Abstract
Chloride intracellular channel-4 (CLIC4) is regulated by p53 and tumor necrosis factor-α (TNF-α), it is linked to the increase of transforming growth factor-β (TGF-β), and myofibroblastic differentiation in skin carcinogenesis. This study analyzed the immunoexpression of CLIC4, p53, TGF-β, TNF-α, and α-SMA in 50 actinic cheilitis (AC) and 50 lower lip squamous cell carcinoma (LLSCC). AC and LLSCC immunoexpression were categorized as score 1 (<5% positive cells), 2 (5-50%) or 3 (>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-β were observed in ACs with low-risk of transformation, while cytoplasmic CLIC4 (CLIC4c), p53 and TNF-α were higher in the high-risk cases (p<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-β decreased as the clinical stage and morphological grade progressed (p<0.05). ACs showed an increased expression of CLIC4n and TGF-β, while CLIC4c and α-SMA were higher in LLSCCs (p<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-β (p<0.05). Change of CLIC4 from the nucleus to cytoplasm and alterations in p53, TGF-β, TNF-α, and α-SMA expression are involved in lip carcinogenesis.
Highlights
Intracellular ion channels are involved in the pathogenesis of several malignancies [1,2]
Upregulation of chloride intracellular channel 4 (CLIC4) in the mitochondria and the presence of its soluble form in the keratinocyte cytoplasm, has been associated to the tumor necrosis factor-alpha (TNF-α), which lead to cell apoptosis, a process mediated by p53 and eMyc [4]
CLIC4 is upregulated in tumors stroma, where it usually co-localizes with alpha smooth muscle actin (α-SMA) in a positive association with TGF-β-mediated myofibroblasts differentiation and epithelial-mesenchymal transition [8], both phenomena related to cancer progression [1,8]
Summary
Intracellular ion channels are involved in the pathogenesis of several malignancies [1,2]. In cells undergoing stress conditions, cytoplasmic CLIC4 translocates to the nucleus, where it acts as a tumor suppressor protein by induction of cell growth arrest via enhancement of the transforming growth factor (TGF-β) signaling, and by participation in p53-mediated apoptosis [4,5,6]. Upregulation of CLIC4 in the mitochondria and the presence of its soluble form in the keratinocyte cytoplasm, has been associated to the tumor necrosis factor-alpha (TNF-α), which lead to cell apoptosis, a process mediated by p53 and eMyc [4]. CLIC4 is nearly or totally absent in the nucleus [7], with reports of direct relationship between the decreasing nuclear expression and the progression of cancer [6,7]. CLIC4 is upregulated in tumors stroma, where it usually co-localizes with alpha smooth muscle actin (α-SMA) in a positive association with TGF-β-mediated myofibroblasts differentiation and epithelial-mesenchymal transition [8], both phenomena related to cancer progression [1,8]
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