食道小细胞癌（SCCE）是一种罕见的恶性肿瘤，具有高度侵袭、早期转移和预后极差的特点，其生物学特征、发病机制和治疗方法尚不明确。我们在12.7% SCCE患者中检测到磷酸二酯酶3A (PDE3A) 突变或扩增；进一步研究发现在未出现突变和扩增的患者中PDE3A普遍高表达；在SCCE细胞中上调PDE3A促进细胞增殖和侵袭，下调则抑制肿瘤增殖、侵袭和生长；过表达PDE3A后其底物cAMP活性下降。据报道cAMP及下游PKA上调可抑制肿瘤发生、生长和转移。然而，PDE3A在肿瘤发生发展中的作用并不明确。因此，本项目拟探索PDE3A突变、扩增激活其功能的分子机制；阐明调控PDE3A高表达的关键转录因子；确证PDE3A通过调控cAMP/PKA影响SCCE发生发展；鉴定靶向PDE3A对SCCE的治疗作用。本研究的完成将揭示PDE3A的促瘤机制，明确靶向PDE3A的治疗作用，为SCCE诊治提供新的思路。

Small cell carcinoma of esophagus (SCCE) is a rare malignancy, with rapid recurrence and dismal prognosis. Its molecular characteristics, pathogenesis and optimal treatments remain unclear. We previously found mutations or amplifications of PDE3A in 12.7% of SCCE patients. In patients with no mutation or amplification, PDE3A is generally overexpressed. In SCCE cell lines, overexpression of PDE3A promotes cell proliferation and invasion, while downregulation of PDE3A did the opposite. Overexpression of PDE3A decreases the level of its substrate cyclic adenosine monophosphate (cAMP). According to the previous reports, upregulation of cAMP and its downstream protein kinase A (PKA) leads to inhibition of tumor initiation, growth and metastasis. However, the role of PDE3A in the development of cancer remains unknown. Therefore, the objectives of the current project are to explore the mechanisms through which PDE3A mutations or amplifications lead to its elevated function, to find the transcription factors regulating its high expression, to confirm cAMP/PKA as the effector of PDE3A on the development of SCCE and to evaluate the therapeutic effect of targeting PDE3A. Completion of this study will not only reveal the mechanisms of PDE3A in promoting tumor development, but also clarify the therapeutic effect of targeting PDE3A, providing new insights into the diagnosis and treatment for SCCE.