肺癌和恶性间皮瘤中普列克底物蛋白同源样结构域家族A（PHLDA）的表达模式及预后意义
The expression patterns and prognostic significance of pleckstrin homology-like domain family A (PHLDA) in lung cancer and malignant mesothelioma.
作者信息
Baldavira Camila M, Machado-Rugolo Juliana, Prieto Tabatha G, Bastos Daniel R, Balancin Marcelo, Ab'Saber Alexandre M, Yaegashi Lygia B, Souza Paola C, Farhat Cecilia, Takagaki Teresa Y, Nagai Maria Ap, Capelozzi Vera L
机构信息
Department of Pathology, University of São Paulo Medical School (USP), São Paulo, Brazil.
Health Technology Assessment Center (NATS), Clinical Hospital (HCFMB), Medical School of São Paulo State University (UNESP), Botucatu, Brazil.
出版信息
J Thorac Dis. 2021 Feb;13(2):689-707. doi: 10.21037/jtd-20-2909.
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 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 mRNA expression in both LUAD and MM was lower than that of normal tissue, mRNA was significantly overexpressed in LUAD, and mRNA was overexpressed in MM. In NSCLC, both low mRNA expression and high mRNA expression correlated with worse overall survival (OS) (P<0.01), whereas high mRNA expression was associated with better OS (P<0.01). In MM, patients presenting high and 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 interacts with Notch family members, whereas 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 had a low risk of death (P=0.01) and a median survival time of 48 months, those with PHLDA3 <70.38 cells/mm 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.
背景
普列克底物蛋白同源结构域家族A（PHLDA）基因在癌症细胞进程中发挥重要作用，包括抑制Akt激活、抑制生长因子信号传导、抑制表皮生长因子受体/ErbB2信号细胞的负反馈以及诱导细胞凋亡。然而，PHLDA在非小细胞肺癌（NSCLC）和恶性胸膜间皮瘤（MM）中的预后意义仍不明确。本研究调查了PHLDA表达模式与其在肺腺癌（LUAD）和MM中的预后价值之间的关联。
方法
我们在基因组水平分析了PHLDA家族成员，以探索它们在LUAD和MM中的mRNA表达模式及预测意义。然后，我们使用不同数据库创建了一个PHLDA-药物相互作用网络和一个蛋白质-蛋白质相互作用（PPI）网络。最后，我们通过免疫组织化学方法评估了长期随访的LUAD和MM队列中组织微阵列（TMA）上每个PHLDA家族成员的蛋白表达。
结果
虽然LUAD和MM中的mRNA表达均低于正常组织，但mRNA在LUAD中显著过表达，mRNA在MM中过表达。在NSCLC中，低mRNA表达和高mRNA表达均与较差的总生存期（OS）相关（P<0.01），而高mRNA表达与较好的OS相关（P<0.01）。在MM中，高mRNA和mRNA表达的患者OS较差（分别为P=0.01和P<0.01）。此外，PHLDA-药物相互作用网络表明几种常用药物可能调节PHLDA表达，PPI网络表明与Notch家族成员相互作用，而与TP53相互作用。我们的结果还显示，PHLDA2和PHLDA3在LUAD和MM中的表达明显高于PHLDA1（P<0.05），且与死亡风险相关。PHLDA2>85.09个细胞/mm²的患者死亡风险较低（P=0.01），中位生存时间为48个月，而PHLDA3<70.38个细胞/mm²的患者死亡风险较高（P=0.03），中位生存时间为34个月。
结论
我们阐明了PHLDA家族作为LUAD和MM中有前景的预测生物标志物和潜在治疗靶点的作用。
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