Low RECK Expression Is Part of the Cervical Carcinogenesis Mechanisms

Autor(es)

Herbster, Suellen ^[1] ; Trombetta-Lima, Marina ^{[2, 3]} ; de Souza-Santos, Paulo Thiago ^[4] ; Paladino, Andressa ^{[1, 5]} ; Silveira, Caio Raony Farina ^{[6, 7]} ; Sogayar, Mari Cleide ^{[8, 2]} ; Villa, Luisa Lina ^{[9, 10]} ; Lepique, Ana Paula ^[6] ; Boccardo, Enrique ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, Lab Oncovirol, BR-05508900 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Cell & Mol Therapy Ctr NUCEL, BR-05508900 Sao Paulo - Brazil

^[3] Univ Groningen, Rijksuniv Groningen, Dept Mol Pharmacol, Antonius Deusinglaan 1, Bldg 3211, Room 401, NL-9713 AV Groningen - Netherlands

^[4] Fiocruz MS, Inst Oswaldo Cruz, Leprosy Lab, BR-21040360 Rio De Janeiro - Brazil

^[5] Citogem Biotecnol Ltd A, Rua Ingles de Sousa 444, BR-01546010 Sao Paulo, SP - Brazil

^[6] Univ Sao Paulo, Inst Ciencias Biomed, Dept Immunol, Lab Immunomodulat, BR-05508900 Sao Paulo - Brazil

^[7] Univ Sao Paulo, Hemoctr, Lab Terapia Celular Avancada, Rua Tenente Catao Roxo 2501, BR-14051140 Ribeirao Preto, SP - Brazil

^[8] Univ Sao Paulo, Inst Chem, Dept Biochem, BR-05508900 Sao Paulo - Brazil

^[9] Univ Sao Paulo, Fac Med, Dept Radiol & Oncol, BR-05508900 Sao Paulo - Brazil

^[10] Univ Sao Paulo, Inst Canc Estado Sao Paulo, Innovat Canc Lab, BR-05508900 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CANCERS; v. 13, n. 9 MAY 2021.
• Citações Web of Science: 0

Resumo

Simple Summary Cervical cancer is one of the most lethal types of cancer in women from developing countries. These tumors are caused by long term infection with some human papillomavirus (HPV) types. Commonly, cervical cancer precursor lesions express high levels of matrix metalloproteinases. These enzymes break down specific components of the extracellular matrix affecting tissue structure and stiffness and cell motility. Matrix metalloproteinases and their natural inhibitors, such as Reversion-inducing Cysteine-rich protein with Kazal motifs (RECK) protein, are important in normal tissue maintenance and remodeling and play a major role in the transformation process. Here, we showed that RECK over expression reduced the tumorigenic capacity of cervical cancer cells in vivo. In addition, tumors over expressing RECK presented altered inflammatory infiltrating cells when compared to controls. Our findings are useful to further understand the biology of cervical cancer and can help to determine if RECK may be a good therapeutic target for cervical cancer treatment in the future. 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. (AU)

• Processo FAPESP: 08/57889-1 - Instituto de Ciência e Tecnologia para o Estudo das Doenças Associadas ao Papilomavírus
• Beneficiário: Luisa Lina Villa
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 17/02997-3 - Papel da proteína RECK no processo de transformação celular mediado por HPV
• Beneficiário: Enrique Mario Boccardo Pierulivo
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/20002-0 - Estudo de Letalidade Sintética em células infectadas por papilomavírus humano (HPV)
• Beneficiário: Enrique Mario Boccardo Pierulivo
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 13/27006-9 - Estudo do papel da proteína reck no processo de carcinogênese mediado pelo papilomavírus humano
• Beneficiário: Suellen da Silva Gomes Herbster
• Modalidade de apoio: Bolsas no Brasil - Doutorado