{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:53:22Z","timestamp":1790877202384,"version":"4.1.0"},"reference-count":30,"publisher":"FapUNIFESP (SciELO)","issue":"3","license":[{"start":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T00:00:00Z","timestamp":1590969600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T00:00:00Z","timestamp":1590969600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T00:00:00Z","timestamp":1590969600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Braz. Dent. J."],"abstract":"<jats:p>Abstract Chloride intracellular channel-4 (CLIC4) is regulated by p53 and tumor necrosis factor-\u03b1 (TNF-\u03b1), it is linked to the increase of transforming growth factor-\u03b2 (TGF-\u03b2), and myofibroblastic differentiation in skin carcinogenesis. This study analyzed the immunoexpression of CLIC4, p53, TGF-\u03b2, TNF-\u03b1, and \u03b1-SMA in 50 actinic cheilitis (AC) and 50 lower lip squamous cell carcinoma (LLSCC). AC and LLSCC immunoexpression were categorized as score 1 (&lt;5% positive cells), 2 (5-50%) or 3 (&gt;50%). For CLIC4, nuclear and cytoplasmic immunostaining of epithelial cells was considered individually. For morphologic analysis, the World Health Organization criteria were used to epithelial dysplasia grade of ACs, and Bryne grading of malignancy system was applied for LLSCC. Higher nuclear CLIC4 (CLIC4n) and TGF-\u03b2 were observed in ACs with low-risk of transformation, while cytoplasmic CLIC4 (CLIC4c), p53 and TNF-\u03b1 were higher in the high-risk cases (p&lt;0.05). In LLSCCs, CLIC4c was higher in cases with lymph node metastasis, advanced clinical stages, and histological high-grade malignancy. p53 expression was higher in high-grade LLSCCs, whereas TGF-\u03b2 decreased as the clinical stage and morphological grade progressed (p&lt;0.05). ACs showed an increased expression of CLIC4n and TGF-\u03b2, while CLIC4c and \u03b1-SMA were higher in LLSCCs (p&lt;0.0001). Both lesions showed negative correlation between CLIC4n and CLIC4c, while in LLSCCs, negative correlation was also verified between CLIC4c and p53, as well as CLIC4c and TGF-\u03b2 (p&lt;0.05). Change of CLIC4 from the nucleus to cytoplasm and alterations in p53, TGF-\u03b2, TNF-\u03b1, and \u03b1-SMA expression are involved in lip carcinogenesis.<\/jats:p>","DOI":"10.1590\/0103-6440202003104","type":"journal-article","created":{"date-parts":[[2020,7,13]],"date-time":"2020-07-13T13:11:43Z","timestamp":1594645903000},"page":"290-297","source":"Crossref","is-referenced-by-count":10,"title":["Modification in CLIC4 Expression is Associated with P53, TGF-\u03b2, TNF-\u03b1 and Myofibroblasts in Lip Carcinogenesis"],"prefix":"10.1590","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7017-2727","authenticated-orcid":false,"given":"Francisco Jadson","family":"Lima","sequence":"first","affiliation":[{"name":"Universidade Federal do Rio Grande do Norte,  Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6894-1366","authenticated-orcid":false,"given":"Maria Luiza Diniz de Souza","family":"Lopes","sequence":"additional","affiliation":[{"name":"Universidade Federal do Rio Grande do Norte,  Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3103-3588","authenticated-orcid":false,"given":"Caio C\u00e9sar da Silva","family":"Barros","sequence":"additional","affiliation":[{"name":"Universidade Federal do Rio Grande do Norte,  Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2380-109X","authenticated-orcid":false,"given":"Cassiano Francisco Weege","family":"Nonaka","sequence":"additional","affiliation":[{"name":"Universidade Estadual da Para\u00edba,  Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2128-0147","authenticated-orcid":false,"given":"\u00c9ricka Janine Dantas da","family":"Silveira","sequence":"additional","affiliation":[{"name":"Universidade Federal do Rio Grande do Norte,  Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"530","published-online":{"date-parts":[[2020,6]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1242\/jcs.002741","article-title":"CLIC4 mediates and is required for Ca2+-induced keratinocyte differentiation","volume":"120","author":"Suh KS","year":"2007","journal-title":"J Cell Sci"},{"key":"ref2","first-page":"2","article-title":"Knockdown of CLIC4 enhances ATPinduced HN4 cell apoptosis through mitochondrial and endoplasmic reticulum pathways","volume":"6","author":"Xue H","year":"2016","journal-title":"Cell Biosci"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1152\/physrev.00029.2001","article-title":"Molecular structure and physiological function of chloride channels","volume":"82","author":"Jentsch TJ","year":"2002","journal-title":"Physiol Rev"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"3610","DOI":"10.1128\/MCB.22.11.3610-3620.2002","article-title":"mtCLIC\/CLIC4, an organellular chloride channel protein, is increased by DNA damage and participates in the apoptotic response to p53","volume":"22","author":"Fern\u00e1ndez-Salas E","year":"2002","journal-title":"Mol Cell Biol"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.4161\/nucl.10920","article-title":"CLIC4 and Schnurri2: A dynamic duo in TGF\u03b2 signaling with broader implications in cellular homeostasis and disease","volume":"1","author":"Shukla A","year":"2010","journal-title":"Nucleus"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1093\/carcin\/bgs115","article-title":"CLIC4 is a tumor suppressor for cutaneous squamous cell cancer","volume":"33","author":"Suh KS","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1158\/1078-0432.CCR-06-1562","article-title":"Reciprocal modifications of CLIC4 in tumor epithelium and stroma mark malignant progression of multiple human cancers","volume":"13","author":"Suh KS","year":"2007","journal-title":"Clin Cancer Res"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/onc.2013.18","article-title":"CLIC4 regulates TGF-\u03b2-dependent myofibroblast differentiation to produce a cancer stroma","volume":"33","author":"Shukla A","year":"2014","journal-title":"Oncogene"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"757","DOI":"10.4317\/medoral.16954","article-title":"Lip squamous cell carcinoma in a Brazilian population: epidemiological study and clinicopathological associations","volume":"16","author":"Souza LR","year":"2011","journal-title":"Med Oral Patol Oral Cir Bucal"},{"key":"ref10","article-title":"Solar, cheilosis: An ominous precursor: part I. 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