Lacerda Pammela A, Oenning Luan C, Bellato Guilherme Cuoghi, Lopes-Santos Lucilene, Antunes Natalícia de Jesus, Mariz Bruno Augusto Linhares Almeida, Teixeira Gabriela, Vasconcelos Rafael, Simões Gustavo Ferreira, de Souza Ivani Aparecida, Pinto Clóvis Antônio Lopes, Salo Tuula, Coletta Ricardo D, Augusto Taize M, de Oliveira Carine Ervolino, Cervigne Nilva K
Laboratory of Molecular Biology and Cell Culture (LBMCC), Faculty of Medicine of Jundiaí (FMJ), Jundiaí, Brazil.
Laboratory of Pharmacology, University of Campinas, Campinas, Brazil.
Front Pharmacol. 2023 Jan 5;13:1098374. doi: 10.3389/fphar.2022.1098374. eCollection 2022.
Oral cancer refers to malignant tumors, of which 90% are squamous cell carcinomas (OSCCs). These malignancies exhibit rapid progression, poor prognosis, and often mutilating therapeutical approaches. The determination of a prophylactic and/or therapeutic antitumor role of the polyphenolic extract would be relevant in developing new tools for prevention and treatment. We aimed to determine the antitumor effect of PL by treating OSCC cell lines with PL metabolites and evaluating its action during OSCC progression . PL treatment successfully impaired cell cycling and proliferation, migration, and invasion, enhanced apoptosis, and modulated macrophage polarization associated with the tumoral immune-inflammatory response of tongue cancer cell lines (TSCC). PL treatment significantly decreased the expression of MMP1 ( < 0.01) and MMP2 ( < 0.001), and increased the expression of TIMP1 ( < 0.001) and TIMP2 ( < 0.0001) in these cells. The mesenchymal-epithelial transition phenotype was promoted in cells treated with PL, through upregulation of E-CAD ( < 0.001) and reduction of N-CAD ( < 0.05). PL restrained OSCC progression by inhibiting tumor volume growth and decreasing the number of severe dysplasia lesions and squamous cell carcinomas. Ki-67 was significantly higher expressed in tongue tissues of animals not treated with PL( < 0.05), and a notable reduction in Bcl2 ( < 0.05) and Pcna ( < 0.05) cell proliferation-associated genes was found in dysplastic lesions and TSCCs of PL-treated mice. Finally, N-cad(Cdh2), Vim, and Twist were significantly reduced in tongue tissues treated with PL. PL significantly decreased OSCC carcinogenic processes and inhibited tumor progression . PL also appears to contribute to the modulation of immune-inflammatory oral tumor-associated responses. Taken together, these results suggest that PL plays an important antitumor role in processes associated with oral carcinogenesis and may be a potential phytotherapeutic target for the prevention and/or adjuvant treatment of TSCCs.
口腔癌是指恶性肿瘤，其中90%为鳞状细胞癌（OSCC）。这些恶性肿瘤进展迅速、预后不良，且治疗方法往往具有毁容性。确定多酚提取物的预防和/或治疗抗肿瘤作用对于开发新的预防和治疗工具具有重要意义。我们旨在通过用PL代谢物处理OSCC细胞系并评估其在OSCC进展过程中的作用来确定PL的抗肿瘤效果。PL处理成功地损害了细胞周期、增殖、迁移和侵袭，增强了凋亡，并调节了与舌癌细胞系（TSCC）肿瘤免疫炎症反应相关的巨噬细胞极化。PL处理显著降低了这些细胞中MMP1（<0.01）和MMP2（<0.001）的表达，并增加了TIMP1（<0.001）和TIMP2（<0.0001）的表达。在用PL处理的细胞中，通过上调E-CAD（<0.001）和降低N-CAD（<0.05）促进了间充质-上皮转化表型。PL通过抑制肿瘤体积生长以及减少重度发育异常病变和鳞状细胞癌的数量来抑制OSCC进展。未用PL处理的动物舌组织中Ki-67表达显著更高（<0.05），在PL处理小鼠的发育异常病变和TSCC中发现与细胞增殖相关的基因Bcl2（<0.05）和Pcna（<0.05）明显减少。最后，在用PL处理的舌组织中，N-cad（Cdh2）、Vim和Twist显著降低。PL显著降低了OSCC致癌过程并抑制了肿瘤进展。PL似乎也有助于调节与口腔肿瘤相关的免疫炎症反应。综上所述，这些结果表明PL在与口腔癌发生相关的过程中发挥重要的抗肿瘤作用，可能是TSCC预防和/或辅助治疗的潜在植物治疗靶点。
