The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma

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Baldavira, Camila M. ^[1] ; Machado-Rugolo, Juliana ^{[1, 2]} ; Prieto, Tabatha G. ^[1] ; Bastos, Daniel R. ^{[3, 4]} ; Balancin, Marcelo ^[1] ; Ab'Saber, Alexandre M. ^[1] ; Yaegashi, Lygia B. ^[1] ; Souza, Paola C. ^[1] ; Farhat, Cecilia ^[1] ; Takagaki, Teresa Y. ^[5] ; Nagai, Maria Ap ^{[3, 4]} ; Capelozzi, Vera L. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Med Sch USP, Dept Pathol, Av Dr Arnaldo 455, Room 1143, BR-01246903 Sao Paulo, SP - Brazil

^[2] Sao Paulo State Univ UNESP, Hlth Technol Assessment Ctr NATS, Clin Hosp HCFMB, Med Sch, Botucatu, SP - Brazil

^[3] Sao Paulo State Univ UNESP, Dept Radiol & Oncol, Med Sch, Sao Paulo, SP - Brazil

^[4] Canc Inst Sao Paulo ICESP, Ctr Translat Res Oncol, Lab Mol Genet, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Inst Coracao Incor, Div Pneumol, Med Sch USP, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF THORACIC DISEASE; v. 13, n. 2 FEB 2021.
• Citações Web of Science: 0

Resumo

Background: Pleckstrin homology domain family A (PHLDA) genes play important roles in cancer cellular processes, including inhibiting Akt activation, repressing growth factor signaling, inhibiting the negative feedback of EGFR/ErbB2 signaling cells, and inducing apoptosis. However, the prognostic significance of PHLDA in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MM) remains unclear. The present study investigates the associations between PHLDA expression patterns and their prognostic value in lung adenocarcinoma (LUAD) and MM. Methods: We analyzed PHLDA family members at the genomic level in silico to explore their mRNA expression pattern and predictive significance in LUAD and MM. We then created a PHLDA-drug interaction network and a protein-protein interaction (PPI) network using different databases. Finally, we immunohistochemically assessed the protein expression of each PHLDA family member on tissue microarrays (TMAs) in both LUAD and MM cohorts with long-term follow-up. Results: While PHLDA1 mRNA expression in both LUAD and MM was lower than that of normal tissue, PHLDA2 mRNA was significantly overexpressed in LUAD, and PHLDA3 mRNA was overexpressed in MM. In NSCLC, both low PHLDA1 mRNA expression and high PHLDA3 mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high PHLDA2 mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high PHLDA1 and PHLDA2 mRNA expression had poor OS (P=0.01 and P<0.01, respectively). In addition, the PHLDA-drug interaction network indicated that several common drugs could potentially modulate PHLDA expression, and the PPI network suggested that PHLDA1 interacts with Notch family members, whereas PHLDA3 interacts with TP53. Our results also showed that the expression of PHLDA2 and PHLDA3 was significantly higher in LUAD and MM than that of PHLDA1 (P<0.05) and was associated with the risk of death. While patients with PHLDA2 >85.09 cells/mm(2) had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm(2) had a high risk of death (P=0.03) and a median survival time of 34 months. Conclusions: We shed light on the role of the PHLDA family as promising predictive biomarkers and potential therapeutic targets in LUAD and MM. (AU)

• Processo FAPESP: 18/20403-6 - Marcadores biomoleculares de proliferação e remodelamento em doenças respiratórias agudas e crônicas: promissores alvos terapêuticos
• Beneficiário: Vera Luiza Capelozzi
• Modalidade de apoio: Auxílio à Pesquisa - Temático