":"additional","affiliation":[{"name":"Department of Pathology, Acharya Harihar Post Graduate Institute of Cancer , Cuttack, Odisha 753007 , India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6997-1054","authenticated-orcid":false,"given":"Manjusha","family":"Dixit","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, National Institute of Science Education and Research , Bhubaneswar, Odisha 752050 , India"},{"name":"Training School Complex, Homi Bhabha National Institute , Anushakti Nagar, Mumbai 400094 , India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,5,10]]},"reference":[{"key":"2023070515080130200_ref1","doi-asserted-by":"crossref","first-page":"e0166361","DOI":"10.1371\/journal.pone.0166361","article-title":"Long-term outcomes and prognostic factors in advanced gallbladder cancer: focus on the advanced T stage","volume":"11","author":"Chen","year":"2016","journal-title":"PLoS One"},{"key":"2023070515080130200_ref2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12885-018-5211-y","article-title":"Therapeutic outcomes and prognostic factors in unresectable gallbladder cancer treated with gemcitabine plus cisplatin","volume":"19","author":"You","year":"2019","journal-title":"BMC Cancer"},{"key":"2023070515080130200_ref3","doi-asserted-by":"crossref","first-page":"3978","DOI":"10.3748\/wjg.v23.i22.3978","article-title":"Gallbladder cancer epidemiology, pathogenesis and molecular genetics: recent update","volume":"23","author":"Sharma","year":"2017","journal-title":"World J. 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