Herbster Suellen, Trombetta-Lima Marina, de Souza-Santos Paulo Thiago, Paladino Andressa, Silveira Caio Raony Farina, Sogayar Mari Cleide, Villa Luisa Lina, Lepique Ana Paula, Boccardo Enrique
Laboratory of Oncovirology, Department of Microbiology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo 05508-900, Brazil.
Cell and Molecular Therapy Center (NUCEL), Faculdade de Medicina, Universidade de São Paulo, São Paulo 05508-900, Brazil.
Cancers (Basel). 2021 May 6;13(9):2217. doi: 10.3390/cancers13092217.
Human papillomavirus (HPV)-induced carcinogenesis comprises alterations in the expression and activity of matrix metalloproteinases (MMP) and their regulators. Reversion-inducing Cysteine-rich protein with Kazal motifs (RECK) inhibits the activation of specific metalloproteinases and its expression is frequently lost in human cancers. Here we analyzed the role of RECK in cervical carcinogenesis. Cervical cancer derived cell lines over expressing RECK were used to determine tumor kinetics as well as, cellular, immune and molecular properties in vivo. Besides, we analyzed RECK expression in cervical cancer samples. RECK over expression (RECK+) delayed tumor growth and increased overall survival in vivo. RECK+ tumors displayed an increase in lymphoid-like inflammatory infiltrating cells, reduced number and viability of tumor and endothelial cells and lower collagenase activity. RECK+ tumors exhibited an enrichment of cell adhesion processes both in the mouse model and cervical cancer clinical samples. Finally, we found that lower RECK mRNA levels were associated with cervical lesions progression and worse response to chemotherapy in cervical cancer patients. Altogether, we show that increased RECK expression reduced the tumorigenic potential of HPV-transformed cells both in vitro and in vivo, and that RECK down regulation is a consistent and clinically relevant event in the natural history of cervical cancer.
人乳头瘤病毒（HPV）诱导的致癌作用包括基质金属蛋白酶（MMP）及其调节因子的表达和活性改变。含Kazal基序的富含半胱氨酸的逆转诱导蛋白（RECK）可抑制特定金属蛋白酶的激活，其表达在人类癌症中经常缺失。在此，我们分析了RECK在宫颈癌发生中的作用。使用过表达RECK的宫颈癌衍生细胞系来确定体内肿瘤动力学以及细胞、免疫和分子特性。此外，我们分析了宫颈癌样本中的RECK表达。RECK过表达（RECK+）在体内延迟了肿瘤生长并提高了总生存率。RECK+肿瘤中淋巴样炎性浸润细胞增加，肿瘤细胞和内皮细胞数量及活力减少，胶原酶活性降低。在小鼠模型和宫颈癌临床样本中，RECK+肿瘤均表现出细胞黏附过程的富集。最后，我们发现较低的RECK mRNA水平与宫颈癌患者的宫颈病变进展及化疗反应较差相关。总之，我们表明RECK表达增加在体外和体内均降低了HPV转化细胞的致瘤潜力，并且RECK下调是宫颈癌自然史中一个一致且与临床相关的事件。
