Alves Márcia Gaião, Kodama Márcio Hideki, da Silva Elaine Zayas Marcelino, Gomes Bruno Belmonte Martinelli, da Silva Rodrigo Alberto Alves, Vieira Gabriel Viliod, Alves Vani Maria, da Fonseca Carol Kobori, Santana Ana Carolina, Cecílio Nerry Tatiana, Costa Mara Silvia Alexandre, Jamur Maria Célia, Oliver Constance, Cunha Thiago Mattar, Bugge Thomas H, Braz-Silva Paulo Henrique, Colli Leandro M, Sales Katiuchia Uzzun
Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil.
Department of Cell and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil; Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Transl Oncol. 2021 Jan;14(1):100970. doi: 10.1016/j.tranon.2020.100970. Epub 2020 Nov 28.
Oral squamous cell carcinoma (OSCC) remains a challenging cancer to treat despite all the advances of the last 50 years. Kallikrein 5 (KLK5) is among the serine proteases implicated in OSCC development. However, whether the activity of KLK5 promotes carcinogenesis is still controversial. Moreover, knowledge regarding the role of the KLK5 cognate inhibitor, Lympho-Epithelial Kazal-Type related Inhibitor (LEKTI), in OSCC is scarce. We have, thus, sought to investigate the importance of KLK5 and LEKTI expression in premalignant and malignant lesions of the oral cavity.
KLK5 and LEKTI protein expression was evaluated in 301 human samples, which were comprised of non-malignant and malignant lesions of the oral cavity. Moreover, a bioinformatic analysis of the overall survival rate from 517 head and neck squamous cell carcinoma (HNSCC) samples was performed. Additionally, to mimic the uncovered KLK5 to serine peptidase inhibitor (SPINK5) imbalance, the KLK5 gene was abrogated in an OSCC cell line using CRISPR-Cas9 technology. The generated cell line was then used for in vivo and in vitro carcinogenesis related experiments.
LEKTI was found to be statistically downregulated in OSCCs, with increased KLK5/SPINK5 mRNA ratio being associated with a shorter overall survival (p = 0.091). Indeed, disruption of KLK5 to SPINK5 balance through the generation of KLK5 null OSCC cells led to smaller xenografted tumors and statistically decreased proliferation rates following multiple time points of BrdU treatment in vitro.
The association of increased enzyme/inhibitor ratio with poor prognosis indicates KLK5 to SPINK5 relative expression as an important prognostic marker in OSCC.
尽管在过去50年里取得了诸多进展，但口腔鳞状细胞癌（OSCC）仍是一种难以治疗的癌症。激肽释放酶5（KLK5）是参与OSCC发展的丝氨酸蛋白酶之一。然而，KLK5的活性是否促进癌变仍存在争议。此外，关于KLK5同源抑制剂淋巴细胞上皮Kazal型相关抑制剂（LEKTI）在OSCC中的作用的知识还很匮乏。因此，我们试图研究KLK5和LEKTI表达在口腔癌前病变和恶性病变中的重要性。
在301份人类样本中评估KLK5和LEKTI蛋白表达，这些样本包括口腔的非恶性和恶性病变。此外，对517例头颈部鳞状细胞癌（HNSCC）样本的总生存率进行了生物信息学分析。另外，为了模拟未发现的KLK5与丝氨酸肽酶抑制剂（SPINK5）失衡，使用CRISPR-Cas9技术在一种OSCC细胞系中敲除KLK5基因。然后将生成的细胞系用于体内和体外癌变相关实验。
发现LEKTI在OSCC中统计学下调，KLK5/SPINK5 mRNA比值增加与总生存期缩短相关（p = 0.091）。实际上，通过生成KLK5缺失的OSCC细胞破坏KLK5与SPINK5的平衡，导致异种移植肿瘤更小，并且在体外多次进行溴脱氧尿苷（BrdU）处理后的多个时间点，增殖率统计学下降。
酶/抑制剂比值增加与预后不良的关联表明，KLK5与SPINK5的相对表达是OSCC中一个重要的预后标志物。
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